15	33411683	EGFR mutations and ALK gene rearrangements are particularly important because of the high brain transmission rate conferred by these entities.	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('brain transmission', 'CPA', (90, 108))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', '238', (19, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
16	33411683	In addition, inactivation of the tumor suppressor gene LKB1 and activation of the KRAS oncogene greatly influence both lung cancer formation and growth and the risk of developing brain metastases.	('inactivation', 'Var', (13, 25))	('lung cancer', 'Disease', (119, 130))	('growth', 'CPA', (145, 151))	('influence', 'Reg', (104, 113))	('KRAS', 'Gene', '3845', (82, 86))	('LKB1', 'Gene', '6794', (55, 59))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('KRAS', 'Gene', (82, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))	('brain metastases', 'Disease', 'MESH:D009362', (179, 195))	('brain metastases', 'Disease', (179, 195))	('LKB1', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))
23	33411683	High expression of HOXB9 has been associated with poor prognosis in NSCLC.	('associated', 'Reg', (34, 44))	('High expression', 'Var', (0, 15))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('HOXB9', 'Gene', '3219', (19, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('HOXB9', 'Gene', (19, 24))	('NSCLC', 'Disease', (68, 73))
25	33411683	Meanwhile, another study showed that PCAF-mediated acetylation of HOXB9 inhibited lung cancer progression.	('HOXB9', 'Gene', '3219', (66, 71))	('acetylation', 'Var', (51, 62))	('HOXB9', 'Gene', (66, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PCAF', 'Gene', '8850', (37, 41))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('inhibited', 'NegReg', (72, 81))	('PCAF', 'Gene', (37, 41))
31	33411683	Knockdown experiments were conducted in two NSCLC cell lines showing high HOXB9 expression (H1915 and H1299) by transfecting HOXB9-siRNA (Figure 2A, 2B).	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('HOXB9', 'Gene', '3219', (125, 130))	('HOXB9', 'Gene', (125, 130))	('H1299', 'Var', (102, 107))	('H1915', 'CellLine', 'CVCL:1505', (92, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('HOXB9', 'Gene', '3219', (74, 79))	('HOXB9', 'Gene', (74, 79))	('H1915', 'Var', (92, 97))	('H1299', 'CellLine', 'CVCL:0060', (102, 107))	('NSCLC', 'Disease', (44, 49))
33	33411683	In contrast, both migration and invasion, assessed respectively by wound healing (Figure 2E-2H) and Transwell Matrigel (Figure 2I-2K) assays, were markedly decreased 24 h after HOXB9 knockdown.	('migration', 'CPA', (18, 27))	('knockdown', 'Var', (183, 192))	('Transwell Matrigel', 'CPA', (100, 118))	('HOXB9', 'Gene', '3219', (177, 182))	('HOXB9', 'Gene', (177, 182))	('decreased', 'NegReg', (156, 165))	('wound healing', 'biological_process', 'GO:0042060', ('67', '80'))	('wound healing', 'CPA', (67, 80))	('invasion', 'CPA', (32, 40))
38	33411683	Considering that HOXB9 expression increased migration and invasion potential in NSCLC cells, we hypothesized that it may facilitate brain metastasis formation.	('HOXB9', 'Gene', '3219', (17, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('HOXB9', 'Gene', (17, 22))	('facilitate', 'PosReg', (121, 131))	('invasion potential', 'CPA', (58, 76))	('NSCLC', 'Disease', (80, 85))	('expression', 'Var', (23, 33))	('brain metastasis formation', 'CPA', (132, 158))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('migration', 'CPA', (44, 53))	('increased', 'PosReg', (34, 43))
39	33411683	To test this hypothesis, H1915 and A549 cells, with high- and low-HOXB9-expression respectively, were transduced with the luciferase gene and injected intracardially into nude mice.	('HOXB9', 'Gene', '3219', (66, 71))	('HOXB9', 'Gene', (66, 71))	('transduced', 'Var', (102, 112))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('nude mice', 'Species', '10090', (171, 180))	('luciferase', 'Gene', (122, 132))	('H1915', 'CellLine', 'CVCL:1505', (25, 30))
40	33411683	The resulting brain metastases were excised, and by in vitro propagation and two rounds of in vivo selection two brain metastatic NSCLC populations (A549-BrM3 and H1915-BrM3) were isolated (Figure 4A).	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('brain metastases', 'Disease', 'MESH:D009362', (14, 30))	('brain metastases', 'Disease', (14, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('H1915-BrM3', 'CellLine', 'CVCL:1505', (163, 173))	('H1915-BrM3', 'Var', (163, 173))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('NSCLC', 'Disease', (130, 135))
41	33411683	Sixty days after tumor implantation, bioluminescence imaging (BLI) showed stronger brain metastatic activity and shorter brain metastasis-free survival in mice injected with H1915 cells, compared to those injected with A549 cells (Figure 4B, 4C).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('A549', 'CellLine', 'CVCL:0023', (219, 223))	('brain metastatic activity', 'CPA', (83, 108))	('shorter', 'NegReg', (113, 120))	('H1915', 'CellLine', 'CVCL:1505', (174, 179))	('mice', 'Species', '10090', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('brain metastasis-free survival', 'CPA', (121, 151))	('bioluminescence', 'biological_process', 'GO:0008218', ('37', '52'))	('H1915', 'Var', (174, 179))	('stronger', 'PosReg', (74, 82))
42	33411683	The resulting brain metastases were excised, and by in vitro propagation and two rounds of in vivo selection two brain metastatic NSCLC populations (A549-BrM3 and H1915-BrM3) were isolated.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('brain metastases', 'Disease', 'MESH:D009362', (14, 30))	('brain metastases', 'Disease', (14, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('H1915-BrM3', 'CellLine', 'CVCL:1505', (163, 173))	('H1915-BrM3', 'Var', (163, 173))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('NSCLC', 'Disease', (130, 135))
49	33411683	Additional analysis showed that these expression changes were reversed after HOXB9 knockdown (Figure 5A).	('HOXB9', 'Gene', (77, 82))	('knockdown', 'Var', (83, 92))	('HOXB9', 'Gene', '3219', (77, 82))
51	33411683	Both qPCR and western blotting showed that ZEB1 was upregulated in BrM3 cells, and its expression decreased after HOXB9 silencing (Figure 5B-5D).	('decreased', 'NegReg', (98, 107))	('ZEB1', 'Gene', (43, 47))	('HOXB9', 'Gene', '3219', (114, 119))	('HOXB9', 'Gene', (114, 119))	('ZEB1', 'Gene', '6935', (43, 47))	('expression', 'MPA', (87, 97))	('silencing', 'Var', (120, 129))	('upregulated', 'PosReg', (52, 63))
56	33411683	However, this number was significantly weakened when HOXB9 was knocked down (Figure 5F-5H).	('weakened', 'NegReg', (39, 47))	('HOXB9', 'Gene', '3219', (53, 58))	('HOXB9', 'Gene', (53, 58))	('knocked down', 'Var', (63, 75))
61	33411683	These results indicate that high expression of HOXB9 in tumor cells may compromise BBB integrity by leading to disruption of adhesion junctions between adjoining endothelial cells.	('adhesion junctions', 'MPA', (125, 143))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('leading to', 'Reg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('disruption', 'MPA', (111, 121))	('HOXB9', 'Gene', '3219', (47, 52))	('HOXB9', 'Gene', (47, 52))	('high expression', 'Var', (28, 43))	('compromise', 'NegReg', (72, 82))	('BBB integrity', 'MPA', (83, 96))
63	33411683	Therefore, we examined through western blot whether MMP9 expression is upregulated by HOXB9 overexpression in NSCLC cells.	('expression', 'MPA', (57, 67))	('HOXB9', 'Gene', '3219', (86, 91))	('MMP9', 'Gene', (52, 56))	('HOXB9', 'Gene', (86, 91))	('MMP9', 'Gene', '4318', (52, 56))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('MMP9', 'molecular_function', 'GO:0004229', ('52', '56'))	('overexpression', 'Var', (92, 106))	('upregulated', 'PosReg', (71, 82))
66	33411683	To verify these data, HUVECs were co-cultured with BrM3 cells in which MMP9 was knocked down via siRNA (Figure 6E, 6F).	('MMP9', 'molecular_function', 'GO:0004229', ('71', '75'))	('MMP9', 'Gene', '4318', (71, 75))	('MMP9', 'Gene', (71, 75))	('HUVEC', 'CellLine', 'CVCL:2959', (22, 27))	('knocked down', 'Var', (80, 92))
67	33411683	Western blot assays showed that MMP9 silencing in BrM3 cells restored the expression of ZO-1, claudin-5, and VE-cadherin in HUVECs (Figure 6B).	('expression', 'MPA', (74, 84))	('restored', 'PosReg', (61, 69))	('ZO-1', 'Gene', (88, 92))	('claudin-5', 'Gene', '7122', (94, 103))	('MMP9', 'molecular_function', 'GO:0004229', ('32', '36'))	('VE-cadherin', 'Gene', (109, 120))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('silencing', 'Var', (37, 46))	('HUVEC', 'CellLine', 'CVCL:2959', (124, 129))	('VE-cadherin', 'Gene', '1003', (109, 120))	('MMP9', 'Gene', (32, 36))	('MMP9', 'Gene', '4318', (32, 36))	('ZO-1', 'Gene', '7082', (88, 92))	('claudin-5', 'Gene', (94, 103))
68	33411683	We found that the expression of MMP9 was downregulated by HOXB9 silencing, but MMP9 silencing had little effect on the expression of HOXB9 (Figure 6G).	('HOXB9', 'Gene', (58, 63))	('MMP9', 'Gene', (79, 83))	('MMP9', 'Gene', '4318', (79, 83))	('downregulated', 'NegReg', (41, 54))	('MMP9', 'molecular_function', 'GO:0004229', ('32', '36'))	('MMP9', 'molecular_function', 'GO:0004229', ('79', '83'))	('MMP9', 'Gene', '4318', (32, 36))	('HOXB9', 'Gene', '3219', (133, 138))	('MMP9', 'Gene', (32, 36))	('HOXB9', 'Gene', (133, 138))	('expression', 'MPA', (18, 28))	('silencing', 'Var', (64, 73))	('HOXB9', 'Gene', '3219', (58, 63))
73	33411683	For example, high HOXB9 expression was shown to promote EMT via TGF-beta signaling and was associated with shorter survival in hepatocellular and oral squamous cell carcinomas.	('oral squamous cell carcinomas', 'Disease', (146, 175))	('TGF-beta', 'Gene', '7039', (64, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (146, 175))	('HOXB9', 'Gene', (18, 23))	('hepatocellular', 'Disease', (127, 141))	('EMT', 'CPA', (56, 59))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('TGF-beta', 'Gene', (64, 72))	('shorter', 'NegReg', (107, 114))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('promote', 'PosReg', (48, 55))	('HOXB9', 'Gene', '3219', (18, 23))
77	33411683	Lung cancer is well established as a highly heterogeneous tumor that harbors various gene alterations including mutations in EGFR, KRAS, BRAF, PD-L1, and PIK3CA, as well as ALK rearrangement and HER2 amplification.	('mutations', 'Var', (112, 121))	('KRAS', 'Gene', '3845', (131, 135))	('HER2', 'Gene', (195, 199))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('tumor', 'Disease', (58, 63))	('PIK3CA', 'Gene', (154, 160))	('KRAS', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (125, 129))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('PD-L1', 'Gene', (143, 148))	('Lung cancer', 'Disease', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PD-L1', 'Gene', '29126', (143, 148))	('amplification', 'Var', (200, 213))	('HER2', 'Gene', '2064', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('ALK', 'Gene', '238', (173, 176))	('PIK3CA', 'Gene', '5290', (154, 160))	('EGFR', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('ALK', 'Gene', (173, 176))
83	33411683	Previous studies have shown that high expression of HOXB9 in NSCLC predicts poor prognosis and promotes EMT and bone and brain metastasis.	('HOXB9', 'Gene', '3219', (52, 57))	('HOXB9', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('EMT', 'biological_process', 'GO:0001837', ('104', '107'))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('promotes', 'PosReg', (95, 103))
85	33411683	In addition, high HOXB9 expression promotes migration and invasion of NSCLC cells without affecting their proliferative potential.	('HOXB9', 'Gene', (18, 23))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('NSCLC', 'Disease', (70, 75))	('promotes', 'PosReg', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('invasion', 'CPA', (58, 66))	('migration', 'CPA', (44, 53))	('HOXB9', 'Gene', '3219', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
104	33411683	In summary, our research suggests that HOXB9 expression in NSCLC cells promotes BBB disruption and mediates invasion into the brain parenchyma by inducing EMT and upregulating MMP9 expression (Figure 7).	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('EMT', 'CPA', (155, 158))	('expression', 'MPA', (181, 191))	('promotes', 'PosReg', (71, 79))	('EMT', 'biological_process', 'GO:0001837', ('155', '158'))	('inducing', 'PosReg', (146, 154))	('HOXB9', 'Gene', '3219', (39, 44))	('MMP9', 'Gene', '4318', (176, 180))	('upregulating', 'PosReg', (163, 175))	('MMP9', 'Gene', (176, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('MMP9', 'molecular_function', 'GO:0004229', ('176', '180'))	('HOXB9', 'Gene', (39, 44))	('invasion into the brain parenchyma', 'CPA', (108, 142))	('expression', 'Var', (45, 55))	('NSCLC', 'Disease', (59, 64))	('BBB disruption', 'CPA', (80, 94))
107	33411683	Human NSCLC cell lines (PC9, A549, H1915, H1975, H1650, and H1299) and human umbilical vein endothelial cells (HUVECs) were purchased from the American Type Culture Collection (Manassas, VA, USA).	('H1975', 'Var', (42, 47))	('Human', 'Species', '9606', (0, 5))	('H1975', 'CellLine', 'CVCL:1511', (42, 47))	('H1915', 'CellLine', 'CVCL:1505', (35, 40))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('H1299', 'Var', (60, 65))	('HUVEC', 'CellLine', 'CVCL:2959', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('H1650', 'CellLine', 'CVCL:1483', (49, 54))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('H1299', 'CellLine', 'CVCL:0060', (60, 65))	('PC9', 'CellLine', 'CVCL:B260', (24, 27))	('NSCLC', 'Disease', (6, 11))	('human', 'Species', '9606', (71, 76))
109	33411683	A549, A549-BrM3, H1915, H1915-BrM3, H1975, H1650, H1299, HUVEC and HBE cells were cultured in RPMI-1640, and PC9 and HA cells were maintained in DMEM (HyClone, Logan, UT, USA).	('H1915', 'Var', (17, 22))	('RPMI-1640', 'Chemical', '-', (94, 103))	('H1915-BrM3', 'CellLine', 'CVCL:1505', (24, 34))	('H1299', 'Var', (50, 55))	('H1915-BrM3', 'Var', (24, 34))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('A549', 'CellLine', 'CVCL:0023', (6, 10))	('H1650', 'CellLine', 'CVCL:1483', (43, 48))	('PC9', 'CellLine', 'CVCL:B260', (109, 112))	('H1975', 'Var', (36, 41))	('DMEM', 'Chemical', '-', (145, 149))	('H1299', 'CellLine', 'CVCL:0060', (50, 55))	('H1975', 'CellLine', 'CVCL:1511', (36, 41))	('H1915', 'CellLine', 'CVCL:1505', (24, 29))	('HUVEC', 'CellLine', 'CVCL:2959', (57, 62))	('H1915', 'CellLine', 'CVCL:1505', (17, 22))	('H1650', 'Var', (43, 48))
136	33547884	Epidemiological studies have reported low CoQ10 levels being associated with an increased risk of various cancers.	('CoQ10', 'Chemical', 'MESH:C024989', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('low', 'Var', (38, 41))	('CoQ10', 'Protein', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
144	33547884	Low plasma CoQ10 was significantly associated with increased lung cancer risk, particularly among current smokers.	('lung cancer', 'Disease', (61, 72))	('CoQ10', 'Gene', (11, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Low plasma', 'Var', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('CoQ10', 'Chemical', 'MESH:C024989', (11, 16))
147	33547884	Low coenzyme Q10 was associated with a greater risk of lung cancer among current smokers and participants diagnosed within 1 year following blood draw.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('coenzyme', 'Protein', (4, 12))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('participants', 'Species', '9606', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('coenzyme Q10', 'Chemical', 'MESH:C024989', (4, 16))	('Low', 'Var', (0, 3))
188	33547884	Alcohol consumption was also positively associated with higher plasma CoQ10 (p < 0.01).	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('Alcohol consumption', 'Var', (0, 19))	('CoQ10', 'Chemical', 'MESH:C024989', (70, 75))	('plasma CoQ10', 'MPA', (63, 75))	('higher', 'PosReg', (56, 62))
204	33547884	In this first prospective case-control study nested within the SCCS, we found an inverse association between plasma CoQ10 and lung cancer risk, particularly in cases diagnosed within 1 year following blood collection.	('CoQ10', 'Chemical', 'MESH:C024989', (116, 121))	('inverse', 'NegReg', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('plasma', 'Var', (109, 115))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))
208	33547884	11 ,  16 ,  17 ,  18  CoQ10 supplementation has been reported to reduce cardiotoxicity and improve survival in cancer patients.	('improve', 'PosReg', (91, 98))	('cardiotoxicity', 'Disease', 'MESH:D066126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cardiotoxicity', 'Disease', (72, 86))	('CoQ10', 'Gene', (22, 27))	('reduce', 'NegReg', (65, 71))	('survival', 'MPA', (99, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('supplementation', 'Var', (28, 43))	('patients', 'Species', '9606', (118, 126))	('CoQ10', 'Chemical', 'MESH:C024989', (22, 27))	('men', 'Species', '9606', (34, 37))
222	33547884	While these data may result from a change in dietary intake or environmental factors due to the symptoms of a clinically undiagnosed lung cancer (reverse causation), a true association demonstrating that low plasma CoQ10 may serve as a biomarker for lung cancer risk cannot be excluded.	('CoQ10', 'Chemical', 'MESH:C024989', (215, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('low', 'Var', (204, 207))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('men', 'Species', '9606', (70, 73))	('result from', 'Reg', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('change', 'Reg', (35, 41))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('lung cancer', 'Disease', (250, 261))
235	33547884	Work was supported in part by NIH grants T32CA160056 (XOS), U01CA202979 (WB and WZ), P30CA71789 (AF), and P30CA068485 (QC).	('T32CA160056', 'Var', (41, 52))	('U01CA202979', 'Var', (60, 71))	('P30CA71789', 'Var', (85, 95))	('P30CA068485', 'Var', (106, 117))	('U01CA202979', 'CellLine', 'CVCL:2220', (60, 71))	('AF', 'Disease', 'MESH:D001281', (97, 99))
245	33152171	Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties.	('malignant properties', 'CPA', (108, 128))	('lung adenocarcinoma', 'Disease', (73, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('promote', 'PosReg', (96, 103))	('DRP1', 'Gene', (65, 69))	('activating', 'Var', (54, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
250	33152171	DNM1L mutations are related to various neurologic diseases in humans [1], and loss of DRP1-mediated mitochondrial fission is associated with cardiomyopathy [3], neurologic disorders [6], and macrophage dysfunction [7] in murine models.	('cardiomyopathy', 'Phenotype', 'HP:0001638', (141, 155))	('cardiomyopathy', 'Disease', 'MESH:D009202', (141, 155))	('neurologic disorders', 'Phenotype', 'HP:0000707', (161, 181))	('DRP1-mediated', 'Gene', (86, 99))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('100', '121'))	('loss', 'Var', (78, 82))	('neurologic diseases', 'Disease', 'MESH:D020271', (39, 58))	('humans', 'Species', '9606', (62, 68))	('murine', 'Species', '10090', (221, 227))	('neurologic diseases', 'Disease', (39, 58))	('macrophage dysfunction', 'Disease', (191, 213))	('neurologic disorders', 'Disease', 'MESH:D009422', (161, 181))	('associated', 'Reg', (125, 135))	('related', 'Reg', (20, 27))	('mutations', 'Var', (6, 15))	('neurologic disorders', 'Disease', (161, 181))	('cardiomyopathy', 'Disease', (141, 155))	('DNM1L', 'Gene', (0, 5))	('macrophage dysfunction', 'Disease', 'MESH:D055501', (191, 213))
296	33152171	The analysis further revealed that tumors with DNM1L expression above the 65th percentile, compared to tumors with DNM1L expression less than the 35th percentile, were significantly associated with decreased PFS and OS (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('PFS', 'Disease', (208, 211))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('decreased', 'NegReg', (198, 207))	('DNM1L', 'Var', (47, 52))
305	33152171	Meanwhile, 131 patients (62.1%) in the study population had stage I lung adenocarcinoma, and our results further revealed that DRP1 and P(S616)-DRP1 expression remained significantly associated with postoperative recurrence in patients with early-stage lung adenocarcinoma (Fig.	('patients', 'Species', '9606', (15, 23))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (253, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('P(S616)-DRP1', 'Var', (136, 148))	('stage', 'Disease', (60, 65))	('DRP1', 'Gene', (127, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (68, 87))	('lung adenocarcinoma', 'Disease', (253, 272))	('associated with', 'Reg', (183, 198))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (253, 272))	('lung adenocarcinoma', 'Disease', (68, 87))	('patients', 'Species', '9606', (227, 235))	('postoperative', 'Disease', (199, 212))
306	33152171	The results showed that lung adenocarcinoma with a high DRP1 or P(S616)-DRP1 H-score was significantly associated with early postoperative recurrence.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('lung adenocarcinoma', 'Disease', (24, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (24, 43))	('P(S616)-DRP1', 'Var', (64, 76))	('associated', 'Reg', (103, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (24, 43))	('DRP1', 'Gene', (56, 60))
307	33152171	We conducted multivariate regression analyses, and the results showed that lung adenocarcinoma with a high DRP1 (HR = 2.451, 95% confidence interval [CI] = 1.266-4.744, p = 0.008) or P(S616)-DRP1 (HR = 5.261, 95% CI = 2.008-13.785, p = 0.001) H-score was independently significantly associated with 5-year postoperative recurrence (Table S4).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('high', 'Var', (102, 106))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('associated with', 'Reg', (283, 298))	('P(S616)-DRP1', 'Var', (183, 195))	('DRP1', 'Gene', (107, 111))
315	33152171	Our results demonstrated that DRP1 depletion modestly increased mitophagy activity in CL1-0 and A549 at the basal states (Fig.	('mitophagy activity', 'CPA', (64, 82))	('mitophagy', 'biological_process', 'GO:0000423', ('64', '73'))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('DRP1', 'Protein', (30, 34))	('increased', 'PosReg', (54, 63))	('mitophagy', 'biological_process', 'GO:0000422', ('64', '73'))	('depletion', 'Var', (35, 44))	('increased mitophagy', 'Phenotype', 'HP:0041045', (54, 73))
318	33152171	Therefore, in consistence with mitochondrial morphological findings, our results indicated that DRP1 depletion in different lung adenocarcinoma cell lines variably augmented mitophagy at baseline and in responses to mitochondrial damage.	('responses', 'MPA', (203, 212))	('augmented', 'PosReg', (164, 173))	('lung adenocarcinoma', 'Disease', (124, 143))	('mitophagy', 'CPA', (174, 183))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('mitophagy', 'biological_process', 'GO:0000422', ('174', '183'))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('DRP1', 'Gene', (96, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('depletion', 'Var', (101, 110))	('mitophagy', 'biological_process', 'GO:0000423', ('174', '183'))
319	33152171	Proper mitochondrial dynamics are crucial for mitochondrial bioenergetics [3, 32], and DRP1 depletion resulted in profoundly impaired mitochondrial respiration in lung adenocarcinoma cell lines (Fig.	('mitochondrial respiration', 'MPA', (134, 159))	('respiration', 'biological_process', 'GO:0007585', ('148', '159'))	('impaired', 'NegReg', (125, 133))	('depletion', 'Var', (92, 101))	('lung adenocarcinoma', 'Disease', (163, 182))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (163, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('respiration', 'biological_process', 'GO:0045333', ('148', '159'))	('DRP1', 'Gene', (87, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (163, 182))
322	33152171	The results showed that DRP1 depletion in lung adenocarcinoma cell lines caused a significant decrease in mtDNA copy numbers (Fig.	('depletion', 'Var', (29, 38))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (42, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('decrease', 'NegReg', (94, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('mtDNA', 'Gene', (106, 111))	('DRP1', 'Gene', (24, 28))	('mtDNA', 'cellular_component', 'GO:0000262', ('106', '111'))	('lung adenocarcinoma', 'Disease', (42, 61))
326	33152171	3D,E) were all inhibited in lung adenocarcinoma cell lines after DRP1 depletion.	('inhibited', 'NegReg', (15, 24))	('lung adenocarcinoma', 'Disease', (28, 47))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('depletion', 'Var', (70, 79))	('DRP1', 'Gene', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
347	33152171	The phosphorylation of DRP1 at serine 616, which activates GTPase activity [38], is mediated by CDK1 in HeLa cells [39] and is regulated by ERK in pancreatic cancer cell lines [10].	('DRP1', 'Protein', (23, 27))	('ERK', 'molecular_function', 'GO:0004707', ('140', '143'))	('GTPase activity', 'molecular_function', 'GO:0003924', ('59', '74'))	('activates', 'PosReg', (49, 58))	('activity', 'MPA', (66, 74))	('ERK', 'Gene', (140, 143))	('HeLa', 'CellLine', 'CVCL:0030', (104, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('serine 616', 'Var', (31, 41))	('CDK1', 'Gene', (96, 100))	('CDK1', 'Gene', '983', (96, 100))	('GTPase', 'Protein', (59, 65))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('phosphorylation', 'MPA', (4, 19))	('serine', 'Chemical', 'MESH:D012694', (31, 37))	('ERK', 'Gene', '5594', (140, 143))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))
364	33152171	To prove our hypothetical model, we first examined whether DRP1 depletion affected cell cycle progression in lung adenocarcinoma.	('affected', 'Reg', (74, 82))	('cell cycle progression', 'CPA', (83, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('depletion', 'Var', (64, 73))	('cell cycle', 'biological_process', 'GO:0007049', ('83', '93'))	('lung adenocarcinoma', 'Disease', (109, 128))	('DRP1', 'Gene', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (109, 128))
366	33152171	S8), and further revealed an increased percentage of cells at S/G2/M phases in DNM1L-KO lung adenocarcinoma cell lines (Fig.	('S/G2', 'SUBSTITUTION', 'None', (62, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinoma', 'Disease', (88, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('KO', 'Gene', '3856', (85, 87))	('S/G2', 'Var', (62, 66))
370	33152171	In addition to palbociclib, we found that both PHA-793887 and roscovitine could decrease DRP1 phosphorylation (Fig.	('PHA-793887', 'Var', (47, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('roscovitine', 'Chemical', 'MESH:D000077546', (62, 73))	('DRP1', 'Protein', (89, 93))	('palbociclib', 'Chemical', 'MESH:C500026', (15, 26))	('phosphorylation', 'MPA', (94, 109))	('decrease', 'NegReg', (80, 88))
372	33152171	To elucidate the regulatory effect of CDKs on DRP1 phosphorylation in lung adenocarcinoma cell lines, we applied siRNA transfection to knock down CDK1, CDK2, and CDK5.	('knock', 'Var', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('CDK5', 'Gene', '1020', (162, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('CDKs', 'Gene', (38, 42))	('CDKs', 'Gene', '983;1017;1019;1020;1021', (38, 42))	('CDK', 'molecular_function', 'GO:0004693', ('162', '165'))	('CDK', 'molecular_function', 'GO:0004693', ('152', '155'))	('CDK', 'molecular_function', 'GO:0004693', ('146', '149'))	('CDK2', 'Gene', (152, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('CDK5', 'Gene', (162, 166))	('CDK1', 'Gene', (146, 150))	('CDK1', 'Gene', '983', (146, 150))	('CDK2', 'Gene', '1017', (152, 156))	('lung adenocarcinoma', 'Disease', (70, 89))
373	33152171	The data revealed that CDK2 knockdown consistently decreased P(S616)-DRP1 in CL1-0 and PC9 cells (Fig.	('CDK2', 'Gene', (23, 27))	('CDK2', 'Gene', '1017', (23, 27))	('decreased', 'NegReg', (51, 60))	('knockdown', 'Var', (28, 37))	('CDK', 'molecular_function', 'GO:0004693', ('23', '26'))	('PC9', 'CellLine', 'CVCL:B260', (87, 90))
376	33152171	6B) and found that P(S616)-DRP1 was decreased after CDK2 depletion (Fig.	('depletion', 'NegReg', (57, 66))	('CDK2', 'Gene', (52, 56))	('CDK', 'molecular_function', 'GO:0004693', ('52', '55'))	('CDK2', 'Gene', '1017', (52, 56))	('decreased', 'NegReg', (36, 45))	('P(S616)-DRP1', 'Var', (19, 31))
380	33152171	Interestingly, depleting CDK2 in lung adenocarcinoma cell lines resulted in similar mitochondrial morphological changes caused by DRP1 depletion and led to an extensive mitochondrial tubular network in CL1-0 cells and perinuclear compaction of swollen mitochondria in A549 cells (Fig.	('extensive', 'PosReg', (159, 168))	('CDK2', 'Gene', (25, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('mitochondrial', 'MPA', (84, 97))	('A549', 'CellLine', 'CVCL:0023', (268, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('DRP1', 'Gene', (130, 134))	('perinuclear compaction', 'CPA', (218, 240))	('CDK2', 'Gene', '1017', (25, 29))	('lung adenocarcinoma', 'Disease', (33, 52))	('depleting', 'Var', (15, 24))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (33, 52))	('mitochondrial tubular network', 'CPA', (169, 198))	('mitochondria', 'cellular_component', 'GO:0005739', ('252', '264'))	('depletion', 'NegReg', (135, 144))
388	33152171	Although deleting DNM1L does not affect OXPOS and mtDNA synthesis in mouse embryonic fibroblasts [6], our results are similar to those of pancreatic cancers [11] and revealed that the loss of DRP1 in lung adenocarcinoma cell lines leads to increased mitophagy to mitochondrial damage and decreased OXPHOS and mtDNA copy numbers.	('deleting', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('pancreatic cancers', 'Disease', 'MESH:D010190', (138, 156))	('mtDNA', 'cellular_component', 'GO:0000262', ('50', '55'))	('decreased', 'NegReg', (288, 297))	('lung adenocarcinoma', 'Disease', (200, 219))	('mouse', 'Species', '10090', (69, 74))	('mtDNA synthesis', 'biological_process', 'GO:0006264', ('50', '65'))	('mitophagy to mitochondrial damage', 'MPA', (250, 283))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('increased', 'PosReg', (240, 249))	('mitophagy', 'biological_process', 'GO:0000422', ('250', '259'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (200, 219))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (138, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('increased mitophagy', 'Phenotype', 'HP:0041045', (240, 259))	('DNM1L', 'Gene', (18, 23))	('mitophagy', 'biological_process', 'GO:0000423', ('250', '259'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (200, 219))	('pancreatic cancers', 'Disease', (138, 156))	('DRP1', 'Gene', (192, 196))	('loss', 'Var', (184, 188))	('mtDNA', 'cellular_component', 'GO:0000262', ('309', '314'))	('OXPHOS', 'biological_process', 'GO:0002082', ('298', '304'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))
390	33152171	The different mitochondrial shape in CL1-0 and A549 may thus reflect different metabolic states of the cells.	('reflect', 'Reg', (61, 68))	('A549', 'CellLine', 'CVCL:0023', (47, 51))	('A549', 'Var', (47, 51))
392	33152171	Meanwhile, we also found that the blockade of OXPHOS promotes the invasiveness of lung adenocarcinoma cell lines.	('invasiveness of lung adenocarcinoma', 'Disease', 'MESH:D000077192', (66, 101))	('promotes', 'PosReg', (53, 61))	('OXPHOS', 'biological_process', 'GO:0002082', ('46', '52'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 101))	('blockade', 'Var', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('invasiveness of lung adenocarcinoma', 'Disease', (66, 101))	('OXPHOS', 'Gene', (46, 52))
393	33152171	A recent study showed that OXPHOS impairment in lung adenocarcinoma cell lines induces AMPK-mediated epithelial-to-mesenchymal transformation (EMT) and promotes invasion [43].	('OXPHOS', 'biological_process', 'GO:0002082', ('27', '33'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('AMPK', 'molecular_function', 'GO:0050405', ('87', '91'))	('AMPK', 'molecular_function', 'GO:0004691', ('87', '91'))	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('OXPHOS impairment', 'Var', (27, 44))	('AMPK', 'Gene', '5563', (87, 91))	('AMPK', 'molecular_function', 'GO:0047322', ('87', '91'))	('invasion', 'CPA', (161, 169))	('induces', 'Reg', (79, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('AMPK', 'Gene', (87, 91))	('promotes', 'PosReg', (152, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinoma', 'Disease', (48, 67))
394	33152171	The findings that DRP1 depletion in lung adenocarcinoma cell lines suppresses OXPHOS without enhancing invasiveness might be due to the perturbation of mitochondrial dynamics.	('suppresses', 'NegReg', (67, 77))	('depletion', 'Var', (23, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (36, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('lung adenocarcinoma', 'Disease', (36, 55))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (36, 55))	('OXPHOS', 'biological_process', 'GO:0002082', ('78', '84'))	('OXPHOS', 'MPA', (78, 84))	('DRP1', 'Gene', (18, 22))
397	33152171	Although impaired mitochondrial fusion has been shown to perturb lipid metabolic homeostasis [14], the detailed biosynthetic changes when DRP1-mediated mitochondrial fission in lung adenocarcinoma cell lines is impaired are unknown.	('mitochondrial fusion', 'CPA', (18, 38))	('perturb lipid metabolic homeostasis', 'Disease', 'MESH:D052439', (57, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('mitochondrial fusion', 'biological_process', 'GO:0008053', ('18', '38'))	('lung adenocarcinoma', 'Disease', (177, 196))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('homeostasis', 'biological_process', 'GO:0042592', ('81', '92'))	('perturb lipid metabolic homeostasis', 'Disease', (57, 92))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('152', '173'))	('impaired', 'Var', (9, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))
398	33152171	Altered substrate synthesis in lung adenocarcinoma cell lines after DRP1 depletion is suggested by the activation of mitochondrial stress responses.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lung adenocarcinoma', 'Disease', (31, 50))	('DRP1', 'Gene', (68, 72))	('substrate synthesis', 'MPA', (8, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('stress', 'Disease', (131, 137))	('stress', 'Disease', 'MESH:D000079225', (131, 137))	('synthesis', 'biological_process', 'GO:0009058', ('18', '27'))	('depletion', 'Var', (73, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('Altered', 'Reg', (0, 7))	('activation', 'PosReg', (103, 113))	('mitochondrial', 'MPA', (117, 130))
399	33152171	Furthermore, since DRP1 might not be a suitable therapeutic target due to the crucial role of mitochondrial dynamics in cellular adaptations [1], the biosynthetic alterations after DRP1 depletion might suggest potential metabolism-related therapeutic targets in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (262, 281))	('metabolism', 'biological_process', 'GO:0008152', ('220', '230'))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (262, 281))	('DRP1', 'Gene', (181, 185))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (262, 281))	('depletion', 'Var', (186, 195))
403	33152171	Although the clinical significance of mitochondrial stress responses in lung adenocarcinoma is not well understood, the expression of PHGDH in lung adenocarcinoma, which is regulated by NRF2-mediated signaling [36], is associated with worse patient survival [35, 36].	('PHGDH', 'Gene', '26227', (134, 139))	('NRF2', 'Gene', '4780', (186, 190))	('stress', 'Disease', 'MESH:D000079225', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('PHGDH', 'Gene', (134, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (143, 162))	('worse', 'NegReg', (235, 240))	('stress', 'Disease', (52, 58))	('patient survival', 'CPA', (241, 257))	('NRF2', 'Gene', (186, 190))	('lung adenocarcinoma', 'Disease', (72, 91))	('expression', 'Var', (120, 130))	('lung adenocarcinoma', 'Disease', (143, 162))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patient', 'Species', '9606', (241, 248))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (143, 162))
407	33152171	Collectively, PHGDH inhibitors are potential therapeutics for lung adenocarcinoma, but the optimal applications of such agents require further investigation.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('PHGDH', 'Gene', '26227', (14, 19))	('inhibitors', 'Var', (20, 30))	('PHGDH', 'Gene', (14, 19))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('lung adenocarcinoma', 'Disease', (62, 81))
411	33152171	The loss of CDK2 in lung adenocarcinoma cell lines cannot dramatically suppress the tumor growth [48], indicating that CDK2-mediated DRP1 activation is dispensable for proliferation.	('CDK', 'molecular_function', 'GO:0004693', ('12', '15'))	('CDK2', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('lung adenocarcinoma', 'Disease', (20, 39))	('CDK2', 'Gene', '1017', (12, 16))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (20, 39))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CDK2', 'Gene', '1017', (119, 123))	('tumor', 'Disease', (84, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (20, 39))	('suppress', 'NegReg', (71, 79))	('CDK2', 'Gene', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('loss', 'Var', (4, 8))
414	33152171	Our data demonstrated that gefitinib decreased DRP1 phosphorylation in cell lines with sensitive EGFR mutation, including PC9 and HCC827, but not in cell lines with wild-type EGFR (CL1-0) or with resistant T790M EGFR mutation (H1975).	('DRP1', 'Protein', (47, 51))	('EGFR', 'Gene', (175, 179))	('EGFR', 'molecular_function', 'GO:0005006', ('212', '216'))	('EGFR', 'Gene', '1956', (97, 101))	('mutation', 'Var', (102, 110))	('gefitinib', 'Chemical', 'MESH:D000077156', (27, 36))	('HCC827', 'CellLine', 'CVCL:2063', (130, 136))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (175, 179))	('T790M', 'Mutation', 'rs121434569', (206, 211))	('PC9', 'CellLine', 'CVCL:B260', (122, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('175', '179'))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('phosphorylation', 'MPA', (52, 67))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('EGFR', 'Gene', '1956', (212, 216))	('decreased', 'NegReg', (37, 46))	('EGFR', 'Gene', (212, 216))
423	33152171	Imbalances in mitochondrial dynamics are associated human neuromuscular diseases and can result in dysfunctions in various organ systems in murine models [1].	('mitochondrial dynamics', 'MPA', (14, 36))	('associated', 'Reg', (41, 51))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('dysfunctions', 'MPA', (99, 111))	('human', 'Species', '9606', (52, 57))	('Imbalances', 'Var', (0, 10))	('result in', 'Reg', (89, 98))	('murine', 'Species', '10090', (140, 146))	('neuromuscular diseases', 'Disease', (58, 80))	('neuromuscular diseases', 'Disease', 'MESH:D009468', (58, 80))
454	32992658	For instance, high expression of PD-L1 on immune cells infiltrating the tumor was shown to be an independent predictor of better melanoma patient outcomes following tumor resection, and a better predictor of response to PD-1 blockade than PD-L1 expression on tumor cells in immunogenic cancers such as melanoma, non-small cell lung cancer and urothelial cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PD-L1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('non-small cell lung cancer', 'Disease', (312, 338))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('better', 'PosReg', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('urothelial cancer', 'Disease', 'MESH:D014523', (343, 360))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (327, 338))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (312, 338))	('urothelial cancer', 'Disease', (343, 360))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('cancers', 'Disease', (286, 293))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (316, 338))	('tumor', 'Disease', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('PD-1 blockade than PD-L1', 'Disease', 'MESH:D010300', (220, 244))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (312, 338))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('melanoma', 'Disease', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('patient', 'Species', '9606', (138, 145))	('high expression', 'Var', (14, 29))	('PD-1 blockade than PD-L1', 'Disease', (220, 244))	('tumor', 'Disease', (259, 264))	('cancers', 'Disease', 'MESH:D009369', (286, 293))
457	32992658	For instance, PD-L1 expression on immunogenic MC38 colorectal tumor cells directly suppressed CD8 T-cell cytotoxicity and was dominant in suppressing anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('colorectal tumor', 'Disease', 'MESH:D015179', (51, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('tumor', 'Disease', (62, 67))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (155, 160))	('MC38', 'CellLine', 'CVCL:B288', (46, 50))	('colorectal tumor', 'Disease', (51, 67))	('CD8', 'Gene', (94, 97))	('PD-L1', 'Gene', (14, 19))	('suppressing', 'NegReg', (138, 149))	('suppressed', 'NegReg', (83, 93))	('CD8', 'Gene', '925', (94, 97))	('cytotoxicity', 'Disease', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
468	32992658	Anti-PD-L1 antibodies release CD80 from this sequestered form and re-instate the CD80-CD28 co-stimulatory interaction while simultaneously blocking the PD-L1-PD-1 inhibitory pathway, resulting in augmented T-cell activation upon antigen recognition (Figure 2).	('CD80', 'Gene', '397161', (30, 34))	('CD80', 'Gene', (81, 85))	('CD28', 'Gene', '940', (86, 90))	('augmented', 'PosReg', (196, 205))	('CD80', 'Gene', (30, 34))	('antibodies', 'Var', (11, 21))	('blocking', 'NegReg', (139, 147))	('Anti-PD-L1', 'Gene', (0, 10))	('PD-L1-PD-1 inhibitory pathway', 'Pathway', (152, 181))	('T-cell activation', 'biological_process', 'GO:0042110', ('206', '223'))	('CD28', 'Gene', (86, 90))	('T-cell activation', 'CPA', (206, 223))	('CD80', 'Gene', '397161', (81, 85))	('augmented T-cell activation', 'Phenotype', 'HP:0005419', (196, 223))
471	32992658	PD-L1-deficient T-cells are more susceptible to killing by cytotoxic T-cells, indicating that PD-L1 protects T-cells undergoing clonal expansion and supports optimal protective immunity.	('PD-L1', 'Var', (94, 99))	('protective immunity', 'CPA', (166, 185))	('PD-L1-deficient T-cells', 'Disease', 'MESH:D010300', (0, 23))	('PD-L1-deficient T-cells', 'Disease', (0, 23))
473	32992658	The ligation of PD-L1 expressed by T-cells can promote tumor immune escape via diverse mechanisms.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PD-L1', 'Gene', (16, 21))	('promote', 'PosReg', (47, 54))	('tumor', 'Disease', (55, 60))	('ligation', 'Var', (4, 12))
475	32992658	This so-called "back-signaling" can promote T-helper 1 (Th1)-to-Th17 switch in CD4 T-cells, a non-responsive (anergic) phenotype in CD8 T-cells and apoptosis in activated T-cells; the ligation of PD-L1 on T-cells was as efficient as PD-1 ligation in suppressing T-cell functionality.	('suppressing', 'NegReg', (250, 261))	('ligation', 'Var', (184, 192))	('promote', 'PosReg', (36, 43))	('CD4', 'Gene', (79, 82))	('T-helper', 'CPA', (44, 52))	('CD4', 'Gene', '404704', (79, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('CD8', 'Gene', (132, 135))	('PD-L1', 'Gene', (196, 201))	('T-cell functionality', 'CPA', (262, 282))	('CD8', 'Gene', '925', (132, 135))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
490	32992658	It is unclear to what extent anti-PD-1 therapeutic antibodies directly modify the biology of PD-1-expressing TAMs, but myeloid cell-targeting therapies, especially a blockade of the colony stimulating factor 1 (CSF1) receptor signaling, potently synergize with immunotherapy in preclinical models of cancer.	('CSF1', 'Gene', (211, 215))	('CSF1', 'Gene', '1435', (211, 215))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('colony stimulating factor 1', 'Gene', (182, 209))	('CSF1', 'molecular_function', 'GO:0005011', ('211', '215'))	('TAMs', 'Chemical', '-', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('blockade', 'Var', (166, 174))	('colony stimulating factor 1', 'Gene', '1435', (182, 209))	('cancer', 'Disease', (300, 306))
501	32992658	Furthermore, anti-angiogenic therapy combined with anti-PD-1 facilitated the formation in the tumor tissue of highly specialized capillaries known as high endothelial venules (HEVs), structures normally present in lymph nodes where they serve as dedicated sites of T-cell homing, likely indicative of the development of tertiary lymphoid structures within the tumor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('tumor', 'Disease', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('facilitated', 'PosReg', (61, 72))	('tumor', 'Disease', (94, 99))	('anti-PD-1', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))
510	32992658	Copy number amplifications of 9p24.1 have been associated with increased PD-L1 expression in several cancers, and occur most commonly in mediastinal large B-cell lymphoma, classical Hodgkin's lymphoma and triple-negative breast cancer, but have also been described in ovarian, head and neck, bladder, cervical cancers, sarcomas and colorectal cancers, albeit at lower frequencies.	('lymphoma', 'Phenotype', 'HP:0002665', (162, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (319, 327))	('colorectal cancers', 'Disease', (332, 350))	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('sarcomas', 'Disease', (319, 327))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (155, 170))	('cancers', 'Phenotype', 'HP:0002664', (343, 350))	('colorectal cancer', 'Phenotype', 'HP:0003003', (332, 349))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('cancers', 'Disease', (343, 350))	('ovarian', 'Disease', (268, 275))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (182, 200))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('PD-L1', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('expression', 'MPA', (79, 89))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('increased PD', 'Phenotype', 'HP:0008151', (63, 75))	("Hodgkin's lymphoma", 'Disease', (182, 200))	('colorectal cancers', 'Disease', 'MESH:D015179', (332, 350))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('cervical cancers', 'Disease', (301, 317))	('B-cell lymphoma', 'Disease', (155, 170))	('cervical cancers', 'Disease', 'MESH:D002583', (301, 317))	('cancers', 'Disease', (310, 317))	('cancers', 'Disease', 'MESH:D009369', (343, 350))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('neck', 'cellular_component', 'GO:0044326', ('286', '290'))	('Copy number amplifications', 'Var', (0, 26))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('increased', 'PosReg', (63, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder', 'Disease', (292, 299))	('sarcomas', 'Disease', 'MESH:D012509', (319, 327))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (182, 200))
511	32992658	Enhanced signaling via JAK2 in cancers with 9p24.1 amplifications, contributed to mixed inflammatory and constitutive tumor-derived PD-L1 expression.	('JAK2', 'Gene', '3717', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('JAK2', 'Gene', (23, 27))	('JAK', 'molecular_function', 'GO:0004713', ('23', '26'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('amplifications', 'Var', (51, 65))	('tumor', 'Disease', (118, 123))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('signaling', 'MPA', (9, 18))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('signaling', 'biological_process', 'GO:0023052', ('9', '18'))	('Enhanced', 'PosReg', (0, 8))
512	32992658	In addition, tumors with CD274 genetic gains demonstrated higher mutational loads compared to non-amplified cases and responded particularly well to PD-1 blockade.	('mutational loads', 'MPA', (65, 81))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('gains', 'PosReg', (39, 44))	('genetic', 'Var', (31, 38))	('CD274', 'Gene', '29126', (25, 30))	('higher', 'PosReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CD274', 'Gene', (25, 30))
513	32992658	Deletions of PD-L1 are also commonly found in melanoma and non-small cell lung cancer, and represent one of the mechanisms leading to the lack of tumor cell PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('found', 'Reg', (37, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', (146, 151))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('expression', 'MPA', (163, 173))	('non-small cell lung cancer', 'Disease', (59, 85))	('PD-L1', 'Gene', (13, 18))	('Deletions', 'Var', (0, 9))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
520	32992658	Furthermore, inactivation of the tumor suppressor TP53, which is often associated with activating RAS mutations in lung adenocarcinoma and increased mutational load due to DNA damage repair defects, drives T-cell activation and immune-mediated elevation of PD-L1 expression, translating into a strong clinical benefit of PD-1 blockade in such patients.	('drives', 'PosReg', (199, 205))	('inactivation', 'Var', (13, 25))	('expression', 'MPA', (263, 273))	('associated', 'Reg', (71, 81))	('lung adenocarcinoma', 'Disease', (115, 134))	('increased', 'PosReg', (139, 148))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('activating', 'PosReg', (87, 97))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (33, 38))	('TP53', 'Gene', (50, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (343, 351))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('defects', 'Var', (190, 197))	('T-cell activation', 'biological_process', 'GO:0042110', ('206', '223'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('mutational load', 'MPA', (149, 164))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('T-cell activation', 'CPA', (206, 223))	('RAS', 'Gene', (98, 101))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('elevation of PD', 'Phenotype', 'HP:0008151', (244, 259))	('PD-L1', 'Gene', (257, 262))
522	32992658	Expression of mutant EGFR was sufficient to induce PD-L1 expression in bronchial epithelial cells, while EGFR targeting reduced PD-L1 expression in EGFR-mutant tumor cells.	('induce', 'PosReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', (105, 109))	('EGFR', 'Gene', '1956', (21, 25))	('expression', 'MPA', (57, 67))	('PD-L1', 'Gene', (128, 133))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('reduced PD', 'Phenotype', 'HP:0032198', (120, 130))	('reduced', 'NegReg', (120, 127))	('expression', 'MPA', (134, 144))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Disease', (160, 165))	('EGFR', 'Gene', (21, 25))	('mutant', 'Var', (14, 20))	('EGFR', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('PD-L1', 'Gene', (51, 56))
524	32992658	Similarly, activating mutations in the fibroblast growth factor receptor 2 (FGFR2) in colorectal cancer activate PD-L1 expression via the JAK/STAT3 pathway.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('fibroblast growth factor receptor 2', 'Gene', '2263', (39, 74))	('expression', 'MPA', (119, 129))	('STAT3', 'Gene', (142, 147))	('FGFR2', 'Gene', (76, 81))	('activate', 'PosReg', (104, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('FGFR2', 'Gene', '2263', (76, 81))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('39', '63'))	('JAK', 'molecular_function', 'GO:0004713', ('138', '141'))	('PD-L1', 'Protein', (113, 118))	('activating mutations', 'Var', (11, 31))	('fibroblast growth factor receptor 2', 'Gene', (39, 74))	('STAT3', 'Gene', '6774', (142, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
532	32992658	In human non-small cell lung cancer, nuclear YAP staining on immunohistochemistry was associated with PD-L1 expression.	('non-small cell lung cancer', 'Disease', (9, 35))	('YAP', 'Gene', (45, 48))	('human', 'Species', '9606', (3, 8))	('nuclear', 'Var', (37, 44))	('associated', 'Reg', (86, 96))	('PD-L1', 'Gene', (102, 107))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (9, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('expression', 'MPA', (108, 118))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (13, 35))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (9, 35))	('YAP', 'Gene', '10413', (45, 48))
534	32992658	Mechanistically, loss of the epithelial marker E-cadherin frees the E-cadherin-associated beta-catenin for cytoplasmic translocation, GSK-3beta-mediated ubiquitination and proteosomal degradation.	('frees', 'MPA', (58, 63))	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('E-cadherin', 'Gene', (47, 57))	('beta-catenin', 'Gene', (90, 102))	('E-cadherin', 'Gene', '999', (47, 57))	('GSK-3beta', 'Gene', '2931', (134, 143))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('GSK', 'molecular_function', 'GO:0050321', ('134', '137'))	('degradation', 'biological_process', 'GO:0009056', ('184', '195'))	('proteosomal degradation', 'MPA', (172, 195))	('beta-catenin', 'Gene', '1499', (90, 102))	('GSK-3beta', 'Gene', (134, 143))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))	('loss', 'Var', (17, 21))
539	32992658	For example, demethylation of the PD-L1 promoter via TGFbeta1-dependent repression of the DNA methyltransferase DNMT1 allowed for expression of PD-L1 upon TNFalpha-mediated NF-kB activation.	('expression', 'MPA', (130, 140))	('TGFbeta1', 'Gene', '7040', (53, 61))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('TGFbeta1', 'Gene', (53, 61))	('DNMT1', 'Gene', (112, 117))	('TNFalpha', 'Gene', (155, 163))	('allowed', 'Reg', (118, 125))	('DNMT1', 'Gene', '1786', (112, 117))	('demethylation', 'biological_process', 'GO:0070988', ('13', '26'))	('demethylation', 'Var', (13, 26))	('PD-L1', 'Gene', (144, 149))	('TNFalpha', 'Gene', '7124', (155, 163))
546	32992658	Loss of IFNgamma responsiveness in tumor cells may result from inactivating mutations in JAK1/2 disrupting INFgamma signaling, leading to tumor immune escape and disease progression.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('JAK', 'molecular_function', 'GO:0004713', ('89', '92'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (138, 143))	('inactivating mutations', 'Var', (63, 85))	('JAK1/2', 'Gene', (89, 95))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('disease progression', 'CPA', (162, 181))	('tumor', 'Disease', (35, 40))	('Loss', 'NegReg', (0, 4))	('INFgamma signaling', 'MPA', (107, 125))	('disrupting', 'NegReg', (96, 106))	('leading to', 'Reg', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('JAK1/2', 'Gene', '3716;3717', (89, 95))	('IFNgamma', 'Protein', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
548	32992658	Tumor cells with disrupted IFNgamma signaling had a defective PD-L1 upregulation and were efficiently controlled by the immune system in a mouse model of melanoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IFNgamma', 'Gene', (27, 35))	('mouse', 'Species', '10090', (139, 144))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('upregulation', 'PosReg', (68, 80))	('melanoma', 'Disease', (154, 162))	('disrupted', 'Var', (17, 26))	('defective', 'NegReg', (52, 61))	('PD-L1', 'Gene', (62, 67))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))
550	32992658	These data also suggest that disrupted IFNgamma signaling is advantageous for tumors in the context of immunotherapy.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('disrupted', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('IFNgamma', 'Protein', (39, 47))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
554	32992658	Hypermethylation of the PD-L1 promoter prevented PD-L1 expression, while a constitutive expression of PD-L1 in melanoma biopsies and cell lines was associated with global DNA hypomethylation patterns.	('prevented', 'NegReg', (39, 48))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('Hypermethylation', 'Var', (0, 16))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('171', '190'))	('expression', 'MPA', (55, 65))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('PD-L1', 'Gene', (49, 54))
556	32992658	Other epigenetic mechanisms such as histone deacetylation and aberrant expression of the Enhancer of zeste homolog 2 (EZH2) contribute to the control of PD-L1 expression in cancer cells by limiting transcription factor access to the PD-L1 promoter region (reviewed in).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('PD-L1', 'Gene', (153, 158))	('cancer', 'Disease', (173, 179))	('transcription factor access', 'MPA', (198, 225))	('Enhancer of zeste homolog 2', 'Gene', (89, 116))	('transcription factor', 'molecular_function', 'GO:0000981', ('198', '218'))	('histone deacetylation', 'biological_process', 'GO:0016575', ('36', '57'))	('aberrant', 'Var', (62, 70))	('expression', 'MPA', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('control', 'MPA', (142, 149))	('transcription', 'biological_process', 'GO:0006351', ('198', '211'))	('EZH2', 'Gene', (118, 122))	('EZH2', 'Gene', '2146', (118, 122))	('Enhancer of zeste homolog 2', 'Gene', '2146', (89, 116))	('limiting', 'NegReg', (189, 197))
558	32992658	A number of miRs can bind to the 3'UTR of the PD-L1 gene and have been shown to directly suppress PD-L1 expression, including miR-513, miR-155, miR-17-5p, miR-33a, miR-34a and multiple others (Table 1).	('PD-L1', 'Gene', (46, 51))	('miR-33a', 'Gene', (155, 162))	('miR-17-5p', 'Gene', '406952', (144, 153))	('miR-17-5p', 'Gene', (144, 153))	('PD-L1', 'Gene', (98, 103))	('miR-513', 'Var', (126, 133))	('suppress', 'NegReg', (89, 97))	('miR-155', 'Gene', '406947', (135, 142))	('miR-34a', 'Gene', '407040', (164, 171))	('expression', 'MPA', (104, 114))	('bind', 'Interaction', (21, 25))	('miR-33a', 'Gene', '407039', (155, 162))	('miR-34a', 'Gene', (164, 171))	('miR-155', 'Gene', (135, 142))
560	32992658	miR-20b, -21 and -130b upregulated PD-L1 expression in colorectal cancer also by targeting PTEN, while miR-135 augmented PD-L1 expression in lung cancer by suppressing the ubiquitination of proteins in the JAK/STAT signaling pathway.	('PD-L1', 'Gene', (121, 126))	('signaling pathway', 'biological_process', 'GO:0007165', ('215', '232'))	('upregulated', 'PosReg', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('lung cancer', 'Disease', (141, 152))	('ubiquitination of', 'MPA', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('suppressing', 'NegReg', (156, 167))	('expression', 'MPA', (41, 51))	('augmented', 'PosReg', (111, 120))	('miR-20b', 'Gene', '574032', (0, 7))	('PTEN', 'Gene', (91, 95))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('expression', 'MPA', (127, 137))	('targeting', 'Reg', (81, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('JAK', 'molecular_function', 'GO:0004713', ('206', '209'))	('JAK/STAT signaling pathway', 'Pathway', (206, 232))	('colorectal cancer', 'Disease', (55, 72))	('miR-135', 'Var', (103, 110))	('PTEN', 'Gene', '5728', (91, 95))	('proteins', 'Protein', (190, 198))	('PD-L1', 'Gene', (35, 40))	('miR-20b', 'Gene', (0, 7))
561	32992658	Nonglycosylated PD-L1 is an unstable protein that is rapidly degraded by the ubiquitin/proteasome system after being phosphorylated by glycogen synthase kinase 3beta (GSK3beta).	('degraded', 'NegReg', (61, 69))	('Nonglycosylated', 'Var', (0, 15))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('GSK', 'molecular_function', 'GO:0050321', ('167', '170'))	('PD-L1', 'Gene', (16, 21))	('proteasome', 'molecular_function', 'GO:0004299', ('87', '97'))	('proteasome', 'cellular_component', 'GO:0000502', ('87', '97'))	('GSK3beta', 'Gene', (167, 175))	('GSK3beta', 'Gene', '2931', (167, 175))	('ubiquitin', 'molecular_function', 'GO:0031386', ('77', '86'))	('glycogen synthase kinase 3beta', 'Gene', '2932', (135, 165))	('glycogen synthase kinase 3beta', 'Gene', (135, 165))
562	32992658	Glycosylation improves PD-L1 stability but also creates a therapeutic vulnerability, where abnormal glycosylation such as that triggered by a commonly used anti-diabetic drug metformin results in endoplasmic reticulum-associated degradation of PD-L1 and improved immune responses.	('diabetic', 'Disease', 'MESH:D003920', (161, 169))	('Glycosylation', 'biological_process', 'GO:0070085', ('0', '13'))	('endoplasmic reticulum-associated degradation', 'MPA', (196, 240))	('improved', 'PosReg', (254, 262))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('196', '217'))	('metformin', 'Chemical', 'MESH:D008687', (175, 184))	('PD-L1', 'Protein', (23, 28))	('glycosylation', 'Var', (100, 113))	('diabetic', 'Disease', (161, 169))	('stability', 'MPA', (29, 38))	('improves', 'PosReg', (14, 22))	('immune responses', 'CPA', (263, 279))	('abnormal glycosylation', 'Phenotype', 'HP:0012345', (91, 113))	('abnormal glycosylation', 'Var', (91, 113))	('glycosylation', 'biological_process', 'GO:0070085', ('100', '113'))	('PD-L1', 'Protein', (244, 249))	('endoplasmic reticulum-associated degradation', 'biological_process', 'GO:0036503', ('196', '240'))
565	32992658	Aberrant glycosylation of PD-L1 in cancer cells may provide some insight into the validity of PD-L1 detection as a predictive biomarker of immunotherapy response.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('PD-L1', 'Gene', (26, 31))	('glycosylation', 'biological_process', 'GO:0070085', ('9', '22'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('glycosylation', 'MPA', (9, 22))	('cancer', 'Disease', (35, 41))
566	32992658	demonstrated, using mass spectrometry and immunohistochemistry on 22 human melanoma samples, a discrepancy in PD-L1 expression assessed by the two methods, which the authors attributed to the aberrant PD-L1 glycosylation interfering with the antibody binding on immunohistochemistry.	('aberrant', 'Var', (192, 200))	('antibody', 'cellular_component', 'GO:0042571', ('242', '250'))	('antibody binding', 'Interaction', (242, 258))	('PD-L1', 'Protein', (201, 206))	('human', 'Species', '9606', (69, 74))	('antibody', 'cellular_component', 'GO:0019815', ('242', '250'))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('antibody', 'cellular_component', 'GO:0019814', ('242', '250'))	('interfering', 'NegReg', (221, 232))	('antibody', 'molecular_function', 'GO:0003823', ('242', '250'))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('binding', 'molecular_function', 'GO:0005488', ('251', '258'))	('glycosylation', 'MPA', (207, 220))	('glycosylation', 'biological_process', 'GO:0070085', ('207', '220'))
573	32992658	Thus, CDK4/6 inhibitors synergized with PD-1 blockade in mouse tumor models.	('tumor', 'Disease', (63, 68))	('CDK4/6', 'Gene', '12567;12571', (6, 12))	('inhibitors', 'Var', (13, 23))	('mouse', 'Species', '10090', (57, 62))	('CDK', 'molecular_function', 'GO:0004693', ('6', '9'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CDK4/6', 'Gene', (6, 12))
577	32992658	In several studies, high levels of circulating sPD-L1 were associated with poor patient outcomes in melanoma, lung and gastric cancers and lymphoma and with reduced response to PD-1 blockade in melanoma.	('PD-1 blockade in melanoma', 'Disease', 'MESH:D010300', (177, 202))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('lung', 'Disease', (110, 114))	('sPD-L1', 'Var', (47, 53))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('gastric cancers', 'Phenotype', 'HP:0012126', (119, 134))	('melanoma', 'Disease', (194, 202))	('poor', 'NegReg', (75, 79))	('PD-1 blockade in melanoma', 'Disease', (177, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('gastric cancers and lymphoma', 'Disease', 'MESH:D013274', (119, 147))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('patient', 'Species', '9606', (80, 87))	('reduced', 'NegReg', (157, 164))
583	32992658	A similar increase in PD-L1 expression in longitudinal biopsies, combined with an immune gene expression signature, was observed in patients treated with anti-CTLA-4 antibodies.	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('anti-CTLA-4', 'Var', (154, 165))	('PD-L1', 'Gene', (22, 27))	('expression', 'MPA', (28, 38))	('anti-CTLA-4', 'Gene', (154, 165))	('increase', 'PosReg', (10, 18))	('patients', 'Species', '9606', (132, 140))
592	32992658	However, inhibition of TGFbeta signaling released matrix metalloproteinase-9 by stromal fibroblasts, resulting in cleavage of PD-L1 from the surface of PD-L1-expressing cancer cells and myeloid cells and generation of soluble PD-L1, thus potentially desensitizing to anti-PD-1 treatment.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('cancer', 'Disease', (169, 175))	('TGFbeta', 'Gene', (23, 30))	('soluble PD-L1', 'MPA', (218, 231))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('PD-L1', 'Gene', (126, 131))	('soluble', 'cellular_component', 'GO:0005625', ('218', '225'))	('cleavage', 'MPA', (114, 122))	('matrix metalloproteinase-9', 'Gene', '4318', (50, 76))	('TGFbeta', 'Gene', '7039', (23, 30))	('inhibition', 'Var', (9, 19))	('matrix metalloproteinase-9', 'Gene', (50, 76))
603	32992658	Epigenetic targeting of tumor PD-L1 expression can also improve tumor-specific antigen expression and the resulting T-cell recognition, thus creating new therapeutic vulnerabilities.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Epigenetic targeting', 'Var', (0, 20))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (24, 29))	('improve', 'PosReg', (56, 63))	('tumor PD-L1', 'Disease', 'MESH:D010300', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('T-cell recognition', 'CPA', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cell recognition', 'biological_process', 'GO:0008037', ('118', '134'))	('tumor PD-L1', 'Disease', (24, 35))
622	32977425	For example, some papers reported that the deletion of TP53 and Rb can cause OS transformation of osteoblasts.	('cause', 'Reg', (71, 76))	('OS transformation of osteoblasts', 'CPA', (77, 109))	('deletion', 'Var', (43, 51))	('TP53', 'Gene', (55, 59))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('Rb', 'Gene', '19645', (64, 66))
623	32977425	The loss of Rb can trigger the transformation of MSCs into OS, and the overexpression of C-myc also has similar consequences for MSCs.	('C-myc', 'Gene', '4609', (89, 94))	('trigger', 'Reg', (19, 26))	('MSCs', 'Disease', (49, 53))	('Rb', 'Gene', '19645', (12, 14))	('MSCs', 'molecular_function', 'GO:0043854', ('129', '133'))	('C-myc', 'Gene', (89, 94))	('MSCs', 'molecular_function', 'GO:0043854', ('49', '53'))	('OS', 'Phenotype', 'HP:0002669', (59, 61))	('loss', 'Var', (4, 8))
625	32977425	The TP53 and Rb are the genes with the highest frequencies of absence and mutations in human OS and transgenic mouse models.	('OS', 'Phenotype', 'HP:0002669', (93, 95))	('TP53', 'Gene', (4, 8))	('human', 'Species', '9606', (87, 92))	('mouse', 'Species', '10090', (111, 116))	('mutations', 'Var', (74, 83))	('Rb', 'Gene', '19645', (13, 15))
634	32977425	For example, the deficiency of TP53 and Rb gene, the aneuploidization and genomic loss of P16/Cdkn2a are common causes of the transition of MSCs to OS cells.	('MSCs', 'molecular_function', 'GO:0043854', ('140', '144'))	('causes', 'Reg', (112, 118))	('OS', 'Phenotype', 'HP:0002669', (148, 150))	('MSCs', 'Disease', (140, 144))	('aneuploidization', 'Disease', 'MESH:D000782', (53, 69))	('Rb', 'Gene', '19645', (40, 42))	('TP53', 'Protein', (31, 35))	('P16/Cdkn2a', 'Gene', (90, 100))	('deficiency', 'NegReg', (17, 27))	('loss', 'Var', (82, 86))	('P16/Cdkn2a', 'Gene', '1029', (90, 100))	('aneuploidization', 'Disease', (53, 69))
657	32977425	Aberrant expressions of a number of genes induced by hypoxia and acidic conditions promote the metastasis of OS (Table 2).	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('metastasis of OS', 'CPA', (95, 111))	('OS', 'Phenotype', 'HP:0002669', (109, 111))	('promote', 'PosReg', (83, 90))	('Aberrant expressions', 'Var', (0, 20))
683	32977425	EVs derived from highly metastatic OS clonal variants induce metastasis of poorly metastatic clones in mouse model.	('mouse', 'Species', '10090', (103, 108))	('variants', 'Var', (45, 53))	('metastasis of poorly metastatic clones', 'CPA', (61, 99))	('OS', 'Phenotype', 'HP:0002669', (35, 37))	('induce', 'Reg', (54, 60))
688	32977425	There are many reports showing that aberrant expression of proteins can active the PI3K/Akt signaling pathway facilitating the progression of OS (Figure 2).	('aberrant expression', 'Var', (36, 55))	('Akt', 'Gene', '207', (88, 91))	('OS', 'Phenotype', 'HP:0002669', (142, 144))	('Akt signaling', 'biological_process', 'GO:0043491', ('88', '101'))	('proteins', 'Protein', (59, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('signaling pathway', 'biological_process', 'GO:0007165', ('92', '109'))	('Akt', 'Gene', (88, 91))	('active', 'Reg', (72, 78))
700	32977425	Silence of LncRNA H19 and LINC00968 can decrease the activation of the PI3K/Akt/mTOR signaling pathway in vitro.	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('decrease', 'NegReg', (40, 48))	('LncRNA', 'Gene', (11, 17))	('mTOR', 'Gene', (80, 84))	('Akt', 'Gene', (76, 79))	('mTOR', 'Gene', '2475', (80, 84))	('LINC00968', 'Gene', (26, 35))	('Akt', 'Gene', '207', (76, 79))	('LINC00968', 'Gene', '100507632', (26, 35))	('Silence', 'Var', (0, 7))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
702	32977425	The LncDANCR via competitive combination of miR-33a-5p promotes the expression of AXL and then facilitates the invasion and metastasis of OS in vitro and in vivo through the PI3K/Akt signaling pathway.	('DANCR', 'Gene', (7, 12))	('signaling pathway', 'biological_process', 'GO:0007165', ('183', '200'))	('DANCR', 'Gene', '57291', (7, 12))	('expression', 'MPA', (68, 78))	('miR-33a-5p', 'Chemical', '-', (44, 54))	('AXL', 'Gene', '558', (82, 85))	('promotes', 'PosReg', (55, 63))	('Akt signaling', 'biological_process', 'GO:0043491', ('179', '192'))	('miR-33a-5p', 'Var', (44, 54))	('Akt', 'Gene', '207', (179, 182))	('AXL', 'Gene', (82, 85))	('PI3K', 'molecular_function', 'GO:0016303', ('174', '178'))	('Akt', 'Gene', (179, 182))	('facilitates', 'PosReg', (95, 106))	('OS', 'Phenotype', 'HP:0002669', (138, 140))
711	32977425	Meanwhile inhibition of miR-135b not only decreases the activation of the Wnt/beta-catenin and Notch signaling pathway but also depresses OS metastasis and reduces recurrence in OS xenografts models.	('miR-135b', 'Gene', '442891', (24, 32))	('Notch', 'Gene', '4851;4853', (95, 100))	('depresses OS metastasis', 'Disease', (128, 151))	('Notch', 'Gene', (95, 100))	('Wnt', 'Gene', (74, 77))	('decreases', 'NegReg', (42, 51))	('Wnt', 'Gene', '7482', (74, 77))	('depresses OS metastasis', 'Disease', 'MESH:D000275', (128, 151))	('OS', 'Phenotype', 'HP:0002669', (178, 180))	('beta-catenin', 'Gene', '1499', (78, 90))	('reduces', 'NegReg', (156, 163))	('recurrence in OS xenografts models', 'CPA', (164, 198))	('inhibition', 'Var', (10, 20))	('beta-catenin', 'Gene', (78, 90))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('95', '118'))	('miR-135b', 'Gene', (24, 32))	('OS', 'Phenotype', 'HP:0002669', (138, 140))
716	32977425	The Wnt antagonist, APCDDI, is downregulated by methylation in the promoter to activate the Wnt/beta-catenin signaling pathway elevating the ability of invasion and migration of OS cells in vitro and in vivo.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('beta-catenin', 'Gene', '1499', (96, 108))	('APCDDI', 'Chemical', '-', (20, 26))	('signaling pathway', 'biological_process', 'GO:0007165', ('109', '126'))	('Wnt', 'Gene', (92, 95))	('activate', 'PosReg', (79, 87))	('Wnt', 'Gene', '7482', (92, 95))	('APCDDI', 'Gene', (20, 26))	('rat', 'Species', '10116', (168, 171))	('OS', 'Phenotype', 'HP:0002669', (178, 180))	('Wnt', 'Gene', (4, 7))	('Wnt', 'Gene', '7482', (4, 7))	('methylation', 'Var', (48, 59))	('elevating', 'PosReg', (127, 136))	('beta-catenin', 'Gene', (96, 108))
721	32977425	Any mutation in the components of this pathway can result in the stop or start of the signaling and along with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('start', 'MPA', (73, 78))	('stop', 'MPA', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutation', 'Var', (4, 12))	('tumor', 'Disease', (111, 116))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('signaling', 'MPA', (86, 95))	('result in', 'Reg', (51, 60))
729	32977425	Moreover, silence of MIF decreases the p-ERK level and inhibits the ability of metastasis and proliferation in vitro and suppresses OS lung metastasis in vivo and raises the sensitivity of OS cells to chemotherapy drugs.	('raises', 'PosReg', (163, 169))	('OS', 'Phenotype', 'HP:0002669', (132, 134))	('silence', 'Var', (10, 17))	('sensitivity', 'MPA', (174, 185))	('rat', 'Species', '10116', (101, 104))	('ERK', 'molecular_function', 'GO:0004707', ('41', '44'))	('OS lung metastasis', 'CPA', (132, 150))	('decreases', 'NegReg', (25, 34))	('inhibits', 'NegReg', (55, 63))	('MIF', 'Gene', '4282', (21, 24))	('ERK', 'Gene', '5594', (41, 44))	('OS', 'Phenotype', 'HP:0002669', (189, 191))	('suppresses', 'NegReg', (121, 131))	('MIF', 'Gene', (21, 24))	('ERK', 'Gene', (41, 44))
732	32977425	The downregulation of the JAK-STAT signaling pathway by miR-125b and miR-126 suppresses migration, invasion, and proliferation in OS cell lines.	('miR-125b', 'Chemical', '-', (56, 64))	('rat', 'Species', '10116', (91, 94))	('suppresses', 'NegReg', (77, 87))	('signaling pathway', 'biological_process', 'GO:0007165', ('35', '52'))	('OS', 'Phenotype', 'HP:0002669', (130, 132))	('migration', 'CPA', (88, 97))	('miR-126', 'Gene', '406913', (69, 76))	('JAK', 'molecular_function', 'GO:0004713', ('26', '29'))	('invasion', 'CPA', (99, 107))	('downregulation', 'NegReg', (4, 18))	('miR-126', 'Gene', (69, 76))	('STAT', 'Gene', '6774;20848', (30, 34))	('STAT', 'Gene', (30, 34))	('miR-125b', 'Var', (56, 64))	('rat', 'Species', '10116', (120, 123))
744	32977425	Moreover, the activation and recycling rate of Notch is suppressed by the activation of PI5P4Kgamma.	('suppressed', 'NegReg', (56, 66))	('PI5P4Kgamma', 'Var', (88, 99))	('rat', 'Species', '10116', (39, 42))	('activation', 'MPA', (14, 24))	('Notch', 'Gene', '4851;4853', (47, 52))	('recycling rate', 'MPA', (29, 43))	('Notch', 'Gene', (47, 52))
748	32977425	The motilities of OS cells are suppressed by the silence of SNHG12.	('silence', 'Var', (49, 56))	('OS', 'Phenotype', 'HP:0002669', (18, 20))	('motilities of OS cells', 'CPA', (4, 26))	('SNHG12', 'Gene', (60, 66))	('suppressed', 'NegReg', (31, 41))	('SNHG12', 'Gene', '85028', (60, 66))
774	32759387	Lung cancer screening (LCS) by low-dose CT (LDCT) has been repeatedly shown in clinical trials to reduce lung cancer mortality.	('low-dose', 'Var', (31, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('reduce', 'NegReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('mortality', 'Disease', 'MESH:D003643', (117, 126))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('lung cancer', 'Disease', (105, 116))	('mortality', 'Disease', (117, 126))
899	31892257	The important metabolites of the G. oblongifolia species; polyisoprenylated benzophenones and xanthones have anticancer, antioxidant, antifungal, apoptotic, and anti-pathogenic properties.	('polyisoprenylated', 'Var', (58, 75))	('oblongifolia species', 'Disease', 'MESH:C564159', (36, 56))	('G. oblongifolia', 'Species', '1009475', (33, 48))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('oblongifolia species', 'Disease', (36, 56))	('cancer', 'Disease', (113, 119))	('apoptotic', 'CPA', (146, 155))	('xanthones', 'Chemical', 'MESH:D044004', (94, 103))	('benzophenones', 'Chemical', 'MESH:D001577', (76, 89))	('antioxidant', 'CPA', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('anti-pathogenic properties', 'CPA', (161, 187))	('antifungal', 'CPA', (134, 144))
905	31892257	The vacuole size was increased at high concentrations of 500 g/mL and 1000 g/mL.	('increased', 'PosReg', (21, 30))	('vacuole', 'cellular_component', 'GO:0005773', ('4', '11'))	('rat', 'Species', '10116', (46, 49))	('1000 g/mL', 'Var', (70, 79))	('vacuole size', 'CPA', (4, 16))
976	31892257	reported the inhibition of cell growth by isoegomaketone when treated for over 24 h, cleaved caspase-3, 8, and 9 in a time-dependent and dose-dependent manner.	('caspase-3', 'Gene', (93, 102))	('caspase-3', 'Gene', '836', (93, 102))	('isoegomaketone', 'Chemical', 'MESH:C568138', (42, 56))	('cleaved', 'Var', (85, 92))	('inhibition', 'NegReg', (13, 23))	('cell growth', 'CPA', (27, 38))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('13', '38'))
986	31892257	In addition, platycodin D upregulate cellular levels of protein Bax and Bcl-2 and downregulate the activation of caspase-9.	('platycodin D', 'Chemical', 'MESH:C108953', (13, 25))	('activation', 'MPA', (99, 109))	('Bcl-2', 'Gene', (72, 77))	('downregulate', 'NegReg', (82, 94))	('caspase-9', 'Gene', '842', (113, 122))	('Bcl-2', 'Gene', '596', (72, 77))	('upregulate', 'PosReg', (26, 36))	('Bax', 'Gene', (64, 67))	('Bcl-2', 'molecular_function', 'GO:0015283', ('72', '77'))	('caspase-9', 'Gene', (113, 122))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('platycodin', 'Var', (13, 23))	('Bax', 'Gene', '581', (64, 67))
991	31892257	showed that suppression of telomerase activity and cytotoxic effect on leukemia cells by platycodin D was through post-translational and transcriptional inhibition of hTERT.	('leukemia', 'Disease', (71, 79))	('platycodin D', 'Chemical', 'MESH:C108953', (89, 101))	('inhibition', 'NegReg', (153, 163))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('cytotoxic effect', 'CPA', (51, 67))	('platycodin', 'Var', (89, 99))	('telomerase activity', 'molecular_function', 'GO:0003720', ('27', '46'))	('suppression', 'NegReg', (12, 23))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))	('hTERT', 'Gene', '7015', (167, 172))	('telomerase', 'CPA', (27, 37))	('hTERT', 'Gene', (167, 172))
1066	31892257	But on the other hand, the knockdown of Tie2 decreases the inhibitory activities of triptolide on endothelial network formation.	('knockdown', 'Var', (27, 36))	('decreases', 'NegReg', (45, 54))	('Tie2', 'Gene', (40, 44))	('inhibitory activities of triptolide', 'MPA', (59, 94))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('endothelial network', 'MPA', (98, 117))	('Tie2', 'Gene', '7010', (40, 44))	('triptolide', 'Chemical', 'MESH:C001899', (84, 94))
1087	31892257	The study of B16F-10 melanoma metastatic cell line showed that the concentrations of some important antioxidant enzymes (including catalase, superoxide dismutase, and glutathione peroxidase) increased many folds in the treatment groups.	('men', 'Species', '9606', (224, 227))	('catalase', 'Gene', (131, 139))	('B16F', 'Var', (13, 17))	('rat', 'Species', '10116', (74, 77))	('concentrations', 'MPA', (67, 81))	('increased', 'PosReg', (191, 200))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('catalase', 'Gene', '12359', (131, 139))	('melanoma', 'Disease', (21, 29))	('antioxidant enzymes', 'MPA', (100, 119))	('B16F', 'SUBSTITUTION', 'None', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('superoxide dismutase', 'MPA', (141, 161))	('superoxide', 'Chemical', 'MESH:D013481', (141, 151))	('glutathione', 'Chemical', 'MESH:D005978', (167, 178))
1093	31892257	For instance, dihydroartemisinin was reported to inhibit tumor tissue, increase the level of interferon-gamma (IFN-gamma), and decrease interleukin 4 (IL-4) in tumor-bearing mice.	('mice', 'Species', '10090', (174, 178))	('IFN-gamma', 'Gene', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('increase', 'PosReg', (71, 79))	('interferon-gamma', 'Gene', '15978', (93, 109))	('interferon-gamma', 'Gene', (93, 109))	('dihydroartemisinin', 'Var', (14, 32))	('interleukin 4', 'Gene', (136, 149))	('IL-4', 'molecular_function', 'GO:0005136', ('151', '155'))	('tumor', 'Disease', (57, 62))	('dihydroartemisinin', 'Chemical', 'MESH:C039060', (14, 32))	('interleukin 4', 'Gene', '16189', (136, 149))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('93', '109'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('IL-4', 'Gene', (151, 155))	('tumor', 'Disease', (160, 165))	('decrease', 'NegReg', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('IL-4', 'Gene', '16189', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IFN-gamma', 'Gene', '15978', (111, 120))	('inhibit', 'NegReg', (49, 56))
1110	31892257	Nuclear changes, DNA condensation, chromatin fragmentation, and apoptosis are induced in A549 cells with a concentration of 0.25, 0.50, and 0.75 mg/mL steroidal saponin.	('chromatin fragmentation', 'CPA', (35, 58))	('men', 'Species', '9606', (49, 52))	('rat', 'Species', '10116', (114, 117))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('DNA condensation', 'biological_process', 'GO:0006323', ('17', '33'))	('saponin', 'Chemical', 'MESH:D012503', (161, 168))	('DNA condensation', 'CPA', (17, 33))	('apoptosis', 'CPA', (64, 73))	('Nuclear changes', 'CPA', (0, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('chromatin', 'cellular_component', 'GO:0000785', ('35', '44'))	('0.50', 'Var', (130, 134))	('DNA condensation', 'biological_process', 'GO:0030261', ('17', '33'))
1118	31892257	Manjamalai and Grace reported the apoptosis along with lowering angiogenesis and lung metastasis activities of the essential oils of W. chinensis by using B16F-10 melanoma cell line in C57BL/6 mice.	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('angiogenesis', 'CPA', (64, 76))	('lung metastasis activities', 'CPA', (81, 107))	('W. chinensis', 'Species', '318065', (133, 145))	('B16F', 'SUBSTITUTION', 'None', (155, 159))	('essential oils', 'Chemical', 'MESH:D009822', (115, 129))	('apoptosis', 'CPA', (34, 43))	('mice', 'Species', '10090', (193, 197))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))	('lowering', 'NegReg', (55, 63))	('B16F', 'Var', (155, 159))
1119	31892257	The mice were injected with B16F-10 melanoma cells through the tail vein and treated with different doses of essential oil.	('B16F', 'SUBSTITUTION', 'None', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('mice', 'Species', '10090', (4, 8))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('essential oil', 'Chemical', 'MESH:D009822', (109, 122))	('B16F', 'Var', (28, 32))
1127	31892257	Results of the study reported that dimer-Sal, dimer-OH, and DHA significantly suppressed tumors in rats compared to the control group.	('tumors', 'Disease', (89, 95))	('rats', 'Species', '10116', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('dimer-OH', 'Var', (46, 54))	('suppressed', 'NegReg', (78, 88))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('DHA', 'Chemical', 'MESH:C039060', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
1165	31892257	Many studies have reported inhibition of enzymes that stops tumor growth.	('enzymes', 'Enzyme', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inhibition', 'Var', (27, 37))	('tumor', 'Disease', (60, 65))
1202	31632701	As an example, mutations in the (ALK) gene in non-small cell lung cancer have been shown to exhibit a propensity for CNS involvement.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('ALK', 'Gene', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (15, 24))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (50, 72))	('ALK', 'Gene', '238', (33, 36))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (46, 72))
1238	31552167	However, in the last decade, our knowledge about oncogenic driver mutations and immune checkpoint inhibitors suffered an outbursting growth which has changed radically the therapeutic landscape of our patients.	('mutations', 'Var', (66, 75))	('patients', 'Species', '9606', (201, 209))	('outbursting growth', 'Phenotype', 'HP:0001548', (121, 139))	('changed', 'Reg', (150, 157))
1239	31552167	EGFR mutations and ALK gene rearrangements, first, but specially immunotherapy, later, has explored new targetable pathways in our fight against lung cancer.	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', '238', (19, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('EGFR', 'Gene', '1956', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
1310	31552167	As we mentioned above, in the 2-year outcomes from nivolumab pivotal trials in second-line NSCLC, OS rates were 23 and 29% with nivolumab vs. 8 and 16% with docetaxel, in, respectively, squamous and non-squamous.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('docetaxel', 'Chemical', 'MESH:C067311', (157, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('nivolumab', 'Var', (128, 137))	('squamous', 'Disease', (186, 194))	('non-squamous', 'Disease', (199, 211))	('NSCLC', 'Disease', (91, 96))
1318	31552167	ORR in PD-L1 positive patients was 27.6%, contrasting with 12.1% of PD-L1 negative patients.	('positive', 'Var', (13, 21))	('PD-L1', 'Gene', '29126', (68, 73))	('patients', 'Species', '9606', (22, 30))	('PD-L1', 'Gene', (68, 73))	('patients', 'Species', '9606', (83, 91))	('PD-L1', 'Gene', (7, 12))	('PD-L1', 'Gene', '29126', (7, 12))
1335	30170377	COX-2 rs5275 and rs689466 polymorphism and risk of lung cancer Cyclooxygenase-2 (COX-2) is an inducible enzyme that mediates the synthesis of prostaglandin, which plays an important role in the inflammation response.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('rs689466', 'Mutation', 'rs689466', (17, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('COX-2', 'Gene', '5743', (81, 86))	('COX-2', 'Gene', '5743', (0, 5))	('inflammation', 'biological_process', 'GO:0006954', ('194', '206'))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cyclooxygenase-2', 'Gene', '5743', (63, 79))	('Cyclooxygenase-2', 'Gene', (63, 79))	('synthesis', 'biological_process', 'GO:0009058', ('129', '138'))	('rs5275', 'Var', (6, 12))	('inflammation', 'Disease', (194, 206))	('rs5275', 'Mutation', 'rs5275', (6, 12))	('lung cancer', 'Disease', (51, 62))	('prostaglandin', 'Chemical', 'MESH:D011453', (142, 155))	('rs689466', 'Var', (17, 25))	('COX-2', 'Gene', (81, 86))	('COX-2', 'Gene', (0, 5))
1337	30170377	There are many previous case-control studies focused on the association between COX-2 polymorphism and lung cancer risk, however, the conclusion remained controversial.	('COX-2', 'Gene', (80, 85))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('COX-2', 'Gene', '5743', (80, 85))	('polymorphism', 'Var', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('association', 'Interaction', (60, 71))
1338	30170377	We performed this meta-analysis to evaluate the association between COX-2 rs5275 and rs689466 polymorphism and susceptibility to lung cancer.	('rs5275', 'Mutation', 'rs5275', (74, 80))	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('rs689466', 'Mutation', 'rs689466', (85, 93))	('COX-2', 'Gene', '5743', (68, 73))	('rs689466', 'Var', (85, 93))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('COX-2', 'Gene', (68, 73))	('rs5275', 'Var', (74, 80))
1341	30170377	We found rs5275 gene polymorphism decreased the risk of lung cancer under heterozygote model (OR: 0.91, 95% CI: 0.84-0.98, P = .02).	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('decreased', 'NegReg', (34, 43))	('rs5275', 'Var', (9, 15))	('rs5275', 'Mutation', 'rs5275', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('polymorphism', 'Var', (21, 33))
1342	30170377	COX-2 rs689466 gene polymorphism was also related to a significantly reduced risk under allele (OR: 0.88, 95% CI: 0.82-0.95, P = .001), homozygote (OR: 0.81, 95% CI: 0.68-0.95, P = .01), heterozygote (OR: 0.81, 95% CI: 0.72-0.91, P < .001), and dominant model (OR: 0.81, 95% CI: 0.72-0.91, P < .001), except for recessive model.	('reduced', 'NegReg', (69, 76))	('rs689466', 'Mutation', 'rs689466', (6, 14))	('rs689466', 'Var', (6, 14))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
1343	30170377	Polymorphism of rs5275 was strongly associated with a reduced risk of lung adenocarcinoma according to stratified analysis by pathological types.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('Polymorphism', 'Var', (0, 12))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('reduced', 'NegReg', (54, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('rs5275', 'Gene', (16, 22))	('rs5275', 'Mutation', 'rs5275', (16, 22))	('lung adenocarcinoma', 'Disease', (70, 89))
1345	30170377	Our meta-analysis demonstrated that COX-2 rs5275 and rs689466 polymorphism significantly decrease the risk of lung cancer in Asians but not in Caucasians, indicating COX-2 could serve as a potential diagnostic marker for lung cancer.	('COX-2', 'Gene', (166, 171))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('rs5275', 'Var', (42, 48))	('rs689466', 'Mutation', 'rs689466', (53, 61))	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('rs689466', 'Var', (53, 61))	('COX-2', 'Gene', '5743', (166, 171))	('decrease', 'NegReg', (89, 97))	('rs5275', 'Mutation', 'rs5275', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('COX-2', 'Gene', (36, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('COX-2', 'Gene', '5743', (36, 41))	('lung cancer', 'Disease', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
1353	30170377	A certain number of single-nucleotide polymorphisms (SNPs) in COX-2 gene may affect the susceptibility to lung cancer through their alteration of enzyme function and expression.	('COX-2', 'Gene', (62, 67))	('lung cancer', 'Disease', (106, 117))	('enzyme function', 'MPA', (146, 161))	('COX-2', 'Gene', '5743', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('alteration', 'Reg', (132, 142))	('affect', 'Reg', (77, 83))	('single-nucleotide polymorphisms', 'Var', (20, 51))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('expression', 'MPA', (166, 176))
1354	30170377	The rs689466 polymorphism was revealed to regulate the transcription levels of COX-2, while rs5275 polymorphism may determine the stability of COX-2 mRNA and translation efficiency.	('COX-2', 'Gene', '5743', (79, 84))	('COX-2', 'Gene', '5743', (143, 148))	('COX-2', 'Gene', (143, 148))	('transcription levels', 'MPA', (55, 75))	('rs689466', 'Mutation', 'rs689466', (4, 12))	('translation', 'biological_process', 'GO:0006412', ('158', '169'))	('translation', 'MPA', (158, 169))	('rs689466', 'Var', (4, 12))	('regulate', 'Reg', (42, 50))	('transcription', 'biological_process', 'GO:0006351', ('55', '68'))	('rs5275', 'Var', (92, 98))	('COX-2', 'Gene', (79, 84))	('stability', 'MPA', (130, 139))	('determine', 'Reg', (116, 125))	('rs5275', 'Mutation', 'rs5275', (92, 98))
1355	30170377	Several researches have been published for investigating the connection between rs5275 and rs689466 gene variation and risk of lung cancer, but the outcomes remain controversial.	('rs689466', 'Var', (91, 99))	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('rs5275', 'Var', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rs5275', 'Mutation', 'rs5275', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('rs689466', 'Mutation', 'rs689466', (91, 99))
1360	30170377	The inclusion criteria were: studies with case-control designs; studies evaluating the potential association between rs5275 and rs689466 polymorphism of COX-2 and lung cancer risk; studies with sufficient data to calculate odds ratios (ORs) and 95% confidence interval (95% CI).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('rs5275', 'Var', (117, 123))	('rs5275', 'Mutation', 'rs5275', (117, 123))	('COX-2', 'Gene', (153, 158))	('COX-2', 'Gene', '5743', (153, 158))	('rs689466', 'Mutation', 'rs689466', (128, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('rs689466', 'Var', (128, 136))	('lung cancer', 'Disease', (163, 174))
1362	30170377	The association between COX-2 polymorphism and lung cancer risk was measured by the pooled ORs and 95% CI with fixed-effect model or random-effect model according to the heterogeneity among studies.	('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))	('polymorphism', 'Var', (30, 42))	('COX-2', 'Gene', (24, 29))	('COX-2', 'Gene', '5743', (24, 29))
1363	30170377	For both rs5275 and rs689466 polymorphism, 5 genetic models were established in overall and subgroup analysis: allele model (C vs T and G vs A), homozygote model (CC vs TT and GG vs AA), heterozygote model (CT vs TT and GA vs AA), dominant model (CC + CT vs TT and GG + GA vs AA), and recessive model (CC vs CT + TT and GG vs GA + AA), respectively.	('rs689466', 'Var', (20, 28))	('rs5275', 'Mutation', 'rs5275', (9, 15))	('rs5275', 'Var', (9, 15))	('rs689466', 'Mutation', 'rs689466', (20, 28))
1365	30170377	The stratified analysis by pathological type in rs689466 polymorphism was not mentioned here due to the insufficient data.	('rs689466', 'Var', (48, 56))	('rs689466', 'Mutation', 'rs689466', (48, 56))	('insufficient', 'Disease', (104, 116))	('insufficient', 'Disease', 'MESH:D000309', (104, 116))
1368	30170377	Therefore, there were eventually 14 studies (7 for rs5275 only, 2 for rs689466 only, and 5 for both) containing 6658 cases and 7678 controls eligible for our meta-analysis exploring the association between rs5275 and rs689466 polymorphism of COX-2 and lung cancer risk.	('rs5275', 'Var', (206, 212))	('rs5275', 'Var', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('COX-2', 'Gene', (242, 247))	('rs5275', 'Mutation', 'rs5275', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (252, 263))	('COX-2', 'Gene', '5743', (242, 247))	('rs5275', 'Mutation', 'rs5275', (51, 57))	('rs689466', 'Mutation', 'rs689466', (217, 225))	('rs689466', 'Var', (217, 225))	('rs689466', 'Mutation', 'rs689466', (70, 78))	('lung cancer', 'Disease', (252, 263))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))
1369	30170377	For both rs5275 and rs689466 polymorphism, the results of HWE test in control groups are also listed in Table 1.	('rs689466', 'Var', (20, 28))	('rs5275', 'Mutation', 'rs5275', (9, 15))	('rs5275', 'Var', (9, 15))	('rs689466', 'Mutation', 'rs689466', (20, 28))
1370	30170377	There are 2 studies for rs689466 and 1 for rs5275 not consistent with Hardy-Weinberg equilibrium.	('rs689466', 'Mutation', 'rs689466', (24, 32))	('rs5275', 'Mutation', 'rs5275', (43, 49))	('rs689466', 'Var', (24, 32))	('rs5275', 'Var', (43, 49))
1371	30170377	The genotype distribution and allele frequency of rs5275 and rs689466 of each study are shown in Tables 3 and 4 respectively.	('rs5275', 'Var', (50, 56))	('rs689466', 'Var', (61, 69))	('rs5275', 'Mutation', 'rs5275', (50, 56))	('rs689466', 'Mutation', 'rs689466', (61, 69))
1372	30170377	For rs5275 polymorphism, we found a significantly decreased risk of lung carcinoma under heterozygote model (OR: 0.91, 95% CI: 0.84-0.98, P = .02, I2 = 46.5%, Pheterogeneity = .04) (Fig.	('polymorphism', 'Var', (11, 23))	('rs5275', 'Mutation', 'rs5275', (4, 10))	('lung carcinoma', 'Disease', 'MESH:D008175', (68, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('decreased', 'NegReg', (50, 59))	('lung carcinoma', 'Disease', (68, 82))	('rs5275 polymorphism', 'Var', (4, 23))
1374	30170377	The complete results of subgroup analysis for rs5275 polymorphism are shown in Table 5.	('rs5275', 'Mutation', 'rs5275', (46, 52))	('rs5275', 'Gene', (46, 52))	('polymorphism', 'Var', (53, 65))
1375	30170377	For rs689466 polymorphism, the pooled analysis indicated a significant association of lower risk with lung cancer under allele model (OR: 0.88, 95% CI: 0.82-0.95, P = .001, I2 = 19.7%, Pheterogeneity = .28), homozygote model (OR: 0.81, 95% CI: 0.68-0.95, P = .01, I2 = 0.0%, Pheterogeneity = .43), heterozygote model (OR: 0.81, 95% CI: 0.72-0.91, P < .001, I2 = 48.1%, Pheterogeneity = .07), and dominant model (OR: 0.81, 95% CI: 0.72-0.91, P < .001, I2 = 45.6%, Pheterogeneity = .09), but except for recessive model (OR: 0.91, 95% CI: 0.79-1.04, P = .18, I2 = 0.0%, Pheterogeneity = .74) (Fig.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('rs689466', 'Mutation', 'rs689466', (4, 12))	('rs689466', 'Var', (4, 12))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))
1378	30170377	5), which suggested no evidence of publication bias (Egger test: P = .88 for rs5275, P = .24 for rs689466).	('rs5275', 'Mutation', 'rs5275', (77, 83))	('publication bias', 'Disease', (35, 51))	('publication bias', 'Disease', 'MESH:D065309', (35, 51))	('rs5275', 'Var', (77, 83))	('rs689466', 'Mutation', 'rs689466', (97, 105))	('rs689466', 'Var', (97, 105))
1379	30170377	Many researches focused on the relationship between COX-2 polymorphism and lung cancer risk were reported, however, the conclusion remains controversial.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('COX-2', 'Gene', (52, 57))	('COX-2', 'Gene', '5743', (52, 57))	('polymorphism', 'Var', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
1380	30170377	Of the 12 studies discussing rs5275 polymorphism, 3 studies revealed an increased risk of lung carcinoma, 3 studies revealed a decreased risk, while other 6 studies reported no significant association.	('lung carcinoma', 'Disease', (90, 104))	('lung carcinoma', 'Disease', 'MESH:D008175', (90, 104))	('rs5275 polymorphism', 'Var', (29, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('rs5275', 'Mutation', 'rs5275', (29, 35))	('polymorphism', 'Var', (36, 48))
1381	30170377	Similarly, of the 7 studies discussing rs689466 polymorphism, 4 studies suggested a reduced risk of lung cancer, but 3 studies indicated no significant relationship.	('rs689466', 'Mutation', 'rs689466', (39, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('reduced', 'NegReg', (84, 91))	('lung cancer', 'Disease', (100, 111))	('rs689466 polymorphism', 'Var', (39, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
1382	30170377	Fourteen eligible studies were consolidated to seek the distribution of rs5275 and rs689466 gene polymorphism to lung neoplasm susceptibility.	('lung neoplasm', 'Disease', (113, 126))	('lung neoplasm', 'Phenotype', 'HP:0100526', (113, 126))	('rs5275', 'Var', (72, 78))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('rs5275', 'Mutation', 'rs5275', (72, 78))	('rs689466', 'Mutation', 'rs689466', (83, 91))	('rs689466', 'Var', (83, 91))	('lung neoplasm', 'Disease', 'MESH:D008175', (113, 126))
1383	30170377	The overall analysis revealed that the variant heterozygote of rs5275 polymorphism reduced the risk of lung cancer significantly compared with wild homozygote.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('rs5275', 'Gene', (63, 69))	('reduced', 'NegReg', (83, 90))	('rs5275', 'Mutation', 'rs5275', (63, 69))	('variant', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
1385	30170377	The subgroup analysis by ethnicity indicated a decreased susceptibility of lung cancer in participants with variant allele in Asian population of rs5275 polymorphism under heterozygote model and dominant model.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('variant', 'Var', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rs5275', 'Gene', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('rs5275', 'Mutation', 'rs5275', (146, 152))	('participants', 'Species', '9606', (90, 102))	('decreased', 'NegReg', (47, 56))
1389	30170377	Furthermore, we found the histological type may also influence the correlation between gene mutation and lung cancer risk.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('influence', 'Reg', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('gene mutation', 'Var', (87, 100))	('correlation', 'Interaction', (67, 78))	('lung cancer', 'Disease', (105, 116))
1390	30170377	C allele carriers of rs5275 polymorphism probably have a significantly reduced risk of getting lung adenocarcinoma according to our findings.	('rs5275', 'Var', (21, 27))	('rs5275', 'Mutation', 'rs5275', (21, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('lung adenocarcinoma', 'Disease', (95, 114))	('reduced', 'NegReg', (71, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))
1392	30170377	In the subgroup analysis categorized by source of controls, we also found meaningful differences in population-based group under allele model and dominant model in rs5275 polymorphism, and all models in hospital-based group of rs689466 polymorphism except the recessive model revealed a similar reduced risk.	('rs5275', 'Mutation', 'rs5275', (164, 170))	('rs689466', 'Mutation', 'rs689466', (227, 235))	('rs689466', 'Var', (227, 235))	('rs5275', 'Gene', (164, 170))	('polymorphism', 'Var', (171, 183))
1396	30170377	Gene targeting therapy has been playing a prominent role in treatment of lung cancer for several years, and the very first step of the therapy is to identify the association between gene mutation and lung cancer susceptibility, as well as the mechanism of it.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('lung cancer', 'Disease', (200, 211))	('association', 'Interaction', (162, 173))	('gene mutation', 'Var', (182, 195))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))
1400	30170377	The COX-2 rs5275 is located in 3'untranslated region (3'UTR) containing plentiful AU sequences, which can achieve the regulation of posttranscriptional level and mediate the stability of mRNA through regulating its degradation, and thus, control the enzyme level.	('control', 'Reg', (238, 245))	('stability', 'MPA', (174, 183))	('degradation', 'biological_process', 'GO:0009056', ('215', '226'))	('mRNA', 'MPA', (187, 191))	('enzyme level', 'MPA', (250, 262))	('rs5275', 'Var', (10, 16))	('regulation', 'MPA', (118, 128))	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('degradation', 'MPA', (215, 226))	('rs5275', 'Mutation', 'rs5275', (10, 16))	('COX-2', 'Gene', (4, 9))	('regulating', 'Reg', (200, 210))	('posttranscriptional level', 'MPA', (132, 157))	('COX-2', 'Gene', '5743', (4, 9))
1401	30170377	The COX-2 rs689466 is located in promoter region as a crucial factors of genetic transcription.	('rs689466', 'Mutation', 'rs689466', (10, 18))	('rs689466', 'Var', (10, 18))	('COX-2', 'Gene', (4, 9))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('COX-2', 'Gene', '5743', (4, 9))
1402	30170377	Therefore, the gene mutations of rs5275 and rs689466 may contribute to the carcinogensis of lung cancer by regulation of COX-2 expression mentioned above.	('COX-2', 'Gene', (121, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('rs689466', 'Mutation', 'rs689466', (44, 52))	('carcinogensis of lung cancer', 'Disease', 'MESH:D008175', (75, 103))	('regulation', 'Reg', (107, 117))	('expression', 'MPA', (127, 137))	('rs689466', 'Var', (44, 52))	('contribute', 'Reg', (57, 67))	('COX-2', 'Gene', '5743', (121, 126))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('rs5275', 'Var', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs5275', 'Mutation', 'rs5275', (33, 39))	('carcinogensis of lung cancer', 'Disease', (75, 103))
1404	30170377	Our meta-analysis showed that COX-2 rs689466 polymorphism, especially in Asians, decreases the risk of lung cancer significantly, while COX-2 rs5275 polymorphism may cause a reduced susceptibility to lung cancer to a certain extent with a stronger association in adenocarcinoma cases.	('adenocarcinoma', 'Disease', 'MESH:D000230', (263, 277))	('polymorphism', 'Var', (45, 57))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('COX-2', 'Gene', '5743', (136, 141))	('rs5275', 'Var', (142, 148))	('COX-2', 'Gene', (30, 35))	('rs5275', 'Mutation', 'rs5275', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('COX-2', 'Gene', '5743', (30, 35))	('adenocarcinoma', 'Disease', (263, 277))	('decreases', 'NegReg', (81, 90))	('rs689466', 'Mutation', 'rs689466', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs689466 polymorphism', 'Var', (36, 57))	('COX-2', 'Gene', (136, 141))
1416	30736829	MiR-21-5p knocked down significantly abrogated the cancer-promoting and macrophage M2 polarizing effects of H-EV treatment.	('MiR-21-5p', 'Gene', '406997', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('knocked down', 'Var', (10, 22))	('MiR-21-5p', 'Gene', (0, 9))	('abrogated', 'NegReg', (37, 46))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('H-EV', 'Chemical', '-', (108, 112))
1417	30736829	H-EV treatment downregulated PTEN, PDCD4 and RECK gene expression largely through miR-21-5p.	('PTEN', 'Gene', (29, 33))	('miR-21-5p', 'Var', (82, 91))	('RECK', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (29, 33))	('expression', 'MPA', (55, 65))	('H-EV', 'Chemical', '-', (0, 4))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('PDCD4', 'Gene', (35, 40))	('downregulated', 'NegReg', (15, 28))	('RECK', 'Gene', '8434', (45, 49))	('PDCD4', 'Gene', '27250', (35, 40))
1419	30736829	H-EV co-injection significantly increased tumor growth, cancer cell proliferation, intra-tumoral angiogenesis and M2 polarization of macrophages in vivo partially through miR-21-5p.	('intra-tumoral', 'Disease', (83, 96))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('M2 polarization of macrophages', 'CPA', (114, 144))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miR-21-5p', 'Var', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('H-EV', 'Chemical', '-', (0, 4))	('increased', 'PosReg', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('intra-tumoral', 'Disease', 'MESH:D009369', (83, 96))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('angiogenesis', 'biological_process', 'GO:0001525', ('97', '109'))
1420	30736829	Increased miR-21-5p delivery by MSC-EV after hypoxia pre-challenge can promote lung cancer development by reducing apoptosis and promoting macrophage M2 polarization.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('promote', 'PosReg', (71, 78))	('reducing', 'NegReg', (106, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('macrophage M2 polarization', 'CPA', (139, 165))	('promoting', 'PosReg', (129, 138))	('hypoxia', 'Disease', (45, 52))	('hypoxia', 'Disease', 'MESH:D000860', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pre', 'molecular_function', 'GO:0003904', ('53', '56'))	('apoptosis', 'CPA', (115, 124))	('miR-21-5p delivery', 'Var', (10, 28))
1424	30736829	Previous researches have demonstrated that EV secreted by MSCs (MSC-EV) mediate the anti-inflammatory and cytoprotective effect of MSCs against ischemia-reperfusion injury or other acute injuries in different tissues by inhibiting apoptosis, immune cell-induced cell death and pro-inflammatory response via microRNA delivery.	('MSCs', 'Var', (131, 135))	('apoptosis', 'CPA', (231, 240))	('apoptosis', 'biological_process', 'GO:0097194', ('231', '240'))	('MSCs', 'molecular_function', 'GO:0043854', ('58', '62'))	('ischemia-reperfusion injury', 'Disease', (144, 171))	('apoptosis', 'biological_process', 'GO:0006915', ('231', '240'))	('immune cell-induced cell death', 'CPA', (242, 272))	('MSCs', 'molecular_function', 'GO:0043854', ('131', '135'))	('cell death', 'biological_process', 'GO:0008219', ('262', '272'))	('inhibiting', 'NegReg', (220, 230))	('microRNA delivery', 'MPA', (307, 324))	('inflammatory response', 'biological_process', 'GO:0006954', ('281', '302'))	('pro-inflammatory response', 'CPA', (277, 302))	('ischemia-reperfusion injury', 'Disease', 'MESH:D015427', (144, 171))
1425	30736829	showed that MSC-EV protect cardiomyocytes from apoptosis during myocardial infarction via miR-21-5p transfer, which inhibits the protein expressions of several pro-apoptotic genes such as PTEN, PDCD4 and Fas ligand, while Song et al.	('PDCD4', 'Gene', (194, 199))	('PDCD4', 'Gene', '27250', (194, 199))	('miR-21-5p transfer', 'Var', (90, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('Fas ligand', 'Gene', (204, 214))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('MSC-EV', 'Var', (12, 18))	('myocardial infarction', 'Phenotype', 'HP:0001658', (64, 85))	('ligand', 'molecular_function', 'GO:0005488', ('208', '214'))	('PTEN', 'Gene', (188, 192))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('PTEN', 'Gene', '5728', (188, 192))	('myocardial infarction', 'Disease', (64, 85))	('Fas ligand', 'Gene', '356', (204, 214))	('myocardial infarction', 'Disease', 'MESH:D009203', (64, 85))	('inhibits', 'NegReg', (116, 124))	('protein expressions', 'MPA', (129, 148))
1438	30736829	both reported that miR-21-5p depletion favors the macrophage M1 polarization, enhancing the macrophage-mediated pro-inflammatory and tumoricidal response.	('enhancing', 'PosReg', (78, 87))	('macrophage-mediated pro-inflammatory', 'MPA', (92, 128))	('favors', 'PosReg', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('miR-21-5p depletion', 'Var', (19, 38))	('macrophage M1 polarization', 'CPA', (50, 76))
1474	30736829	Cell proliferation and intra-tumoral angiogenesis was determined by immunohistochemical staining of Ki67 (ab15580, Abcam) and CD31 (ab28364, Abcam), respectively, in xenograft tumor derived tissue section.	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('xenograft tumor', 'Disease', 'MESH:D009369', (166, 181))	('intra-tumoral', 'Disease', 'MESH:D009369', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('angiogenesis', 'biological_process', 'GO:0001525', ('37', '49'))	('intra-tumoral', 'Disease', (23, 36))	('CD31', 'Gene', (126, 130))	('ab15580', 'Var', (106, 113))	('CD31', 'Gene', '5175', (126, 130))	('ab28364', 'Var', (132, 139))	('xenograft tumor', 'Disease', (166, 181))	('Cell proliferation', 'CPA', (0, 18))
1502	30736829	These data suggested that hypoxia challenge could significantly increase miR-21-5p expression level in MSC-EV, and treatment with H-EV could significantly increase miR-21-5p in NSCLC cells primarily by EV delivery but not by induction of miR-21-5p expression in the recipient cells.	('increase', 'PosReg', (155, 163))	('hypoxia', 'Disease', (26, 33))	('miR-21-5p expression level', 'MPA', (73, 99))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('miR-21-5p', 'MPA', (164, 173))	('H-EV', 'Chemical', '-', (130, 134))	('increase', 'PosReg', (64, 72))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('EV delivery', 'Var', (202, 213))
1505	30736829	Trans-well assay results also suggested that increase in A549 and H23 cell mobility by H-EV treatment could be inhibited by miR-21-5p inhibitor transfection in MSCs, A549 or H23 cells.	('miR-21-5p', 'Gene', (124, 133))	('transfection', 'Var', (144, 156))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('H23', 'CellLine', 'CVCL:1547', (174, 177))	('inhibited', 'NegReg', (111, 120))	('MSCs', 'molecular_function', 'GO:0043854', ('160', '164'))	('H-EV', 'Chemical', '-', (87, 91))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('H23', 'CellLine', 'CVCL:1547', (66, 69))	('increase', 'PosReg', (45, 53))
1506	30736829	Western blot results further demonstrated that inhibition of miR-21-5p in either MSCs or NSCLC cells could significantly abrogate the EMT-promoting effect of H-EV on A549 or H23 cells.	('MSCs', 'molecular_function', 'GO:0043854', ('81', '85'))	('EMT', 'biological_process', 'GO:0001837', ('134', '137'))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('EMT-promoting effect', 'CPA', (134, 154))	('inhibition', 'NegReg', (47, 57))	('miR-21-5p', 'Var', (61, 70))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('H-EV', 'Chemical', '-', (158, 162))	('H23', 'CellLine', 'CVCL:1547', (174, 177))	('NSCLC', 'Disease', (89, 94))	('abrogate', 'NegReg', (121, 129))
1512	30736829	These data further confirmed that the effect of H-EV treatment on NSCLC cells is based on miR-21-5p targeting cancer suppressing genes such as PTEN, PDCD4 and RECK.	('cancer', 'Disease', (110, 116))	('PDCD4', 'Gene', '27250', (149, 154))	('NSCLC', 'Disease', (66, 71))	('RECK', 'Gene', '8434', (159, 163))	('H-EV', 'Chemical', '-', (48, 52))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('PTEN', 'Gene', (143, 147))	('RECK', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (143, 147))	('miR-21-5p', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('PDCD4', 'Gene', (149, 154))
1514	30736829	We therefor investigated whether N-EV- and H-EV-induced macrophage M2 polarization is due to miR-21-5p targeting PTEN (Fig.	('H-EV', 'Chemical', '-', (43, 47))	('miR-21-5p targeting', 'Var', (93, 112))	('N-EV', 'Chemical', '-', (33, 37))	('PTEN', 'Gene', (113, 117))	('PTEN', 'Gene', '5728', (113, 117))
1517	30736829	Western blot results further confirmed that macrophage M2 polarization was associated with increased Akt and STAT3 activation, marked by their phosphorylation status, and inhibition of miR-21-5p or PTEN overexpression significantly reduced AKT and STAT3 activation induced by H-EV treatment.	('activation', 'PosReg', (115, 125))	('PTEN', 'Gene', '5728', (198, 202))	('reduced', 'NegReg', (232, 239))	('overexpression', 'PosReg', (203, 217))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('AKT', 'Gene', '207', (240, 243))	('Akt', 'Gene', (101, 104))	('activation', 'PosReg', (254, 264))	('increased', 'PosReg', (91, 100))	('STAT3', 'Gene', (109, 114))	('macrophage M2 polarization', 'CPA', (44, 70))	('Akt', 'Gene', '207', (101, 104))	('H-EV', 'Chemical', '-', (276, 280))	('STAT3', 'Gene', '6774', (109, 114))	('miR-21-5p', 'Gene', (185, 194))	('STAT3', 'Gene', (248, 253))	('inhibition', 'Var', (171, 181))	('AKT', 'Gene', (240, 243))	('PTEN', 'Gene', (198, 202))	('STAT3', 'Gene', '6774', (248, 253))
1518	30736829	These data suggested that N-EV or H-EV treatment induced macrophage M2 polarization by miR-21-5p delivery, which targets PTEN and thus liberates AKT and STAT3 activation.	('liberates', 'NegReg', (135, 144))	('PTEN', 'Gene', (121, 125))	('STAT3', 'Gene', '6774', (153, 158))	('PTEN', 'Gene', '5728', (121, 125))	('AKT', 'Gene', (145, 148))	('miR-21-5p delivery', 'Var', (87, 105))	('STAT3', 'Gene', (153, 158))	('H-EV', 'Chemical', '-', (34, 38))	('induced', 'Reg', (49, 56))	('N-EV', 'Chemical', '-', (26, 30))	('AKT', 'Gene', '207', (145, 148))	('macrophage M2 polarization', 'CPA', (57, 83))
1541	30736829	We further revealed that hypoxia pre-challenge increased miR-21-5p load in MSC-EV, which can be delivered to NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('pre', 'molecular_function', 'GO:0003904', ('33', '36'))	('increased', 'PosReg', (47, 56))	('hypoxia', 'Disease', (25, 32))	('hypoxia', 'Disease', 'MESH:D000860', (25, 32))	('miR-21-5p load', 'Var', (57, 71))	('NSCLC', 'Disease', (109, 114))
1543	30736829	We further confirmed that the cell proliferation and survival-promoting effect of miR-21-5p on NSCLC cells delivered by H-EV is achieved by PTEN and PDCD4 targeting, and upregulation in NSCLC cell mobility by RECK targeting.	('survival-promoting effect', 'CPA', (53, 78))	('PDCD4', 'Gene', '27250', (149, 154))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('cell proliferation', 'CPA', (30, 48))	('miR-21-5p', 'Var', (82, 91))	('upregulation', 'PosReg', (170, 182))	('RECK', 'Gene', (209, 213))	('H-EV', 'Chemical', '-', (120, 124))	('NSCLC', 'Disease', (186, 191))	('PTEN', 'Gene', '5728', (140, 144))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))	('RECK', 'Gene', '8434', (209, 213))	('PTEN', 'Gene', (140, 144))	('NSCLC', 'Disease', (95, 100))	('PDCD4', 'Gene', (149, 154))
1545	30736829	On macrophage differentiation, our data suggested that increased miR-21-5p delivery by MSC-EV after hypoxia pre-challenge can reduce PTEN expression, thus liberating Akt and STAT3 activation and facilitate macrophage M2 polarization.	('macrophage differentiation', 'biological_process', 'GO:0030225', ('3', '29'))	('pre', 'molecular_function', 'GO:0003904', ('108', '111'))	('macrophage M2 polarization', 'CPA', (206, 232))	('reduce', 'NegReg', (126, 132))	('miR-21-5p delivery', 'Var', (65, 83))	('increased', 'PosReg', (55, 64))	('Akt', 'Gene', (166, 169))	('liberating', 'NegReg', (155, 165))	('PTEN', 'Gene', (133, 137))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('STAT3', 'Gene', '6774', (174, 179))	('PTEN', 'Gene', '5728', (133, 137))	('hypoxia', 'Disease', (100, 107))	('Akt', 'Gene', '207', (166, 169))	('STAT3', 'Gene', (174, 179))	('facilitate', 'PosReg', (195, 205))	('activation', 'PosReg', (180, 190))
1554	30736829	Collectively, our data suggested that the cancer promoting effect of EV secreted by hypoxia pre-challenged MSCs was mediated at least partially by miR-21-5p delivery.	('hypoxia', 'Disease', (84, 91))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('miR-21-5p delivery', 'Var', (147, 165))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pre', 'molecular_function', 'GO:0003904', ('92', '95'))	('MSCs', 'molecular_function', 'GO:0043854', ('107', '111'))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
1566	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))
1567	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))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (81, 112))	('> 400,000/mm3', 'Var', (65, 78))	('platelet count', 'MPA', (49, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))
1602	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))
1621	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))
1635	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))
1636	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))
1637	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))	('endometrial carcinoma', 'Disease', (49, 70))	('lymph node metastasis', 'Disease', (169, 190))	('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))	('deep myometrial invasion', 'Disease', (136, 160))	('lymph node metastasis', 'Disease', 'MESH:D009362', (169, 190))	('monocytes > 700/mm3', 'Var', (80, 99))
1638	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))
1662	30615629	Excluding immunotherapeutic agents, which have recently shown significant success in a relatively small subset of patients, the most effective targeted therapies for this diseases were designed to inhibit tyrosine kinase proteins harboring genetic alterations that induce aberrant activation of downstream pathways.	('downstream pathways', 'Pathway', (295, 314))	('tyrosine kinase', 'Gene', (205, 220))	('inhibit', 'NegReg', (197, 204))	('activation', 'PosReg', (281, 291))	('tyrosine kinase', 'Gene', '7294', (205, 220))	('patients', 'Species', '9606', (114, 122))	('genetic alterations', 'Var', (240, 259))
1663	30615629	Among these, the most frequent actionable alterations include EGFR mutations and EML4-ALK fusion events, in ~15% and ~3-7% of LUAD patients, respectively.	('patients', 'Species', '9606', (131, 139))	('EML4', 'Gene', (81, 85))	('EGFR', 'Gene', '1956', (62, 66))	('ALK', 'Gene', '238', (86, 89))	('EML4', 'Gene', '27436', (81, 85))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('ALK', 'Gene', (86, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))
1664	30615629	Yet, while targeted therapy is initially effective in a significant fraction of tumors harboring these genetic alterations, the vast majority of treated patients will either fail to respond or will develop resistance to mono-therapy.	('develop', 'Reg', (198, 205))	('genetic alterations', 'Var', (103, 122))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('resistance', 'MPA', (206, 216))
1737	30615629	This can either be the result of associated genetic or epigenetic alterations in these cell lines or the result of field effects, where multiple genetic alterations or alterations in upstream pathway contribute to the cell line dependency on a specific TK activity.	('epigenetic alterations', 'Var', (55, 77))	('alterations', 'Var', (153, 164))	('TK', 'Gene', '7294', (253, 255))	('alterations', 'Reg', (168, 179))	('contribute', 'Reg', (200, 210))	('upstream pathway', 'Pathway', (183, 199))
1740	30615629	Chromosomal alterations involving ALK translocations and fusion events have been identified in several cancer types including LUAD, diffuse large B-cell lymphomas, neuroblastoma, and inflammatory myofibroblastic tumors, among others.	('lymphomas', 'Disease', (153, 162))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (196, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Disease', (103, 109))	('identified', 'Reg', (81, 91))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (146, 162))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('inflammatory myofibroblastic tumors', 'Disease', (183, 218))	('ALK', 'Gene', '238', (34, 37))	('lymphomas', 'Disease', 'MESH:D008223', (153, 162))	('ALK', 'Gene', (34, 37))	('lymphomas', 'Phenotype', 'HP:0002665', (153, 162))	('fusion events', 'Var', (57, 70))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('neuroblastoma', 'Disease', (164, 177))	('LUAD', 'Disease', (126, 130))	('neuroblastoma', 'Phenotype', 'HP:0003006', (164, 177))	('neuroblastoma', 'Disease', 'MESH:D009447', (164, 177))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (183, 218))
1743	30615629	Interestingly, among all available LUAD cell lines for which a phosphoproteomic profile was available, H2228 was the only one with an established EML4-ALK fusion event and with established sensitivity to ALK inhibitor.	('ALK', 'Gene', (204, 207))	('H2228', 'Var', (103, 108))	('ALK', 'Gene', '238', (204, 207))	('ALK', 'Gene', (151, 154))	('EML4', 'Gene', (146, 150))	('H2228', 'Chemical', '-', (103, 108))	('ALK', 'Gene', '238', (151, 154))	('EML4', 'Gene', '27436', (146, 150))
1751	30615629	To validate pVIPER-predicted, cell line specific EGFR/c-MET synthetic lethality, we selected a panel of 14 cell lines, 11 of which were predicted to be synergistically dependent on EGFR/c-MET (H226, H2122, H1666, H2172, Cal-12T, H2023, H1568, Calu-3, H1650, HCC78, and A549), as well as 3 negative controls with no predicted synergistic or individual dependencies on the two TKs (H2170, H460, and H520).	('H460', 'CellLine', 'CVCL:0459', (387, 391))	('H1650', 'Var', (251, 256))	('HCC78', 'CellLine', 'CVCL:2061', (258, 263))	('H2023', 'Var', (229, 234))	('EGFR', 'Gene', '1956', (181, 185))	('H226', 'Var', (193, 197))	('H1568', 'CellLine', 'CVCL:1476', (236, 241))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('H460', 'Var', (387, 391))	('EGFR', 'Gene', (49, 53))	('VIPER', 'Species', '31156', (13, 18))	('Cal', 'Chemical', 'MESH:C005413', (220, 223))	('c-MET', 'Gene', '4233', (54, 59))	('H2172', 'CellLine', 'CVCL:1537', (213, 218))	('A549', 'CellLine', 'CVCL:0023', (269, 273))	('c-MET', 'Gene', (54, 59))	('Cal', 'Chemical', 'MESH:C005413', (243, 246))	('c-MET', 'Gene', '4233', (186, 191))	('H1666', 'Var', (206, 211))	('TK', 'Gene', '7294', (375, 377))	('EGFR', 'Gene', '1956', (49, 53))	('H2122', 'Var', (199, 204))	('H1568', 'Var', (236, 241))	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('EGFR', 'Gene', (181, 185))	('H2122', 'CellLine', 'CVCL:1531', (199, 204))	('H520', 'Var', (397, 401))	('c-MET', 'Gene', (186, 191))	('H2172', 'Var', (213, 218))	('H2170', 'CellLine', 'CVCL:1535', (380, 385))	('H1666', 'CellLine', 'CVCL:1485', (206, 211))
1755	30615629	For MTT assay, first, cells were treated with EGFR inhibitor (Erlotinib) or MET inhibitor (Crizotinib) individually at various concentrations to identify IC50 (concentration resulting in 50% cell death).	('EGFR', 'Gene', '1956', (46, 50))	('Erlotinib', 'Chemical', 'MESH:D000069347', (62, 71))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('cell death', 'biological_process', 'GO:0008219', ('191', '201'))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('Crizotinib', 'Chemical', 'MESH:D000077547', (91, 101))	('IC50', 'Var', (154, 158))
1757	30615629	Across all 11 cell lines tested in colony formation assay, 8 showed significant sensitivity (Based on half maximal inhibitory concentration, IC50, which represents the concentration of a drug that is required for 50% inhibition) to either individual inhibitors (H226E,C, H2122E, H1666E,C, Cal-12TE, Calu-3E,C, H1650E) or synergistic sensitivity to the combination (HCC78E+C and H2023 E+C) (Fig 4A).	('synergistic sensitivity', 'Reg', (321, 344))	('H2122E', 'SUBSTITUTION', 'None', (271, 277))	('Cal', 'Chemical', 'MESH:C005413', (299, 302))	('Cal', 'Chemical', 'MESH:C005413', (289, 292))	('H1650E', 'SUBSTITUTION', 'None', (310, 316))	('H1666E', 'SUBSTITUTION', 'None', (279, 285))	('formation', 'biological_process', 'GO:0009058', ('42', '51'))	('H226E', 'SUBSTITUTION', 'None', (262, 267))	('H1666E', 'Var', (279, 285))	('H2023 E+C', 'Var', (378, 387))	('sensitivity', 'Reg', (80, 91))	('H2122E', 'Var', (271, 277))	('H226E', 'Var', (262, 267))	('HCC78E+C', 'Var', (365, 373))	('H1650E', 'Var', (310, 316))	('HCC78', 'CellLine', 'CVCL:2061', (365, 370))	('H2023 E', 'Mutation', 'p.H2023E', (378, 385))	('12TE', 'Chemical', '-', (293, 297))
1760	30615629	Several cell lines presented striking sensitivity to either one (H2122E, Cal-12TE, H1650E) or both inhibitors (H226E,C, H1666E,C, Calu-3E,C) in isolation, thus making the assessment of synergistic drug sensitivity difficult.	('sensitivity', 'Reg', (38, 49))	('H1650E', 'SUBSTITUTION', 'None', (83, 89))	('12TE', 'Chemical', '-', (77, 81))	('drug sensitivity', 'Phenotype', 'HP:0020174', (197, 213))	('H2122E', 'SUBSTITUTION', 'None', (65, 71))	('Cal', 'Chemical', 'MESH:C005413', (73, 76))	('H1650E', 'Var', (83, 89))	('Cal', 'Chemical', 'MESH:C005413', (130, 133))	('H226E', 'SUBSTITUTION', 'None', (111, 116))	('H226E', 'Var', (111, 116))	('H2122E', 'Var', (65, 71))	('H1666E', 'SUBSTITUTION', 'None', (120, 126))	('H1666E', 'Var', (120, 126))
1761	30615629	In addition, three EGFRWT cell lines harboring BRAF (Cal-12T and H1666) or KRAS (H2122) mutations were also highly sensitive to Erlotinib as a single agent, as predicted by pVIPER, despite the fact that KRAS pathway mutations are mutually exclusive with EGFR mutations and predictive of Erlotinib resistance (Fig 4B).	('KRAS', 'Gene', '3845', (203, 207))	('mutations', 'Var', (88, 97))	('Erlotinib resistance', 'MPA', (287, 307))	('VIPER', 'Species', '31156', (174, 179))	('Erlotinib', 'Chemical', 'MESH:D000069347', (128, 137))	('EGFR', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (75, 79))	('KRAS', 'Gene', (203, 207))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('H1666', 'CellLine', 'CVCL:1485', (65, 70))	('KRAS', 'Gene', (75, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('254', '258'))	('EGFR', 'Gene', (254, 258))	('mutations', 'Var', (259, 268))	('EGFR', 'Gene', '1956', (19, 23))	('Cal', 'Chemical', 'MESH:C005413', (53, 56))	('sensitive', 'MPA', (115, 124))	('H2122', 'CellLine', 'CVCL:1531', (81, 86))	('Erlotinib', 'Chemical', 'MESH:D000069347', (287, 296))	('mutations', 'Var', (216, 225))	('EGFR', 'Gene', '1956', (254, 258))
1764	30615629	To evaluate the short-term interaction between EGFR and c-MET, we performed MTT assay across 11 cell lines (HCC78, H2023, H1650, Calu-3, H2172, H2122, H1568, A549, H1666, H520 and H2170) including 2 negative control cell lines (H520 and H2170).	('H2170', 'CellLine', 'CVCL:1535', (180, 185))	('H1568', 'CellLine', 'CVCL:1476', (151, 156))	('H1666', 'CellLine', 'CVCL:1485', (164, 169))	('c-MET', 'Gene', '4233', (56, 61))	('EGFR', 'Gene', '1956', (47, 51))	('HCC78', 'CellLine', 'CVCL:2061', (108, 113))	('c-MET', 'Gene', (56, 61))	('H1650', 'Var', (122, 127))	('H2172', 'CellLine', 'CVCL:1537', (137, 142))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('H2172', 'Var', (137, 142))	('H1568', 'Var', (151, 156))	('H2023', 'Var', (115, 120))	('EGFR', 'Gene', (47, 51))	('H2122', 'Var', (144, 149))	('H2122', 'CellLine', 'CVCL:1531', (144, 149))	('H1666', 'Var', (164, 169))	('Cal', 'Chemical', 'MESH:C005413', (129, 132))	('H2170', 'Var', (180, 185))	('MTT', 'Chemical', 'MESH:C070243', (76, 79))	('H2170', 'CellLine', 'CVCL:1535', (237, 242))
1766	30615629	However, for two cell lines, H1666 and H2170 (a negative control), results were inconsistent between long term colony formation and MTT assays.	('H1666', 'CellLine', 'CVCL:1485', (29, 34))	('H1666', 'Var', (29, 34))	('H2170', 'Var', (39, 44))	('H2170', 'CellLine', 'CVCL:1535', (39, 44))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('MTT', 'Chemical', 'MESH:C070243', (132, 135))
1772	30615629	Conversely, when predictions were not based on either phosphotyrosine, cells exhibited no sensitivity to the individual inhibitors or the combination (H2172, H226, A549, H460, H520, H1568).	('A549', 'CellLine', 'CVCL:0023', (164, 168))	('H460', 'CellLine', 'CVCL:0459', (170, 174))	('H226', 'Var', (158, 162))	('A549', 'Var', (164, 168))	('H1568', 'CellLine', 'CVCL:1476', (182, 187))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (54, 69))	('H460', 'Var', (170, 174))	('H1568', 'Var', (182, 187))	('H2172', 'CellLine', 'CVCL:1537', (151, 156))	('H2172', 'Var', (151, 156))	('H520', 'Var', (176, 180))
1773	30615629	Thus, predictions based on these two phosphosites produced no false positives (6 out of 6 predicted and validated as non-sensitive) and only 2 false negatives (H2170 and H2122), resulting in an error rate of only 2 out of 14 cell lines (14%, p = 0.0093 using fisher exact test).	('false', 'biological_process', 'GO:0071877', ('143', '148'))	('H2170', 'Var', (160, 165))	('false', 'biological_process', 'GO:0071878', ('62', '67'))	('H2170', 'CellLine', 'CVCL:1535', (160, 165))	('false', 'biological_process', 'GO:0071877', ('62', '67'))	('H2122', 'Var', (170, 175))	('H2122', 'CellLine', 'CVCL:1531', (170, 175))	('phosphosite', 'Chemical', '-', (37, 48))	('false', 'biological_process', 'GO:0071878', ('143', '148'))
1781	30615629	Of these, 5 harbored EGFR mutations, while the remaining 7 patients had not been tested for this mutation, showing a high consistency between our predictions and the genetic predisposition for sensitivity to EGFR inhibitors.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (208, 212))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (59, 67))	('EGFR', 'Gene', (208, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))	('harbored', 'Reg', (12, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))
1782	30615629	In the entire cohort, there were only 3 patients with EGFR mutations that were not identified as EGFR dependent by pVIPER, resulting in an overall sensitivity of 62.5% (5/8).	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('EGFR', 'Gene', '1956', (97, 101))	('patients', 'Species', '9606', (40, 48))	('VIPER', 'Species', '31156', (116, 121))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (54, 58))	('mutations', 'Var', (59, 68))	('EGFR', 'Gene', (54, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
1783	30615629	However, it is well known from literature that >50% of patients harboring EGFR mutations do not respond to Erlotinib suggesting that these may not be false negatives but rather patients with low activation of downstream EGFR pathways, despite their EGFRMut state.	('EGFR', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (220, 224))	('false', 'biological_process', 'GO:0071878', ('150', '155'))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('patients', 'Species', '9606', (177, 185))	('Erlotinib', 'Chemical', 'MESH:D000069347', (107, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('220', '224'))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (249, 253))	('patients', 'Species', '9606', (55, 63))	('false', 'biological_process', 'GO:0071877', ('150', '155'))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('respond', 'MPA', (96, 103))
1788	30615629	An independent study in a cohort of 83 lung cancer specimens found that silencing of DDR1 in these samples leads to the hampering of cell survival, reduced invasiveness in collagen matrices, increased apoptosis in basal condition and decreased metastatic activity in model of tumor metastasis to bone, signifying it as a potential novel therapeutic target.	('silencing', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('collagen', 'molecular_function', 'GO:0005202', ('172', '180'))	('DDR1', 'Gene', '780', (85, 89))	('tumor metastasis to bone', 'Phenotype', 'HP:0010622', (276, 300))	('lung cancer', 'Disease', (39, 50))	('apoptosis', 'CPA', (201, 210))	('invasiveness in collagen matrices', 'CPA', (156, 189))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('cell survival', 'CPA', (133, 146))	('tumor metastasis', 'Disease', 'MESH:D009362', (276, 292))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('decreased', 'NegReg', (234, 243))	('reduced', 'NegReg', (148, 155))	('increased', 'PosReg', (191, 200))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('hampering', 'NegReg', (120, 129))	('DDR1', 'Gene', (85, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('tumor metastasis', 'Disease', (276, 292))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
1803	30615629	It is important to note that clinically, only patients with base-pair deletion at exon 19 (del746_A750) or a point mutation at exon 21 mutation (L858R) in EGFR shows sensitivity to EGFR inhibitor such as Cetuximab or Erlotinib.	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('Erlotinib', 'Chemical', 'MESH:D000069347', (217, 226))	('patients', 'Species', '9606', (46, 54))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', '1956', (155, 159))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('Cetuximab', 'Chemical', 'MESH:D000068818', (204, 213))	('EGFR', 'Gene', '1956', (181, 185))	('EGFR', 'Gene', (155, 159))	('L858R', 'Var', (145, 150))	('L858R', 'Mutation', 'rs121434568', (145, 150))	('sensitivity', 'MPA', (166, 177))	('del746_A750', 'Var', (91, 102))
1867	30205969	Criteria to identify significantly different proteins included p-value < 0.05, minimum +- 0.1 log2 abundance change between comparisons and quantified in at least 50 patient pairs per protein.	('p-value <', 'Var', (63, 72))	('patient', 'Species', '9606', (166, 173))	('minimum +-', 'Var', (79, 89))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))
1900	30205969	Inhibition of heparanase prevented neutrophil adhesion and attenuated sepsis induced acute lung injury in mice.	('attenuated sepsis induced acute lung injury', 'Disease', 'MESH:D055371', (59, 102))	('mice', 'Species', '10090', (106, 110))	('neutrophil adhesion', 'CPA', (35, 54))	('heparanase', 'Protein', (14, 24))	('prevented', 'NegReg', (25, 34))	('sepsis', 'Phenotype', 'HP:0100806', (70, 76))	('Inhibition', 'Var', (0, 10))	('attenuated sepsis induced acute lung injury', 'Disease', (59, 102))
1935	29934362	Any deregulation of this core group of enzymes often leads to cancer development.	('deregulation', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('men', 'Species', '9606', (76, 79))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('core', 'cellular_component', 'GO:0019013', ('25', '29'))	('leads to', 'Reg', (53, 61))
1937	29934362	An exciting really interesting new gene (RING) family of E3 ubiquitin ligases, known as RNF20 and RNF40, monoubiquitinates histone H2A at K119 or H2B at K120, is known to function in transcriptional elongation, DNA double-strand break (DSB) repair processes, maintenance of chromatin differentiation, and exerting tumor suppressor activity.	('RNF40', 'Gene', (98, 103))	('K120', 'Chemical', '-', (153, 157))	('at K120', 'Var', (150, 157))	('tumor', 'Disease', (314, 319))	('H2A', 'Gene', '8337', (131, 134))	('H2B', 'Gene', (146, 149))	('function', 'Reg', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('chromatin', 'cellular_component', 'GO:0000785', ('274', '283'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('314', '330'))	('RNF40', 'Gene', '9810', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('monoubiquitinates', 'Var', (105, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('314', '330'))	('H2A', 'Gene', (131, 134))	('H2B', 'Gene', '8349', (146, 149))	('transcriptional elongation', 'CPA', (183, 209))	('ubiquitin', 'molecular_function', 'GO:0031386', ('60', '69'))
1945	29934362	Recent advances in research and technology have identified additional inherent risk factors that may or may not be heritable, which range from cellular allelic mutations, somatic mutations, accumulating mutations such as hot spot mutation, homozygous gene deletion, or gene amplification, non-synonymous single nucleotide polymorphisms, inflammatory tumor microenvironment, angiogenesis, and epigenetic alterations in the genome of normal cells that transforms them into cancer cells with characteristic properties such as uncontrolled cell proliferation, and are associated with invasive and metastatic potential.	('epigenetic alterations', 'Var', (392, 414))	('cell proliferation', 'biological_process', 'GO:0008283', ('536', '554'))	('men', 'Species', '9606', (368, 371))	('cancer', 'Phenotype', 'HP:0002664', (471, 477))	('uncontrolled cell proliferation', 'CPA', (523, 554))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('mutations', 'Var', (203, 212))	('angiogenesis', 'biological_process', 'GO:0001525', ('374', '386'))	('associated with', 'Reg', (564, 579))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('cancer', 'Disease', 'MESH:D009369', (471, 477))	('cancer', 'Disease', (471, 477))	('tumor', 'Disease', (350, 355))
1946	29934362	The epigenetic impact in cancer development is yet a largely unexplored area and it is potentially an evolving strategy to counter the development and progression of cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('men', 'Species', '9606', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('men', 'Species', '9606', (39, 42))	('cancer', 'Disease', (25, 31))	('epigenetic impact', 'Var', (4, 21))
1947	29934362	Several studies have indicated that cancer cells are often associated with modifications or alterations in their chromatin landscape and are associated with DNA replication and repair.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('associated', 'Reg', (59, 69))	('chromatin landscape', 'MPA', (113, 132))	('associated', 'Reg', (141, 151))	('alterations', 'Reg', (92, 103))	('DNA replication', 'biological_process', 'GO:0006260', ('157', '172'))	('chromatin', 'cellular_component', 'GO:0000785', ('113', '122'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('modifications', 'Var', (75, 88))
1957	29934362	Several studies have demonstrated that modifications such as addition or deletion on DNA and/or histones by methylation, acetylation, SUMOylation, ADP ribosylation, ubiquitination, phosphorylation, and several other modifications on histone serine, threonine, and lysine residues or the DNA itself by specific enzymes regulating several processes such as maintaining cell identity, cell cycle regulation, proliferation, and genome integrity.	('DNA', 'cellular_component', 'GO:0005574', ('287', '290'))	('addition', 'Var', (61, 69))	('deletion', 'Var', (73, 81))	('genome integrity', 'CPA', (424, 440))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('serine', 'Chemical', 'MESH:D012694', (241, 247))	('modifications', 'Var', (39, 52))	('cell identity', 'CPA', (367, 380))	('SUMOylation', 'biological_process', 'GO:0016925', ('134', '145'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('382', '403'))	('phosphorylation', 'MPA', (181, 196))	('threonine', 'Chemical', 'MESH:D013912', (249, 258))	('acetylation', 'MPA', (121, 132))	('DNA', 'Gene', (85, 88))	('lysine', 'Chemical', 'MESH:D008239', (264, 270))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('ubiquitination', 'MPA', (165, 179))	('cell cycle regulation', 'CPA', (382, 403))	('proliferation', 'CPA', (405, 418))
1960	29934362	Deregulated epigenetic changes have been associated with the development of several diseases including chronic inflammation-driven cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('inflammation', 'biological_process', 'GO:0006954', ('111', '123'))	('Deregulated epigenetic changes', 'Var', (0, 30))	('inflammation-driven cancers', 'Disease', 'MESH:D007249', (111, 138))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('inflammation-driven cancers', 'Disease', (111, 138))	('men', 'Species', '9606', (68, 71))
1961	29934362	In cancer cells, numerous epigenetic alterations are observed in genes regulating cell cycle, oncogenes, tumor suppressor genes, and apoptosis related genes, such as aberrant methylation or acetylation of the histones and/or DNA.	('methylation', 'biological_process', 'GO:0032259', ('175', '186'))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('acetylation', 'MPA', (190, 201))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('DNA', 'cellular_component', 'GO:0005574', ('225', '228'))	('histones', 'Protein', (209, 217))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('tumor', 'Disease', (105, 110))	('cell', 'CPA', (82, 86))	('aberrant methylation', 'Var', (166, 186))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('apoptosis related genes', 'Gene', (133, 156))	('epigenetic alterations', 'Var', (26, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
1966	29934362	H2A monoubiquitination on K119 plays a role in transcriptional silencing of polycomb proteins and in genome maintenance compared with H2B, which is ubiquitinated at K120.	('H2B', 'Gene', (134, 137))	('polycomb proteins', 'Protein', (76, 93))	('H2A', 'Gene', (0, 3))	('H2B', 'Gene', '8349', (134, 137))	('K120', 'Chemical', '-', (165, 169))	('transcriptional', 'MPA', (47, 62))	('genome maintenance', 'CPA', (101, 119))	('silencing', 'NegReg', (63, 72))	('H2A', 'Gene', '8337', (0, 3))	('monoubiquitination', 'Var', (4, 22))
1970	29934362	In eukaryotic cells, RNF20/RNF40 can exclusively monoubiquitinate K120 on histone H2B.	('monoubiquitinate', 'MPA', (49, 65))	('histone H2B', 'Protein', (74, 85))	('RNF40', 'Gene', (27, 32))	('RNF40', 'Gene', '9810', (27, 32))	('K120', 'Var', (66, 70))	('K120', 'Chemical', '-', (66, 70))
1974	29934362	Aberrant H2Bub1 is the key to initiation of malignant transformation and directly influences chromatin structure beyond the level of the single nucleosome.	('influences', 'Reg', (82, 92))	('Aberrant', 'Var', (0, 8))	('H2Bub1', 'Gene', '8349', (9, 15))	('nucleosome', 'cellular_component', 'GO:0000786', ('144', '154'))	('malignant transformation', 'CPA', (44, 68))	('chromatin structure', 'MPA', (93, 112))	('H2Bub1', 'Gene', (9, 15))	('chromatin', 'cellular_component', 'GO:0000785', ('93', '102'))
1976	29934362	Deregulation in any of these process leads to the development of tumors, as evidenced with hypermethylation of RNF20 promoters in breast tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RNF20', 'Gene', (111, 116))	('Deregulation', 'Var', (0, 12))	('breast tumor', 'Phenotype', 'HP:0100013', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('hypermethylation', 'Var', (91, 107))	('breast tumor', 'Disease', 'MESH:D001943', (130, 142))	('men', 'Species', '9606', (57, 60))	('leads to', 'Reg', (37, 45))	('breast tumor', 'Disease', (130, 142))
1977	29934362	Mutations in cell division cycle 73 (CDC73) lead to loss of maintenance of H2Bub1 PTM both in vitro and in vivo.	('loss', 'NegReg', (52, 56))	('H2Bub1', 'Gene', (75, 81))	('CDC73', 'Gene', (37, 42))	('PTM', 'biological_process', 'GO:0043687', ('82', '85'))	('CDC73', 'Gene', '79577', (37, 42))	('Mutations', 'Var', (0, 9))	('maintenance of', 'MPA', (60, 74))	('H2Bub1', 'Gene', '8349', (75, 81))	('cell division cycle', 'biological_process', 'GO:0007049', ('13', '32'))
1978	29934362	Abnormally regulated or mutated CDC73 has been reported in several tumors such as breast, colorectal, gastric, parathyroid, renal, and in patients with familial disorder-hyperparathyroidism jaw tumor syndrome.	('mutated', 'Var', (24, 31))	('parathyroid', 'Disease', (111, 122))	('patients', 'Species', '9606', (138, 146))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (170, 189))	('gastric', 'Disease', (102, 109))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('jaw tumor', 'Phenotype', 'HP:0030792', (190, 199))	('renal', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CDC73', 'Gene', (32, 37))	('CDC73', 'Gene', '79577', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('familial disorder-hyperparathyroidism jaw tumor syndrome', 'Disease', 'MESH:C563273', (152, 208))	('colorectal', 'Disease', (90, 100))	('tumors', 'Disease', (67, 73))	('reported', 'Reg', (47, 55))	('breast', 'Disease', (82, 88))
1980	29934362	Deregulated expression and hyperactivation of deubiquitination enzymes also upset the overall expression of H2Bub1.	('hyperactivation of deubiquitination', 'Disease', (27, 62))	('Deregulated', 'Var', (0, 11))	('H2Bub1', 'Gene', '8349', (108, 114))	('H2Bub1', 'Gene', (108, 114))	('deubiquitination', 'biological_process', 'GO:0016579', ('46', '62'))	('expression', 'MPA', (94, 104))	('upset', 'Reg', (76, 81))	('expression', 'MPA', (12, 22))	('hyperactivation of deubiquitination', 'Disease', 'MESH:D011504', (27, 62))
2000	29934362	(2016) showed that RNF20 depletion with a concomitant reduction in H2Bub1 augments tumor necrosis factor-induced activation of NF-kappaB and its subsequent pro-inflammatory cytokine and chemokine genes.	('tumor', 'Disease', (83, 88))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('RNF20', 'Gene', (19, 24))	('necrosis', 'biological_process', 'GO:0070265', ('89', '97'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('necrosis', 'biological_process', 'GO:0019835', ('89', '97'))	('necrosis', 'Disease', (89, 97))	('necrosis', 'biological_process', 'GO:0001906', ('89', '97'))	('activation', 'PosReg', (113, 123))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('113', '136'))	('H2Bub1', 'Gene', '8349', (67, 73))	('NF-kappaB', 'Gene', (127, 136))	('H2Bub1', 'Gene', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('augments', 'PosReg', (74, 82))	('pro-inflammatory cytokine', 'MPA', (156, 181))	('NF-kappaB', 'Gene', '4790', (127, 136))	('men', 'Species', '9606', (77, 80))	('depletion', 'Var', (25, 34))	('necrosis', 'biological_process', 'GO:0008219', ('89', '97'))	('reduction', 'NegReg', (54, 63))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('83', '104'))	('necrosis', 'biological_process', 'GO:0008220', ('89', '97'))
2002	29934362	In vivo RNF20+/- mice were shown to be predisposed to acute and chronic colonic inflammation and development of colorectal cancer.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colonic inflammation', 'Disease', 'MESH:D007249', (72, 92))	('mice', 'Species', '10090', (17, 21))	('colonic inflammation', 'Disease', (72, 92))	('men', 'Species', '9606', (104, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('inflammation', 'biological_process', 'GO:0006954', ('80', '92'))	('chronic colonic inflammation', 'Phenotype', 'HP:0100281', (64, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('predisposed', 'Reg', (39, 50))	('RNF20+/-', 'Var', (8, 16))
2004	29934362	Genetic instability has been identified to play a critical role in the development of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('Genetic instability', 'Var', (0, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('men', 'Species', '9606', (78, 81))
2005	29934362	(2008) for the first time identified five genes SMC1L1 (two independent mutations), CSPG6, NIPBL, STAG3, and RNF20 involved in sister chromatid cohesion and mutations in these genes can lead to chromosome instability in colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('127', '152'))	('CSPG6', 'Gene', (84, 89))	('chromosome instability', 'Phenotype', 'HP:0040012', (194, 216))	('chromatid', 'cellular_component', 'GO:0005694', ('134', '143'))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('SMC1L1', 'Gene', (48, 54))	('mutations', 'Var', (157, 166))	('colorectal cancers', 'Disease', (220, 238))	('SMC1L1', 'Gene', '8243', (48, 54))	('STAG3', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('chromatid', 'cellular_component', 'GO:0005695', ('134', '143'))	('NIPBL', 'Gene', '25836', (91, 96))	('NIPBL', 'Gene', (91, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('194', '204'))	('lead to', 'Reg', (186, 193))	('chromosome instability', 'CPA', (194, 216))	('STAG3', 'Gene', '10734', (98, 103))	('SMC', 'cellular_component', 'GO:0016029', ('48', '51'))	('colorectal cancers', 'Disease', 'MESH:D015179', (220, 238))	('CSPG6', 'Gene', '9126', (84, 89))	('RNF20', 'Gene', (109, 114))
2009	29934362	The RNF20/40 heterodimeric complex is a known major E3 ligase that is responsible for H2Bub1 on K120 and also facilitates H3 methylation on K4 and K79, thereby regulating transcription.	('transcription', 'MPA', (171, 184))	('methylation', 'biological_process', 'GO:0032259', ('125', '136'))	('regulating', 'Reg', (160, 170))	('H2Bub1', 'Gene', '8349', (86, 92))	('facilitates', 'PosReg', (110, 121))	('H2Bub1', 'Gene', (86, 92))	('K120', 'Var', (96, 100))	('K79', 'Gene', (147, 150))	('K79', 'Gene', '338785', (147, 150))	('K120', 'Chemical', '-', (96, 100))	('transcription', 'biological_process', 'GO:0006351', ('171', '184'))
2013	29934362	Furthermore, athymic nude mice receiving MCF-7 cells infected by lentiviruses carrying empty vectors or MCF-7 cells with lentivirus-delivered Eg5, RNF20, or RNF40 knockdown, the tumor growth was significantly suppressed compared with control mice, suggesting that an RNF20/40-Eg5 axis is involved in breast carcinogenesis.	('RNF20', 'Gene', (147, 152))	('RNF40', 'Gene', '9810', (157, 162))	('tumor', 'Disease', (178, 183))	('RNF40', 'Gene', (157, 162))	('knockdown', 'Var', (163, 172))	('suppressed', 'NegReg', (209, 219))	('MCF-7', 'CellLine', 'CVCL:0031', (41, 46))	('breast carcinogenesis', 'Disease', (300, 321))	('MCF-7', 'CellLine', 'CVCL:0031', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('nude mice', 'Species', '10090', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mice', 'Species', '10090', (242, 246))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (300, 321))	('mice', 'Species', '10090', (26, 30))
2018	29934362	RNF20 knockdown significantly reduces H2Bub1 expression and promotes migration in both breast cancer cells and in non-transformed mammary epithelial cells.	('promotes', 'PosReg', (60, 68))	('H2Bub1', 'Gene', '8349', (38, 44))	('H2Bub1', 'Gene', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (45, 55))	('breast cancer', 'Disease', (87, 100))	('reduces', 'NegReg', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('knockdown', 'Var', (6, 15))	('RNF20', 'Gene', (0, 5))	('migration', 'CPA', (69, 78))
2020	29934362	Silencing of RNF20 in breast cancer cells can function as a tumor promoter.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RNF20', 'Gene', (13, 18))	('tumor', 'Disease', (60, 65))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
2021	29934362	It was found that depletion of RNF20 increased breast cancer cell proliferation and migration potential.	('RNF20', 'Gene', (31, 36))	('breast cancer', 'Disease', (47, 60))	('migration potential', 'CPA', (84, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('depletion', 'Var', (18, 27))	('increased', 'PosReg', (37, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
2022	29934362	It is of note that RNF20 promotes CpG island hypermethylation in several breast cancers and that down-regulation of H2B ubiquitination promotes tumorigenesis.	('H2B', 'Gene', (116, 119))	('down-regulation', 'NegReg', (97, 112))	('RNF20', 'Gene', (19, 24))	('ubiquitination', 'MPA', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('regulation', 'biological_process', 'GO:0065007', ('102', '112'))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('tumor', 'Disease', (144, 149))	('hypermethylation', 'Var', (45, 61))	('promotes', 'PosReg', (25, 33))	('H2B', 'Gene', '8349', (116, 119))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('promotes', 'PosReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CpG island', 'Protein', (34, 44))
2023	29934362	In NIH3T3 mouse cells, RNF20 silencing up-regulated formation of colonies in soft agar, indicating neoplastic transformation of cells.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('mouse', 'Species', '10090', (10, 15))	('agar', 'Chemical', 'MESH:D000362', (82, 86))	('NIH3T3', 'CellLine', 'CVCL:0594', (3, 9))	('silencing', 'Var', (29, 38))	('colon', 'Disease', (65, 70))	('RNF20', 'Gene', (23, 28))	('up-regulated', 'PosReg', (39, 51))	('neoplastic transformation', 'CPA', (99, 124))	('colon', 'Disease', 'MESH:D015179', (65, 70))
2025	29934362	The mixed-lineage leukemia (MLL) proto-oncogene MLL1 was found to be involved in chromosomal translocations occurring frequently in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), infant acute leukemia, and in patients treated with topoisomerase II inhibitors.	('ALL', 'Phenotype', 'HP:0006721', (192, 195))	('leukemia', 'Disease', 'MESH:D007938', (18, 26))	('MLL1', 'Gene', '4297', (48, 52))	('leukemia', 'Disease', (18, 26))	('chromosomal translocations', 'Var', (81, 107))	('acute leukemia', 'Phenotype', 'HP:0002488', (205, 219))	('MLL1', 'Gene', (48, 52))	('leukemia', 'Phenotype', 'HP:0001909', (182, 190))	('patients', 'Species', '9606', (228, 236))	('MLL', 'Gene', (48, 51))	('acute lymphoblastic leukemia', 'Disease', (162, 190))	('MLL', 'Gene', '4297', (48, 51))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (162, 190))	('acute myeloid leukemia', 'Disease', (132, 154))	('leukemia', 'Disease', 'MESH:D007938', (182, 190))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (162, 190))	('involved', 'Reg', (69, 77))	('leukemia', 'Disease', (182, 190))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('250', '266'))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (138, 154))	('leukemia', 'Disease', (211, 219))	('leukemia', 'Disease', 'MESH:D007938', (211, 219))	('AML', 'Disease', 'MESH:D015470', (156, 159))	('AML', 'Phenotype', 'HP:0004808', (156, 159))	('AML', 'Disease', (156, 159))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (132, 154))	('MLL', 'Gene', (28, 31))	('infant', 'Species', '9606', (198, 204))	('MLL', 'Gene', '4297', (28, 31))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('leukemia', 'Disease', (146, 154))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (168, 190))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (132, 154))
2026	29934362	MLL rearrangements initiate aggressive forms of acute leukemia and are associated with poor outcome.	('leukemia', 'Disease', (54, 62))	('acute leukemia', 'Phenotype', 'HP:0002488', (48, 62))	('rearrangements', 'Var', (4, 18))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('MLL', 'Gene', '4297', (0, 3))	('MLL', 'Gene', (0, 3))	('initiate', 'Reg', (19, 27))	('men', 'Species', '9606', (13, 16))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))
2029	29934362	Suppression of RNF20 slowed down leukemia progression in an in vivo animal model and was associated with down-regulation of the MLL-AF9 target gene.	('down-regulation', 'NegReg', (105, 120))	('slowed down', 'NegReg', (21, 32))	('Suppression', 'Var', (0, 11))	('MLL', 'Gene', '4297', (128, 131))	('RNF20', 'Gene', (15, 20))	('AF9', 'Gene', '4300', (132, 135))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('MLL', 'Gene', (128, 131))	('AF9', 'Gene', (132, 135))	('leukemia', 'Phenotype', 'HP:0001909', (33, 41))	('leukemia', 'Disease', 'MESH:D007938', (33, 41))	('leukemia', 'Disease', (33, 41))
2040	29934362	In a previous study, it was shown that RNF20 and RNF40 interact with androgen receptor and modulate its transcritpional activity in androgen-dependent LNCaP prostate cancer cells, and depletion of RNF20 or RNF40 is strongly correlated with inhibition of LNCaP cell proliferation and a reduction in H2Bub1 levels.	('inhibition', 'NegReg', (240, 250))	('reduction', 'NegReg', (285, 294))	('RNF20', 'Var', (197, 202))	('interact', 'Interaction', (55, 63))	('modulate', 'Reg', (91, 99))	('RNF40', 'Gene', '9810', (206, 211))	('LNCaP', 'CellLine', 'CVCL:0395', (151, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('260', '278'))	('androgen receptor', 'Gene', (69, 86))	('transcritpional activity', 'MPA', (104, 128))	('androgen receptor', 'Gene', '367', (69, 86))	('RNF40', 'Gene', (49, 54))	('depletion', 'Var', (184, 193))	('H2Bub1', 'Gene', '8349', (298, 304))	('H2Bub1', 'Gene', (298, 304))	('RNF20', 'Gene', (39, 44))	('LNCaP cell proliferation', 'CPA', (254, 278))	('RNF40', 'Gene', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('LNCaP prostate cancer', 'Disease', (151, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('RNF40', 'Gene', '9810', (49, 54))	('LNCaP', 'CellLine', 'CVCL:0395', (254, 259))	('LNCaP prostate cancer', 'Disease', 'MESH:D011471', (151, 172))
2043	29934362	Using human lung cancer A549, H1299, and H460 cell lines, and normal lung epithelial cells, suppression of H2Bub1 by RNF20 knockdown was associated with significant decrease in H3K4 and H3K79 trimethylation.	('lung cancer A549', 'Disease', (12, 28))	('RNF20', 'Gene', (117, 122))	('human', 'Species', '9606', (6, 11))	('H3K4', 'Protein', (177, 181))	('H460', 'CellLine', 'CVCL:0459', (41, 45))	('H2Bub1', 'Gene', '8349', (107, 113))	('decrease', 'NegReg', (165, 173))	('trimethylation', 'MPA', (192, 206))	('lung cancer A549', 'Disease', 'MESH:D008175', (12, 28))	('H1299', 'CellLine', 'CVCL:0060', (30, 35))	('K79', 'Gene', (188, 191))	('suppression', 'NegReg', (92, 103))	('H2Bub1', 'Gene', (107, 113))	('K79', 'Gene', '338785', (188, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('knockdown', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
2044	29934362	It was also observed that RNF20 knockdown and down-regulation of H2Bub1 affect several cellular signaling pathways and enhanced proliferation, migration, invasion, and cisplatin resistance of these cells.	('cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('affect', 'Reg', (72, 78))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('down-regulation', 'NegReg', (46, 61))	('H2Bub1', 'Gene', '8349', (65, 71))	('knockdown', 'Var', (32, 41))	('cisplatin resistance', 'CPA', (168, 188))	('cellular signaling pathways', 'Pathway', (87, 114))	('invasion', 'CPA', (154, 162))	('proliferation', 'CPA', (128, 141))	('H2Bub1', 'Gene', (65, 71))	('RNF20', 'Gene', (26, 31))	('migration', 'CPA', (143, 152))	('enhanced', 'PosReg', (119, 127))
2046	29934362	The present study, has for the first time demonstrated that loss of H2Bub1 is associated with enhanced malignancy and poor differentiation of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('poor differentiation', 'CPA', (118, 138))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('H2Bub1', 'Gene', (68, 74))	('malignancy', 'Disease', (103, 113))	('lung adenocarcinoma', 'Disease', (142, 161))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (142, 161))	('loss', 'Var', (60, 64))	('enhanced', 'PosReg', (94, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (142, 161))	('H2Bub1', 'Gene', '8349', (68, 74))
2061	29934362	In addition, tumor-associated mutant p53 has been shown to bind and transcriptionally activate SREBP2 and activate the mevalonate pathway; it is highly possible that p53 and SREBPs may potentially regulate each other.	('tumor', 'Disease', (13, 18))	('mevalonate', 'Chemical', 'MESH:D008798', (119, 129))	('SREBP', 'Gene', (95, 100))	('SREBP', 'Gene', (174, 179))	('activate', 'PosReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('SREBP', 'Gene', '7555', (95, 100))	('SREBP', 'Gene', '7555', (174, 179))	('mevalonate pathway', 'Pathway', (119, 137))	('p53', 'Gene', '7157', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('activate', 'PosReg', (106, 114))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (37, 40))	('mutant', 'Var', (30, 36))	('SREBP2', 'Gene', (95, 101))	('p53', 'Gene', (37, 40))	('SREBP2', 'Gene', '6721', (95, 101))	('bind', 'Interaction', (59, 63))
2068	29934362	In yeast, the BRE1 mutant showed higher sensitivity to ionizing radiation and was associated with RAD51, a key molecule in homologous recombination repair.	('higher', 'PosReg', (33, 39))	('associated', 'Reg', (82, 92))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (40, 73))	('RAD', 'biological_process', 'GO:1990116', ('98', '101'))	('BRE1', 'Gene', (14, 18))	('mutant', 'Var', (19, 25))	('yeast', 'Species', '4932', (3, 8))	('RAD51', 'Gene', (98, 103))	('homologous recombination', 'biological_process', 'GO:0035825', ('123', '147'))	('sensitivity', 'MPA', (40, 51))
2073	29934362	Mutated or defective NBS1 potentiates cell death upon ionizing radiation due to impaired homologous recombination and NHEJ repair mechanisms.	('homologous recombination', 'CPA', (89, 113))	('NBS1', 'Gene', '4683', (21, 25))	('NHEJ', 'biological_process', 'GO:0006303', ('118', '122'))	('impaired', 'NegReg', (80, 88))	('defective', 'Var', (11, 20))	('NBS1', 'Gene', (21, 25))	('potentiates', 'PosReg', (26, 37))	('cell death', 'CPA', (38, 48))	('homologous recombination', 'biological_process', 'GO:0035825', ('89', '113'))	('Mutated', 'Var', (0, 7))	('cell death', 'biological_process', 'GO:0008219', ('38', '48'))
2077	29934362	Silencing of RNF20 by si/shRNA in cells augmented ionizing radiation and DNA damaging agents such as camptothecin, neocarzinostatin, and mitomycin C, with severe impairment of DNA repair mechanisms.	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('mitomycin C', 'Chemical', 'MESH:D016685', (137, 148))	('augmented', 'PosReg', (40, 49))	('DNA repair', 'biological_process', 'GO:0006281', ('176', '186'))	('neocarzinostatin', 'Chemical', 'MESH:D009353', (115, 131))	('camptothecin', 'Chemical', 'MESH:D002166', (101, 113))	('men', 'Species', '9606', (43, 46))	('si/shRNA', 'Var', (22, 30))	('RNF20', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('men', 'Species', '9606', (168, 171))
2078	29934362	Moreover, overexpression of mutant H2B and silencing of RNF20 did not have any additional effect on cells, indicating that RNF20 functions by ubiquitinating H2B in DSB repair.	('RNF20', 'Gene', (56, 61))	('mutant', 'Var', (28, 34))	('H2B', 'Gene', (157, 160))	('H2B', 'Gene', (35, 38))	('DSB', 'Disease', (164, 167))	('silencing', 'Var', (43, 52))	('H2B', 'Gene', '8349', (157, 160))	('ubiquitinating', 'MPA', (142, 156))	('H2B', 'Gene', '8349', (35, 38))	('RNF20', 'Gene', (123, 128))
2079	29934362	(2011) showed that H2B ubiquitination obstructs chromatin compaction, resulting in an open and biochemically accessible fiber conformation.	('ubiquitination', 'Var', (23, 37))	('H2B', 'Gene', '8349', (19, 22))	('chromatin', 'MPA', (48, 57))	('obstructs', 'NegReg', (38, 47))	('H2B', 'Gene', (19, 22))	('chromatin', 'cellular_component', 'GO:0000785', ('48', '57'))
2089	29934362	(2018) showed that abrogation of RNF20 is strongly associated with suppression of H2Bub1 and DNA transcription.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('H2Bub1', 'Gene', (82, 88))	('suppression', 'NegReg', (67, 78))	('RNF20', 'Gene', (33, 38))	('abrogation', 'Var', (19, 29))	('DNA transcription', 'MPA', (93, 110))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('H2Bub1', 'Gene', '8349', (82, 88))
2095	29934362	Deregulated epigenetic changes have been implicated in the development of several inflammation-driven diseases, including cancer.	('inflammation', 'Disease', (82, 94))	('men', 'Species', '9606', (66, 69))	('Deregulated epigenetic changes', 'Var', (0, 30))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('implicated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inflammation', 'biological_process', 'GO:0006954', ('82', '94'))
2100	29934362	Interestingly, RNF20 depletion has been shown to enhance NF-kappaB-dependent gene transcription, and TNF-mediated H2Bub1 down-regulation augments NF-kappaB's response in the up-regulation of proinflammatory cytokines or chemokines that may act in an autocrine or paracrine fashion to sustain the prosurvival gene expression in cancer cells.	('men', 'Species', '9606', (140, 143))	('NF-kappaB', 'Gene', (57, 66))	('depletion', 'Var', (21, 30))	('TNF', 'Gene', '7124', (101, 104))	('NF-kappaB', 'Gene', '4790', (57, 66))	('cancer', 'Disease', (327, 333))	('gene expression', 'biological_process', 'GO:0010467', ('308', '323'))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('up-regulation', 'PosReg', (174, 187))	('down-regulation augments', 'NegReg', (121, 145))	('H2Bub1', 'Gene', '8349', (114, 120))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('RNF20', 'Gene', (15, 20))	('H2Bub1', 'Gene', (114, 120))	('NF-kappaB', 'Gene', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('enhance', 'PosReg', (49, 56))	('TNF', 'Gene', (101, 104))	('NF-kappaB', 'Gene', '4790', (146, 155))	('regulation', 'biological_process', 'GO:0065007', ('177', '187'))
2108	29977749	EGFR T790M mutation after chemotherapy for small cell lung cancer transformation of EGFR-positive non-small cell lung cancer In non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation, 50%-65% of cases acquire resistance after treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) because of an EGFR T790M point mutation and 3%-14% of these cases transformed to small cell lung cancer (SCLC).	('EGFR', 'Gene', '1956', (278, 282))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('T790M', 'Mutation', 'rs121434569', (5, 10))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (43, 65))	('SCLC', 'Disease', (427, 431))	('EGFR', 'Gene', '1956', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('non-small cell lung cancer', 'Disease', (98, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('311', '315'))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('small cell lung cancer', 'Disease', 'MESH:D055752', (102, 124))	('cancer', 'Disease', 'MESH:D009369', (419, 425))	('SCLC', 'Phenotype', 'HP:0030357', (427, 431))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('T790M point mutation', 'Var', (341, 361))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('EGFR', 'Gene', (336, 340))	('small cell lung cancer', 'Disease', 'MESH:D055752', (403, 425))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'Gene', '1956', (84, 88))	('small cell lung cancer', 'Disease', (403, 425))	('SCLC', 'Disease', 'MESH:D018288', (157, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (414, 425))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('171', '194'))	('epidermal growth factor receptor', 'Gene', (171, 203))	('cancer', 'Disease', (118, 124))	('EGFR', 'Gene', (311, 315))	('EGFR', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', (128, 154))	('EGFR', 'Gene', (278, 282))	('small cell lung cancer', 'Disease', 'MESH:D055752', (132, 154))	('small cell lung cancer', 'Disease', 'MESH:D055752', (43, 65))	('EGFR', 'Gene', '1956', (311, 315))	('SCLC', 'Disease', 'MESH:D018288', (427, 431))	('EGFR', 'Gene', (205, 209))	('epidermal growth factor receptor', 'Gene', '1956', (171, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('NSCLC', 'Disease', (156, 161))	('small cell lung cancer', 'Disease', (43, 65))	('EGFR', 'Gene', '1956', (336, 340))	('cancer', 'Disease', (419, 425))	('EGFR', 'molecular_function', 'GO:0005006', ('336', '340'))	('T790M', 'Mutation', 'rs121434569', (341, 346))	('cancer', 'Disease', (148, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('278', '282'))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (403, 425))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('transformed', 'Reg', (388, 399))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('SCLC', 'Disease', (157, 161))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', (84, 88))	('cancer', 'Disease', (59, 65))	('EGFR', 'Gene', '1956', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (157, 161))
2109	29977749	Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition.	('T790M', 'Mutation', 'rs121434569', (20, 25))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('T790M', 'Var', (20, 25))	('ATP', 'Chemical', 'MESH:D000255', (67, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))
2111	29977749	The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy.	('SCLC', 'Disease', 'MESH:D018288', (31, 35))	('T790M', 'Mutation', 'rs121434569', (105, 110))	('SCLC', 'Phenotype', 'HP:0030357', (31, 35))	('T790M', 'Var', (105, 110))	('EGFR', 'Gene', '1956', (90, 94))	('L858R', 'Mutation', 'rs121434568', (95, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('adenocarcinoma', 'Disease', (70, 84))	('EGFR', 'Gene', (90, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('SCLC', 'Disease', (31, 35))	('L858R', 'Var', (95, 100))
2116	29977749	Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are key drugs for EGFR mutation-positive non-small cell lung cancers (NSCLCs), most patients become resistant to the drugs within 1 year, which has become an important issue.	('epidermal growth factor receptor', 'Gene', '1956', (9, 41))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('non-small cell lung cancer', 'Disease', (122, 148))	('patients', 'Species', '9606', (165, 173))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (126, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('mutation-positive', 'Var', (104, 121))	('EGFR', 'Gene', (99, 103))	('NSCLC', 'Disease', (151, 156))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('9', '32'))	('EGFR', 'Gene', '1956', (70, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('NSCLCs', 'Phenotype', 'HP:0030358', (151, 157))	('cell lung cancers', 'Disease', 'MESH:D008175', (132, 149))	('lung cancers', 'Phenotype', 'HP:0100526', (137, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cell lung cancers', 'Disease', (132, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (122, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('SCLC', 'Phenotype', 'HP:0030357', (152, 156))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('EGFR', 'Gene', '1956', (99, 103))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('EGFR', 'Gene', (70, 74))	('epidermal growth factor receptor', 'Gene', (9, 41))
2117	29977749	Several resistance mechanisms were recently clarified, including an EGFR T790M secondary mutation, small cell lung cancer (SCLC) transformation, and activation of bypass signaling.	('small cell lung cancer', 'Disease', (99, 121))	('T790M', 'Var', (73, 78))	('bypass signaling', 'CPA', (163, 179))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('SCLC', 'Disease', 'MESH:D018288', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SCLC', 'Disease', (123, 127))	('small cell lung cancer', 'Disease', 'MESH:D055752', (99, 121))	('EGFR', 'Gene', '1956', (68, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (99, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))	('T790M', 'Mutation', 'rs121434569', (73, 78))	('SCLC', 'Phenotype', 'HP:0030357', (123, 127))
2118	29977749	Here, we report a case with an EGFR T790M mutation detected during chemotherapy for SCLC transformation of gefitinib resistance that responded to osimertinib.	('EGFR', 'Gene', '1956', (31, 35))	('T790M', 'Mutation', 'rs121434569', (36, 41))	('gefitinib', 'Chemical', 'MESH:D000077156', (107, 116))	('SCLC', 'Disease', (84, 88))	('EGFR', 'Gene', (31, 35))	('T790M', 'Var', (36, 41))	('SCLC', 'Disease', 'MESH:D018288', (84, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('responded', 'MPA', (133, 142))	('osimertinib', 'Chemical', 'MESH:C000603933', (146, 157))	('SCLC', 'Phenotype', 'HP:0030357', (84, 88))
2123	29977749	A re-biopsy of the primary lesion during gefitinib treatment showed SCLC transformation, which was supported by positive immunohistochemical (IHC) staining of the neural cell adhesion molecule (NCAM) and synaptophysin, with an EGFR L858R mutation, but not T790M (Table 1).	('neural cell adhesion molecule (NCAM', 'Gene', (163, 198))	('synaptophysin', 'Gene', (204, 217))	('EGFR', 'Gene', '1956', (227, 231))	('gefitinib', 'Chemical', 'MESH:D000077156', (41, 50))	('L858R', 'Mutation', 'rs121434568', (232, 237))	('T790M', 'Mutation', 'rs121434569', (256, 261))	('EGFR', 'molecular_function', 'GO:0005006', ('227', '231'))	('synaptophysin', 'Gene', '6855', (204, 217))	('SCLC', 'Disease', (68, 72))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('170', '192'))	('EGFR', 'Gene', (227, 231))	('SCLC', 'Disease', 'MESH:D018288', (68, 72))	('neural cell adhesion molecule (NCAM)', 'Gene', '4684', (163, 199))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('L858R', 'Var', (232, 237))	('cell adhesion', 'biological_process', 'GO:0007155', ('170', '183'))
2128	29977749	At this point, mutation analysis revealed the presence of EGFR L858R and T790M mutations.	('EGFR', 'Gene', '1956', (58, 62))	('T790M', 'Var', (73, 78))	('L858R', 'Var', (63, 68))	('EGFR', 'Gene', (58, 62))	('L858R', 'Mutation', 'rs121434568', (63, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('T790M', 'Mutation', 'rs121434569', (73, 78))
2132	29977749	The most frequent acquired resistance is the EGFR T790M point mutation, which occurs in 50%-65% of resistant cases, and SCLC transformation in 3%-14%.	('acquired resistance', 'MPA', (18, 37))	('EGFR', 'Gene', (45, 49))	('T790M point', 'Var', (50, 61))	('T790M', 'Mutation', 'rs121434569', (50, 55))	('SCLC', 'Disease', (120, 124))	('SCLC', 'Disease', 'MESH:D018288', (120, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('SCLC', 'Phenotype', 'HP:0030357', (120, 124))	('EGFR', 'Gene', '1956', (45, 49))
2133	29977749	Generally, a T790M secondary mutation develops with ongoing ATP competitive inhibition or T790M, which can be detected in a small proportion of tumors before treatment with EGFR-TKIs, with increasing frequency post-treatment, consistent with ongoing selection of T790M clones upon EGFR-TKI.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('T790M', 'Var', (90, 95))	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('T790M', 'Mutation', 'rs121434569', (263, 268))	('EGFR', 'molecular_function', 'GO:0005006', ('281', '285'))	('ATP competitive', 'MPA', (60, 75))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('T790M', 'Mutation', 'rs121434569', (13, 18))	('T790M', 'Var', (13, 18))	('EGFR', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('EGFR', 'Gene', '1956', (281, 285))	('T790M', 'Mutation', 'rs121434569', (90, 95))	('EGFR', 'Gene', (281, 285))
2134	29977749	Third-generation TKIs, such as osimertinib, demonstrated efficacy for patients who developed resistance to first or second generation EGFR-TKIs due to T790M mutation.	('patients', 'Species', '9606', (70, 78))	('EGFR', 'Gene', (134, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('osimertinib', 'Chemical', 'MESH:C000603933', (31, 42))	('T790M', 'Mutation', 'rs121434569', (151, 156))	('T790M', 'Var', (151, 156))	('EGFR', 'Gene', '1956', (134, 138))
2135	29977749	Several case reports have described SCLC transformation from adenocarcinoma with an EGFR mutation after resistance to EGFR-TKI.	('SCLC', 'Disease', (36, 40))	('SCLC', 'Disease', 'MESH:D018288', (36, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('mutation', 'Var', (89, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('SCLC', 'Phenotype', 'HP:0030357', (36, 40))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('EGFR', 'Gene', (84, 88))	('adenocarcinoma', 'Disease', (61, 75))
2140	29977749	SCLC with an EGFR mutation may be sensitive to standard chemotherapy.	('SCLC', 'Phenotype', 'HP:0030357', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('mutation', 'Var', (18, 26))	('SCLC', 'Disease', (0, 4))	('SCLC', 'Disease', 'MESH:D018288', (0, 4))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
2141	29977749	Our patient had an EGFR L858R mutation and received multiple treatments, including first generation EGFR-TKIs, chemotherapy, and third generation EGFR-TKIs.	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('L858R', 'Var', (24, 29))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('L858R', 'Mutation', 'rs121434568', (24, 29))	('EGFR', 'Gene', (146, 150))	('patient', 'Species', '9606', (4, 11))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('EGFR', 'Gene', (19, 23))
2143	29977749	The first resistance was SCLC transformation with an L858R mutation during gefitinib treatment and the second resistance was an unexpected EGFR-T790M mutation identified during chemotherapy.	('SCLC', 'Phenotype', 'HP:0030357', (25, 29))	('L858R', 'Mutation', 'rs121434568', (53, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('EGFR', 'Gene', '1956', (139, 143))	('T790M', 'Mutation', 'rs121434569', (144, 149))	('L858R', 'Var', (53, 58))	('SCLC', 'Disease', (25, 29))	('EGFR', 'Gene', (139, 143))	('SCLC', 'Disease', 'MESH:D018288', (25, 29))	('gefitinib', 'Chemical', 'MESH:D000077156', (75, 84))
2145	29977749	Although the developing mechanism of EGFR T790M mutation without last-minute EGFR-TKI exposure is unclear, we considered that EGFR T790M mutated cells might have been involved in SCLC transformation at first resistance, but this mutation could not be detected because of the small biopsy sample and was detected after chemotherapy.	('T790M', 'Var', (131, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'Gene', (126, 130))	('involved', 'Reg', (167, 175))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('EGFR', 'Gene', '1956', (37, 41))	('SCLC', 'Disease', (179, 183))	('EGFR', 'Gene', '1956', (77, 81))	('SCLC', 'Disease', 'MESH:D018288', (179, 183))	('T790M', 'Mutation', 'rs121434569', (42, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (37, 41))	('T790M', 'Mutation', 'rs121434569', (131, 136))	('EGFR', 'Gene', (77, 81))	('SCLC', 'Phenotype', 'HP:0030357', (179, 183))	('EGFR', 'Gene', '1956', (126, 130))
2147	29977749	However, it remains unclear why the proportion of cells with the EGFR T790M mutation had increased without ongoing selection of T790M clones upon EGFR-TKI.	('T790M', 'Var', (70, 75))	('T790M', 'Mutation', 'rs121434569', (128, 133))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', (146, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('T790M', 'Mutation', 'rs121434569', (70, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
2148	29977749	This case suggested that serial biopsies are necessary to choose an effective treatment strategy and testing for the T790M mutation should be performed even after SCLC transformation.	('SCLC', 'Disease', 'MESH:D018288', (163, 167))	('SCLC', 'Disease', (163, 167))	('SCLC', 'Phenotype', 'HP:0030357', (163, 167))	('T790M', 'Mutation', 'rs121434569', (117, 122))	('T790M', 'Var', (117, 122))
2237	29595143	Next, tumor cells growing in IPNs that were treated with M0 or M2c macrophage-conditioned media were harvested after 6 days in order to perform qPCR analysis.	('IPNs', 'Chemical', '-', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('M2c', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
2256	29595143	A marked effect of the stiffness was also observed in both tumor cell mono-cultures and co-cultures, as upregulation of VIM was more pronounced at high stiffness (310 Pa).	('upregulation', 'PosReg', (104, 116))	('tumor', 'Disease', (59, 64))	('VIM', 'Gene', '7431', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('VIM', 'Gene', (120, 123))	('310 Pa', 'Var', (163, 169))
2257	29595143	In M2c cultures, the upregulation of VIM was only observed in the co-cultures at high stiffness (310 Pa), irrespective of the time (Fig 5A).	('310', 'Var', (97, 100))	('VIM', 'Gene', '7431', (37, 40))	('upregulation', 'PosReg', (21, 33))	('VIM', 'Gene', (37, 40))
2259	29595143	CDH1 was downregulated when tumor cells were co-cultured with M2c macrophages (Fig 5B), but not with M0 macrophages (Fig S5B).	('tumor', 'Disease', (28, 33))	('CDH1', 'Gene', '999', (0, 4))	('S5B', 'Gene', '5711', (121, 124))	('M2c', 'Var', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('S5B', 'Gene', (121, 124))	('downregulated', 'NegReg', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CDH1', 'Gene', (0, 4))
2265	29595143	PD-L1 expression levels were increased in both M0 and M2c co-cultures in a stiffness dependent manner after 3, and especially after 6 days in M2c co-cultures (Fig 5D).	('M2c', 'Var', (54, 57))	('increased', 'PosReg', (29, 38))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', '29126', (0, 5))	('expression levels', 'MPA', (6, 23))
2267	29595143	The first set of studies, examining the impact of stiffness in the absence of macrophages, demonstrated that changes in ECM stiffness enhance proliferation and the invasive phenotype of A549 lung adenocarcinoma cells.	('proliferation', 'CPA', (142, 155))	('A549 lung adenocarcinoma', 'Disease', (186, 210))	('changes', 'Var', (109, 116))	('invasive phenotype', 'CPA', (164, 182))	('enhance', 'PosReg', (134, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))	('A549 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (186, 210))
2295	29296211	We further defined a panel of four lipid markers (LPE(18:1), ePE(40:4), C(18:2)CE and SM(22:0)) for prediction of early cancer with a accuracy of 82.3% AUC (Area under ROC curve), sensitivity of 81.9% and specificity of 70.7% at the training stage and yielded the predictive power with accuracy (AUC,80.8%), sensitivity 78.7%, specificity 69.4% and in the validation stage.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('LPE', 'Chemical', 'MESH:C008301', (50, 53))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('ePE', 'Chemical', '-', (61, 64))	('C(18:2', 'Var', (72, 78))	('SM', 'Chemical', 'MESH:D013109', (86, 88))
2308	29296211	Dysregulation of lipid metabolism contributes to the onset of pathology and progression in a wide variety of human diseases, such as diabetes, Alzheimer's disease, hypertension, and human cancers.	('human', 'Species', '9606', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	("Alzheimer's disease", 'Disease', (143, 162))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (143, 162))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('Dysregulation', 'Var', (0, 13))	('human', 'Species', '9606', (182, 187))	('hypertension', 'Disease', 'MESH:D006973', (164, 176))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('lipid metabolism', 'MPA', (17, 33))	('lipid metabolism', 'biological_process', 'GO:0006629', ('17', '33'))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('hypertension', 'Disease', (164, 176))	('hypertension', 'Phenotype', 'HP:0000822', (164, 176))	('diabetes', 'Disease', (133, 141))	('diabetes', 'Disease', 'MESH:D003920', (133, 141))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (143, 162))
2309	29296211	Aberrant lipid metabolism in lung cancer has also been demonstrated in previous studies, by lipid profiling in twenty-one pairs of resected frozen NSCLCs and adjacent normal tissue samples.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lipid metabolism', 'MPA', (9, 25))	('Aberrant lipid metabolism', 'Phenotype', 'HP:0003119', (0, 25))	('Aberrant', 'Var', (0, 8))	('NSCLCs', 'Disease', 'MESH:D002289', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('lipid metabolism', 'biological_process', 'GO:0006629', ('9', '25'))	('lipid', 'Chemical', 'MESH:D008055', (9, 14))	('lipid', 'Chemical', 'MESH:D008055', (92, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('lung cancer', 'Disease', (29, 40))	('NSCLCs', 'Disease', (147, 153))
2328	29296211	We finally determined a panel of four lipid species, including LPE (18:1), ePE(40:4), C(18:2)CE and SM(22:0), as candidate biomarkers for early detection of NSCLC disease at the training stage (Table 3).	('SM', 'Chemical', 'MESH:D013109', (100, 102))	('lipid', 'Chemical', 'MESH:D008055', (38, 43))	('NSCLC disease', 'Disease', 'MESH:D004194', (157, 170))	('ePE', 'Chemical', '-', (75, 78))	('C(18:2', 'Var', (86, 92))	('LPE', 'Chemical', 'MESH:C008301', (63, 66))	('NSCLC disease', 'Disease', (157, 170))
2340	29296211	The cholesteryl linoleate C(18:2)CE is identified as one of the three major cholesteryl esters present in human low-density lipoprotein (LDL), and the oxidization of C(18:2)CE is believed to be correlated with atherosclerosis.	('human', 'Species', '9606', (106, 111))	('low-density lipoprotein', 'molecular_function', 'GO:0005322', ('112', '135'))	('correlated', 'Reg', (194, 204))	('LDL', 'molecular_function', 'GO:0005322', ('137', '140'))	('cholesteryl linoleate', 'Chemical', 'MESH:C021976', (4, 25))	('atherosclerosis', 'Disease', 'MESH:D050197', (210, 225))	('oxidization', 'Var', (151, 162))	('atherosclerosis', 'Phenotype', 'HP:0002621', (210, 225))	('atherosclerosis', 'Disease', (210, 225))	('cholesteryl esters', 'Chemical', 'MESH:D002788', (76, 94))
2498	29276511	Viral vectors have been used for cancer immunotherapy to intratumorally deliver and express transgenes and to thereby increase therapeutic protein delivery while simultaneously reducing systemic toxicity.	('cancer', 'Disease', (33, 39))	('therapeutic protein delivery', 'MPA', (127, 155))	('increase', 'PosReg', (118, 126))	('l', 'Chemical', '-', (174, 175))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('l', 'Chemical', '-', (149, 150))	('reducing', 'NegReg', (177, 185))	('transgenes', 'Var', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('l', 'Chemical', '-', (4, 5))	('express', 'MPA', (84, 91))	('l', 'Chemical', '-', (69, 70))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('l', 'Chemical', '-', (74, 75))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('toxicity', 'Disease', 'MESH:D064420', (195, 203))	('l', 'Chemical', '-', (68, 69))	('toxicity', 'Disease', (195, 203))	('tumor', 'Disease', (62, 67))	('l', 'Chemical', '-', (159, 160))	('l', 'Chemical', '-', (166, 167))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
2510	29276511	Furthermore, it has been shown that IFN-gamma enhances macrophage activation toward a tumoricidal phenotype in vitro and in vivo.	('enhances', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('l', 'Chemical', '-', (96, 97))	('macrophage activation', 'CPA', (55, 76))	('IFN-gamma', 'Var', (36, 45))	('macrophage activation', 'biological_process', 'GO:0042116', ('55', '76'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
2522	29276511	Moreover, in this study, we show that rSFV-encoded IFN-gamma effectively enhanced macrophage activation toward a cancer-suppressive phenotype in vitro.	('IFN-gamma', 'Gene', (51, 60))	('macrophage activation', 'CPA', (82, 103))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('macrophage activation', 'biological_process', 'GO:0042116', ('82', '103'))	('enhanced', 'PosReg', (73, 81))	('rSFV-encoded', 'Var', (38, 50))	('rSFV', 'Chemical', '-', (38, 42))	('l', 'Chemical', '-', (70, 71))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
2536	29276511	The J774A.1 cells were cultured in RPMI-1640 medium supplemented with 10% FBS (Cat.	('l', 'Chemical', '-', (15, 16))	('FBS', 'Disease', 'MESH:D005198', (74, 77))	('l', 'Chemical', '-', (25, 26))	('l', 'Chemical', '-', (14, 15))	('FBS', 'Disease', (74, 77))	('J774A.1', 'Var', (4, 11))	('J774A.1', 'CellLine', 'CVCL:0358', (4, 11))	('Cat', 'molecular_function', 'GO:0004096', ('79', '82'))	('l', 'Chemical', '-', (56, 57))	('RPMI-1640 medium', 'Chemical', '-', (35, 51))
2571	29276511	To generate the pSFV1-Tnfa-Flag plasmid, we used the pSFV1-NruI vector, which is a derivate of pSFV1 that was generated in our lab by deleting a 527 bp StuI-HindIII fragment from pSFV1 (bp 7603-8130) and changing a unique SpeI site to a NruI site.	('pSFV1', 'Gene', (179, 184))	('SFV', 'Species', '11033', (17, 20))	('changing', 'Reg', (204, 212))	('l', 'Chemical', '-', (33, 34))	('SFV', 'Species', '11033', (96, 99))	('l', 'Chemical', '-', (136, 137))	('deleting', 'Var', (134, 142))	('l', 'Chemical', '-', (127, 128))	('SFV', 'Species', '11033', (180, 183))	('l', 'Chemical', '-', (28, 29))	('SFV', 'Species', '11033', (54, 57))	('bp 7603-8130', 'Var', (186, 198))
2639	29276511	171G5017M and 171G5023M; Bio-Rad, Hercules, CA, USA) according to the manufacturer's instructions.	('Rad', 'biological_process', 'GO:1990116', ('29', '32'))	('l', 'Chemical', '-', (39, 40))	('Rad', 'Gene', '6236', (29, 32))	('Rad', 'Gene', (29, 32))	('Hercules', 'CPA', (34, 42))	('171G5023M', 'Var', (14, 23))	('171G5017M', 'Var', (0, 9))
2645	29276511	171G5017M and 171G5023M; Bio-Rad) according to manufacturer's recommended protocols.	('Rad', 'biological_process', 'GO:1990116', ('29', '32'))	('l', 'Chemical', '-', (81, 82))	('Rad', 'Gene', '6236', (29, 32))	('Rad', 'Gene', (29, 32))	('171G5023M', 'Var', (14, 23))	('171G5017M', 'Var', (0, 9))
2715	29276511	In these experiments, 30% of the positive control sample (the human cancer cell line A549) was infected with SFV-DsRed, whereas the HMDMs remained uninfected (Figure 3, middle panel).	('l', 'Chemical', '-', (173, 174))	('SFV-DsRed', 'Var', (109, 118))	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('l', 'Chemical', '-', (78, 79))	('l', 'Chemical', '-', (54, 55))	('human', 'Species', '9606', (62, 67))	('l', 'Chemical', '-', (77, 78))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('l', 'Chemical', '-', (48, 49))	('cancer', 'Disease', (68, 74))	('SFV', 'Species', '11033', (109, 112))	('l', 'Chemical', '-', (180, 181))	('l', 'Chemical', '-', (80, 81))
2717	29276511	Taken together, these data show that lung carcinoma cells are efficiently infected by rSFV, whereas primary mouse and human macrophages are resistant to SFV infection, suggesting that rSFV may be used to deliver genes for cancer therapy without killing tumor-associated macrophages.	('l', 'Chemical', '-', (71, 72))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('lung carcinoma', 'Disease', (37, 51))	('l', 'Chemical', '-', (206, 207))	('l', 'Chemical', '-', (55, 56))	('l', 'Chemical', '-', (37, 38))	('rSFV', 'Chemical', '-', (184, 188))	('l', 'Chemical', '-', (54, 55))	('cancer', 'Disease', (222, 228))	('rSFV', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung carcinoma', 'Disease', 'MESH:D008175', (37, 51))	('SFV infection', 'Disease', 'MESH:D007239', (153, 166))	('SFV infection', 'Disease', (153, 166))	('mouse', 'Species', '10090', (108, 113))	('l', 'Chemical', '-', (248, 249))	('tumor', 'Disease', (253, 258))	('human', 'Species', '9606', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('rSFV', 'Chemical', '-', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('l', 'Chemical', '-', (247, 248))	('infected', 'Reg', (74, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
2742	29276511	LLC cell growth was inhibited by half 47 h after infection with SFV-Ifng and by 80% after infection with SFV-Tnfa (Figure 5D).	('SFV-Ifng', 'Var', (64, 72))	('LLC cell growth', 'CPA', (0, 15))	('LLC', 'cellular_component', 'GO:0038045', ('0', '3'))	('SFV-Tnfa', 'Disease', 'None', (105, 113))	('l', 'Chemical', '-', (6, 7))	('SFV', 'Species', '11033', (105, 108))	('SFV-Tnfa', 'Disease', (105, 113))	('inhibited', 'NegReg', (20, 29))	('cell growth', 'biological_process', 'GO:0016049', ('4', '15'))	('l', 'Chemical', '-', (7, 8))	('SFV', 'Species', '11033', (64, 67))	('l', 'Chemical', '-', (35, 36))
2752	29276511	In LLC cells, infection with SFV-Ifng resulted in the secretion of vdIFN-gamma into the growth medium at a concentration ranging from 2.9 to 9.9 x 102 ng/mL at 24 h after infection (Figure 6B).	('l', 'Chemical', '-', (9, 10))	('l', 'Chemical', '-', (10, 11))	('l', 'Chemical', '-', (42, 43))	('vdIFN-gamma', 'Gene', (67, 78))	('secretion', 'biological_process', 'GO:0046903', ('54', '63'))	('SFV', 'Species', '11033', (29, 32))	('secretion', 'MPA', (54, 63))	('to 9', 'Species', '1214577', (138, 142))	('LLC', 'cellular_component', 'GO:0038045', ('3', '6'))	('SFV-Ifng', 'Var', (29, 37))
2762	29276511	Treatment with staurosporine was used as the control for apoptotic cell death, where annexin V-positive/PI-negative cells were regarded as early apoptotic, whereas annexin V-positive/PI-positive cells were regarded as late apoptotic undergoing secondary necrosis (Figure 7B).	('l', 'Chemical', '-', (198, 199))	('l', 'Chemical', '-', (119, 120))	('necrosis', 'Disease', 'MESH:D009336', (254, 262))	('necrosis', 'biological_process', 'GO:0070265', ('254', '262'))	('necrosis', 'biological_process', 'GO:0019835', ('254', '262'))	('l', 'Chemical', '-', (70, 71))	('necrosis', 'biological_process', 'GO:0001906', ('254', '262'))	('l', 'Chemical', '-', (118, 119))	('l', 'Chemical', '-', (197, 198))	('secondary necrosis', 'Phenotype', 'HP:0010885', (244, 262))	('necrosis', 'Disease', (254, 262))	('annexin', 'Var', (85, 92))	('l', 'Chemical', '-', (69, 70))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('57', '77'))	('l', 'Chemical', '-', (218, 219))	('necrosis', 'biological_process', 'GO:0008219', ('254', '262'))	('l', 'Chemical', '-', (51, 52))	('l', 'Chemical', '-', (142, 143))	('necrosis', 'biological_process', 'GO:0008220', ('254', '262'))	('staurosporine', 'Chemical', 'MESH:D019311', (15, 28))
2770	29276511	Moreover, after treatment with rTNF-alpha or vdTNF-alpha, we observed necrotic cell morphology characterized by round, swollen cells with translucent cytoplasm.	('vdTNF-alpha', 'Var', (45, 56))	('l', 'Chemical', '-', (37, 38))	('necrotic', 'Disease', (70, 78))	('l', 'Chemical', '-', (82, 83))	('l', 'Chemical', '-', (130, 131))	('l', 'Chemical', '-', (122, 123))	('l', 'Chemical', '-', (81, 82))	('l', 'Chemical', '-', (123, 124))	('l', 'Chemical', '-', (129, 130))	('rTNF-alpha', 'Gene', '24835', (31, 41))	('cytoplasm', 'cellular_component', 'GO:0005737', ('150', '159'))	('necrotic', 'Disease', 'MESH:D009336', (70, 78))	('l', 'Chemical', '-', (143, 144))	('l', 'Chemical', '-', (52, 53))	('l', 'Chemical', '-', (90, 91))	('rTNF-alpha', 'Gene', (31, 41))	('l', 'Chemical', '-', (155, 156))
2796	29276511	Some growth inhibition was also observed at 0.098-0.39 ng/mL rIFN-gamma, but minor or no effect was observed at concentrations <=0.024 ng/mL (Figure 9B).	('rIFN-gamma', 'Gene', '25712', (61, 71))	('rIFN-gamma', 'Gene', (61, 71))	('l', 'Chemical', '-', (28, 29))	('growth', 'CPA', (5, 11))	('0.098-0.39 ng/mL', 'Var', (44, 60))
2856	29276511	This property is of particular interest for lung cancer therapy since a mutated p53 is one of the key molecular markers in many solid cancers, including human lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('solid cancers', 'Disease', 'MESH:D009369', (128, 141))	('lung cancers', 'Disease', 'MESH:D008175', (159, 171))	('human', 'Species', '9606', (153, 158))	('solid cancers', 'Disease', (128, 141))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('lung cancers', 'Disease', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('p53', 'Gene', '7157', (80, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('lung cancers', 'Phenotype', 'HP:0100526', (159, 171))	('l', 'Chemical', '-', (146, 147))	('l', 'Chemical', '-', (108, 109))	('lung cancer', 'Disease', (44, 55))	('l', 'Chemical', '-', (130, 131))	('p53', 'Gene', (80, 83))	('l', 'Chemical', '-', (44, 45))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('l', 'Chemical', '-', (27, 28))	('mutated', 'Var', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('l', 'Chemical', '-', (159, 160))	('l', 'Chemical', '-', (104, 105))
2884	29276511	Previous studies suggest IFN-gamma as a good candidate for tumor-associated macrophage re-education due to the ability of IFN-gamma to re-polarize tumor-associated macrophages toward an M1 phenotype in vitro and its ability to render macrophages tumor-suppressive in mouse tumor models in vivo.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('l', 'Chemical', '-', (283, 284))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mouse', 'Species', '10090', (267, 272))	('l', 'Chemical', '-', (140, 141))	('l', 'Chemical', '-', (219, 220))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('tumor', 'Disease', (246, 251))	('IFN-gamma', 'Var', (122, 131))	('l', 'Chemical', '-', (114, 115))
2911	28950878	Kirsten rat sarcoma (KRAS) gene mutation is one of the key drivers for lung cancer development, and is detected in 6-30% of non-small-cell lung cancer (NSCLC) patients.	('rat', 'Species', '10116', (8, 11))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('sarcoma', 'Disease', (12, 19))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('mutation', 'Var', (32, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('patients', 'Species', '9606', (159, 167))	('lung cancer', 'Disease', (139, 150))	('detected', 'Reg', (103, 111))	('NSCLC', 'Disease', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('KRAS', 'Gene', (21, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))	('lung cancer', 'Disease', (71, 82))
2912	28950878	Patients with KRAS mutations can easily develop metastasis, and usually have poor prognosis.	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('develop', 'PosReg', (40, 47))	('metastasis', 'CPA', (48, 58))	('KRAS', 'Gene', (14, 18))
2918	28950878	Serum levels of cytokeratin (CK)-19 fragment CYFRA21-1 and CA153 were 3.57 ng/mL and 47.2U/mL, respectively.	('CA153', 'Gene', '4582', (59, 64))	('rat', 'Species', '10116', (22, 25))	('CA153', 'Gene', (59, 64))	('CYFRA21-1', 'Var', (45, 54))
2928	28950878	Serum levels of CA125, CA199, and CA153 were 474.3U/mL, 467.5 U/mL, and 28.4 U/mL respectively.	('CA125', 'Gene', '94025', (16, 21))	('CA199', 'Var', (23, 28))	('CA153', 'Gene', '4582', (34, 39))	('CA199', 'Chemical', '-', (23, 28))	('CA125', 'Gene', (16, 21))	('CA153', 'Gene', (34, 39))
2943	28950878	The third, genetic alterations such as KRAS mutations can increase the activities of matrix metalloproteases, cysteine proteases, serine proteases, urokinase plasminogen activator, and enzymes responsible for tumor invasion and metastasis.	('increase', 'PosReg', (58, 66))	('tumor', 'Disease', (209, 214))	('enzymes', 'Enzyme', (185, 192))	('activities', 'MPA', (71, 81))	('rat', 'Species', '10116', (23, 26))	('urokinase plasminogen activator', 'molecular_function', 'GO:0008243', ('148', '179'))	('serine proteases', 'Enzyme', (130, 146))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cysteine proteases', 'Enzyme', (110, 128))	('matrix metalloproteases', 'Enzyme', (85, 108))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('urokinase', 'MPA', (148, 157))
2944	28950878	In the present case, the mutation in KRAS may have played a pivotal role in the metastasis of lung cancer.	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (80, 105))	('mutation', 'Var', (25, 33))	('metastasis of lung cancer', 'Disease', (80, 105))	('KRAS', 'Gene', (37, 41))	('played', 'Reg', (51, 57))	('role', 'Reg', (68, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
2946	28950878	reported that lung cancer with KRAS mutation had an increased incidence of distant metastasis.	('KRAS', 'Gene', (31, 35))	('distant metastasis', 'CPA', (75, 93))	('lung cancer', 'Disease', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutation', 'Var', (36, 44))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
2947	28950878	In summary, according to the present case and reported literature, lung adenosquamous cell carcinoma with KRAS mutations has high susceptibility to distant metastasis including peritoneal metastasis and a very rapid progression of clinical course.	('mutations', 'Var', (111, 120))	('adenosquamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 100))	('lung adenosquamous cell carcinoma', 'Disease', 'MESH:D018196', (67, 100))	('peritoneal metastasis', 'CPA', (177, 198))	('distant metastasis', 'CPA', (148, 166))	('lung adenosquamous cell carcinoma', 'Disease', (67, 100))	('lung adenosquamous cell carcinoma', 'Phenotype', 'HP:0030078', (67, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('KRAS', 'Gene', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('rat', 'Species', '10116', (59, 62))
3062	28279063	Examples of studies that have been implemented by CTONG include the INFORM Study, FASTACT 2, and others in the pipeline, including CTONG 1103 on stage III epidermal growth factor receptor (EGFR) mutation positive adenocarcinoma, and CTONG 1104 on adjuvant EGFR tyrosine kinase inhibitor (TKI) in resectable lung cancer with EGFR mutation.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('155', '178'))	('adenocarcinoma', 'Disease', (213, 227))	('EGFR', 'molecular_function', 'GO:0005006', ('324', '328'))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('EGFR', 'Gene', '1956', (189, 193))	('EGFR', 'Gene', '1956', (324, 328))	('mutation', 'Var', (329, 337))	('epidermal growth factor receptor', 'Gene', (155, 187))	('men', 'Species', '9606', (40, 43))	('lung cancer', 'Disease', (307, 318))	('adenocarcinoma', 'Disease', 'MESH:D000230', (213, 227))	('epidermal growth factor receptor', 'Gene', '1956', (155, 187))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('270', '286'))	('EGFR', 'Gene', (256, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('256', '260'))	('lung cancer', 'Disease', 'MESH:D008175', (307, 318))	('EGFR', 'Gene', (189, 193))	('EGFR', 'Gene', (324, 328))	('EGFR', 'Gene', '1956', (256, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('189', '193'))	('lung cancer', 'Phenotype', 'HP:0100526', (307, 318))
3064	28279063	The first study that ATORG will engage in is for stage IV adenocarcinoma EGFR mutation positive resistance to EGFR TKI plasma cell-free DNA positive for T790M.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('T790M', 'Mutation', 'rs121434569', (153, 158))	('IV adenocarcinoma', 'Disease', (55, 72))	('EGFR', 'Gene', '1956', (73, 77))	('mutation', 'Var', (78, 86))	('EGFR', 'Gene', '1956', (110, 114))	('IV adenocarcinoma', 'Disease', 'MESH:D000230', (55, 72))	('EGFR', 'Gene', (110, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('EGFR', 'Gene', (73, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('resistance', 'MPA', (96, 106))
3112	27502709	PD-L1 can be expressed adaptively in response to stimuli such as IFN-gamma, or constitutively (intrinsically) due to oncogenic signaling such as loss of phosphatase and tensin homolog (PTEN), activating mutations in epidermal growth factor receptor (EGFR) or other mechanisms.	('PTEN', 'Gene', '5728', (185, 189))	('activating', 'PosReg', (192, 202))	('IFN-gamma', 'Gene', '3458', (65, 74))	('IFN-gamma', 'Gene', (65, 74))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('epidermal growth factor receptor', 'Gene', (216, 248))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('153', '183'))	('loss', 'NegReg', (145, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('250', '254'))	('phosphatase', 'molecular_function', 'GO:0016791', ('153', '164'))	('PD-L1', 'Gene', (0, 5))	('epidermal growth factor receptor', 'Gene', '1956', (216, 248))	('EGFR', 'Gene', '1956', (250, 254))	('EGFR', 'Gene', (250, 254))	('PD-L1', 'Gene', '29126', (0, 5))	('mutations', 'Var', (203, 212))	('PTEN', 'Gene', (185, 189))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('216', '239'))
3115	27502709	With the incorporation of PD-L1 expression as a test for treatment selection with PD-1 inhibitors in NSCLC, it remains uncertain whether archival or new tumor samples should be used for testing.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('PD-1', 'Gene', (82, 86))	('PD-1', 'Gene', '5133', (82, 86))	('NSCLC', 'Disease', (101, 106))	('PD-L1', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('PD-L1', 'Gene', '29126', (26, 31))	('inhibitors', 'Var', (87, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
3172	27502709	Also, since we used the E1L3N PD-L1 clone, we are not certain at this time how it compares with the companion and complementary PD-L1 diagnostic tests associated with the approved PD-1 inhibitors.	('PD-L1', 'Gene', (128, 133))	('E1L3N', 'Var', (24, 29))	('PD-L1', 'Gene', '29126', (128, 133))	('PD-L1', 'Gene', (30, 35))	('PD-1', 'Gene', (180, 184))	('PD-L1', 'Gene', '29126', (30, 35))	('PD-1', 'Gene', '5133', (180, 184))
3186	27502709	Both the lung adenocarcinoma and brain metastasis displayed concordant PD-L1 immunostaining with diffuse and strong membranous staining (B:lung PD-L1, 200x; E:brain PD-L1, 200x); however, TILs as demonstrated with CD3 were present in the lung primary (C:CD3, 200x) but not the brain metastasis (F:CD3, 200x).	('PD-L1', 'Gene', '29126', (144, 149))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('TIL', 'Gene', (188, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung adenocarcinoma', 'Disease', (9, 28))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', '29126', (71, 76))	('PD-L1', 'Gene', (165, 170))	('TIL', 'Gene', '7096', (188, 191))	('PD-L1', 'Gene', (144, 149))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (9, 28))	('C:CD3, 200x', 'Var', (252, 263))	('PD-L1', 'Gene', '29126', (165, 170))
3199	27429979	Moreover, lentivirus-mediated shRNA knockdown of PTGR1 reduced cell viability in human lung carcinoma cells 95D and A549 by MTT and colony formation assay.	('cell viability in human', 'CPA', (63, 86))	('PTGR1', 'Gene', '22949', (49, 54))	('reduced', 'NegReg', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('knockdown', 'Var', (36, 45))	('lung carcinoma', 'Disease', 'MESH:D008175', (87, 101))	('human', 'Species', '9606', (81, 86))	('MTT', 'Chemical', 'MESH:C070243', (124, 127))	('lung carcinoma', 'Disease', (87, 101))	('A549', 'CellLine', 'CVCL:0023', (116, 120))	('PTGR1', 'Gene', (49, 54))
3200	27429979	PTGR1 depletion led to G2/M phase cell cycle arrest and increased the proportion of apoptotic cells in 95D cells by flow cytometry.	('arrest', 'Disease', (45, 51))	('increased', 'PosReg', (56, 65))	('M phase', 'biological_process', 'GO:0000279', ('26', '33'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('34', '51'))	('depletion', 'Var', (6, 15))	('PTGR1', 'Gene', (0, 5))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (34, 51))	('PTGR1', 'Gene', '22949', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
3201	27429979	Furthermore, silencing PTGR1 in 95D cells resulted in decreased levels of cyclin-dependent protein kinase complex (CDK1, CDK2, cyclin A2, and cyclin B1) by western blotting and then PTGR1 is positively correlated with cyclin-dependent protein by using the data mining of the Oncomine database.	('CDK', 'molecular_function', 'GO:0004693', ('115', '118'))	('cyclin', 'Gene', '5111', (127, 133))	('cyclin', 'Gene', (74, 80))	('levels', 'MPA', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('CDK2', 'Gene', '1017', (121, 125))	('cyclin', 'Gene', '5111', (142, 148))	('CDK1', 'Gene', (115, 119))	('cyclin A2', 'Gene', '890', (127, 136))	('CDK1', 'Gene', '983', (115, 119))	('CDK2', 'Gene', (121, 125))	('PTGR1', 'Gene', '22949', (23, 28))	('decreased', 'NegReg', (54, 63))	('cyclin', 'Gene', (127, 133))	('Oncomine', 'Chemical', '-', (275, 283))	('silencing', 'Var', (13, 22))	('cyclin', 'Gene', (142, 148))	('cyclin', 'molecular_function', 'GO:0016538', ('74', '80'))	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('cyclin', 'Gene', '5111', (218, 224))	('PTGR1', 'Gene', '22949', (182, 187))	('cyclin', 'molecular_function', 'GO:0016538', ('142', '148'))	('PTGR1', 'Gene', (23, 28))	('cyclin', 'molecular_function', 'GO:0016538', ('127', '133'))	('PTGR1', 'Gene', (182, 187))	('cyclin', 'molecular_function', 'GO:0016538', ('218', '224'))	('cyclin B1', 'Gene', '891', (142, 151))	('cyclin', 'Gene', '5111', (74, 80))	('cyclin', 'Gene', (218, 224))	('protein kinase complex', 'cellular_component', 'GO:1902911', ('91', '113'))	('cyclin B1', 'Gene', (142, 151))	('cyclin A2', 'Gene', (127, 136))
3279	27429979	To assess the inhibitory effect of silencing PTGR1 on cell proliferation, 95D and A549 cells were seeded on 96-well plates for a continuous 5-day MTT assay.	('PTGR1', 'Gene', (45, 50))	('PTGR1', 'Gene', '22949', (45, 50))	('silencing', 'Var', (35, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('MTT', 'Chemical', 'MESH:C070243', (146, 149))	('A549', 'CellLine', 'CVCL:0023', (82, 86))
3283	27429979	As shown, silencing PTGR1 resulted in smaller clone size (Figure 3(b)) and fewer colony numbers (Figure 3(c)) compared to shCon in both 95D and A549 cells (p < 0.001).	('PTGR1', 'Gene', '22949', (20, 25))	('clone size', 'CPA', (46, 56))	('A549', 'CellLine', 'CVCL:0023', (144, 148))	('colony numbers', 'CPA', (81, 95))	('smaller', 'NegReg', (38, 45))	('fewer', 'NegReg', (75, 80))	('PTGR1', 'Gene', (20, 25))	('silencing', 'Var', (10, 19))
3284	27429979	Taken together, the results revealed that specific PTGR1 silencing inhibits the capacity of proliferation of 95D and A549 cells.	('PTGR1', 'Gene', (51, 56))	('PTGR1', 'Gene', '22949', (51, 56))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('silencing', 'Var', (57, 66))	('inhibits', 'NegReg', (67, 75))
3287	27429979	Moreover, infection of shPTGR1 into 95D cells resulted in a remarkable increase in the sub-G1 phase (0.45%  +-  0.08% versus 0.16%  +-  0.04%, p < 0.05, Figure 4(c)), suggesting that knockdown of PTGR1 could induce cell apoptosis.	('PTGR1', 'Gene', (25, 30))	('PTGR1', 'Gene', '22949', (25, 30))	('apoptosis', 'biological_process', 'GO:0097194', ('220', '229'))	('cell apoptosis', 'CPA', (215, 229))	('PTGR1', 'Gene', '22949', (196, 201))	('knockdown', 'Var', (183, 192))	('apoptosis', 'biological_process', 'GO:0006915', ('220', '229'))	('sub-G1 phase', 'CPA', (87, 99))	('G1 phase', 'biological_process', 'GO:0051318', ('91', '99'))	('increase', 'PosReg', (71, 79))	('infection', 'Var', (10, 19))	('induce', 'PosReg', (208, 214))	('PTGR1', 'Gene', (196, 201))
3288	27429979	In addition, we analyzed whether knockdown of PTGR1 could result in apoptosis in 95D cells.	('PTGR1', 'Gene', (46, 51))	('knockdown', 'Var', (33, 42))	('apoptosis', 'CPA', (68, 77))	('PTGR1', 'Gene', '22949', (46, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('result in', 'Reg', (58, 67))
3291	27429979	Therefore, the ratio of apoptosis cells has significantly increased as PTGR1 was knocked down in 95D cells.	('increased', 'PosReg', (58, 67))	('knocked', 'Var', (81, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('PTGR1', 'Gene', (71, 76))	('PTGR1', 'Gene', '22949', (71, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))
3306	27429979	What is more, previous report has demonstrated that knockdown of PTGR1 could inhibit the growth of gastric carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('gastric carcinoma', 'Disease', 'MESH:D013274', (99, 116))	('inhibit', 'NegReg', (77, 84))	('gastric carcinoma', 'Disease', (99, 116))	('PTGR1', 'Gene', (65, 70))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (99, 116))	('growth of', 'CPA', (89, 98))	('knockdown', 'Var', (52, 61))	('PTGR1', 'Gene', '22949', (65, 70))
3321	27429979	Misregulation of CDKs can induce unscheduled proliferation and genomic and chromosomal instability.	('CDKs', 'Gene', '983;1017', (17, 21))	('chromosomal instability', 'Phenotype', 'HP:0040012', (75, 98))	('CDKs', 'Gene', (17, 21))	('unscheduled proliferation', 'CPA', (33, 58))	('Misregulation', 'Var', (0, 13))	('induce', 'Reg', (26, 32))
3322	27429979	As expected, it is reasonable to speculate that the mechanisms of PTGR1 knockdown suppressing the growth of lung cancer cells may be via suppression of the related cell cycle regulators to some extent.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('PTGR1', 'Gene', '22949', (66, 71))	('suppressing', 'NegReg', (82, 93))	('lung cancer', 'Disease', (108, 119))	('growth', 'CPA', (98, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cell cycle', 'biological_process', 'GO:0007049', ('164', '174'))	('suppression', 'NegReg', (137, 148))	('knockdown', 'Var', (72, 81))	('PTGR1', 'Gene', (66, 71))
3403	30552994	The monitored (M + H)+ ions were m/z 208.2 for NNK, m/z 211.2 for D3-NNK, m/z 210.2 for NNAL, and m/z 213.2 for D3-NNAL.	('m/z 213.2', 'Var', (98, 107))	('m/z 211.2', 'Var', (52, 61))	('NNK', 'Chemical', 'MESH:C016583', (47, 50))	('D3-NNK', 'Var', (66, 72))	('NNAL', 'Chemical', 'MESH:C099565', (115, 119))	('NNAL', 'Chemical', 'MESH:C099565', (88, 92))	('NNK', 'Chemical', 'MESH:C016583', (69, 72))	('m/z 210.2', 'Var', (74, 83))	('m/z 208.2', 'Var', (33, 42))
3475	30552994	These observations indicate that NNK may selectively induce DNA damage in a sub-population of cells in the ALI cultures.	('NNK', 'Chemical', 'MESH:C016583', (33, 36))	('DNA damage', 'MPA', (60, 70))	('NNK', 'Var', (33, 36))	('induce', 'Reg', (53, 59))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))
3485	33182665	Furthermore, cells treated with doxorubicin/extract combinations were shown to have lower migratory and colony formation potentials than untreated cells or cells treated with doxorubicin alone.	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('doxorubicin', 'Chemical', 'MESH:D004317', (175, 186))	('combinations', 'Var', (52, 64))	('lower', 'NegReg', (84, 89))	('doxorubicin', 'Chemical', 'MESH:D004317', (32, 43))
3511	33182665	However, treatment of cells with IC20 and IC50 DOX led to a significant increase in the percentage of cells in the G2/M phase (Figure 1A), while cells treated with combination of DOX (IC20 or IC50) and MAW or MAE (20 microg/mL) were shown to accumulate in the G1 phase compared to those treated with DOX alone (Figure 1B).	('increase', 'PosReg', (72, 80))	('DOX', 'Chemical', 'MESH:D004317', (179, 182))	('MAW', 'Chemical', '-', (202, 205))	('MAE', 'Chemical', 'MESH:C063694', (209, 212))	('G1 phase', 'CPA', (260, 268))	('DOX', 'Chemical', 'MESH:D004317', (300, 303))	('accumulate', 'PosReg', (242, 252))	('DOX', 'Var', (47, 50))	('M phase', 'biological_process', 'GO:0000279', ('118', '125'))	('IC20', 'Var', (33, 37))	('DOX', 'Chemical', 'MESH:D004317', (47, 50))	('IC50 DOX', 'Var', (42, 50))	('G1 phase', 'biological_process', 'GO:0051318', ('260', '268'))
3512	33182665	Samples treated with combinations of DOX (IC20 or IC50) and extracts showed an increase in the subG1 phase as well, compared to samples treated with DOX alone, and this increase in the number of subG1 cells was shown to be statistically significant for cells treated with combination of DOX and MAE (Figure 1B).	('increase', 'PosReg', (79, 87))	('MAE', 'Chemical', 'MESH:C063694', (295, 298))	('IC50', 'Var', (50, 54))	('DOX', 'Chemical', 'MESH:D004317', (149, 152))	('IC20', 'Var', (42, 46))	('subG1 phase', 'CPA', (95, 106))	('DOX', 'Chemical', 'MESH:D004317', (37, 40))	('DOX', 'Chemical', 'MESH:D004317', (287, 290))
3543	33182665	A549 cell cycle analysis has demonstrated that DOX induces a strong G2/M transition block as well as a considerable increase in the percentage of cells in the subG1 phase in contrast to that in the control sample, indicating that treated cells cannot pass through mitosis, which ultimately leads to apoptosis.	('mitosis', 'CPA', (264, 271))	('cell cycle', 'biological_process', 'GO:0007049', ('5', '15'))	('mitosis', 'biological_process', 'GO:0000278', ('264', '271'))	('apoptosis', 'biological_process', 'GO:0097194', ('299', '308'))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('299', '308'))	('G2/M transition block', 'CPA', (68, 89))	('DOX', 'Chemical', 'MESH:D004317', (47, 50))	('DOX', 'Var', (47, 50))	('increase', 'PosReg', (116, 124))	('leads to', 'Reg', (290, 298))
3545	33182665	Furthermore, we observed an increase in the number of cells in the G1 phase following treatment of cells with DOX/plant extract combinations in contrast to the number of cells in the G1 phase treated with DOX alone.	('increase', 'PosReg', (28, 36))	('DOX', 'Chemical', 'MESH:D004317', (110, 113))	('G1 phase', 'biological_process', 'GO:0051318', ('183', '191'))	('DOX', 'Chemical', 'MESH:D004317', (205, 208))	('combinations', 'Var', (128, 140))	('cells in the G1 phase', 'CPA', (54, 75))	('G1 phase', 'biological_process', 'GO:0051318', ('67', '75'))
3554	33182665	The inhibitors of matrix metalloproteinases are considered potential novel agents able to inhibit tumor growth and metastases, but they were shown to be unsuccessful in several clinical trials, which may result from the dual role of matrix metalloproteinases during cancer cell invasion and metastases.	('inhibit', 'NegReg', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('metastases', 'Disease', (115, 125))	('cancer', 'Disease', (266, 272))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('metastases', 'Disease', (291, 301))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('inhibitors', 'Var', (4, 14))	('metastases', 'Disease', 'MESH:D009362', (291, 301))	('tumor', 'Disease', (98, 103))
3559	33182665	MMP9 inhibitors lead to a decrease in the number of tumor colonies, but tumors in vivo are larger and more vascularized, which may provide a rationale for the coadministration of MMP inhibitors and antiangiogenic agents.	('tumor colonies', 'Disease', 'MESH:D009369', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('MMP', 'Gene', (0, 3))	('MMP', 'Gene', (179, 182))	('decrease', 'NegReg', (26, 34))	('tumor colonies', 'Disease', (52, 66))	('more', 'PosReg', (102, 106))	('MMP9', 'molecular_function', 'GO:0004229', ('0', '4'))	('inhibitors', 'Var', (5, 15))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('MMP', 'molecular_function', 'GO:0004235', ('179', '182'))	('MMP', 'Gene', '4313;4318;17395', (0, 3))	('MMP', 'Gene', '4313;4318;17395', (179, 182))
3580	33182665	After 24 h, the cells were treated with concentrations corresponding to IC20 or IC50 values of DOX with 20 mug/mL of extracts or with combination of IC20 or IC50 DOX with 20 mug/mL of extracts.	('IC20', 'Var', (149, 153))	('combination', 'Interaction', (134, 145))	('mug', 'molecular_function', 'GO:0043739', ('174', '177'))	('DOX', 'Chemical', 'MESH:D004317', (162, 165))	('mug', 'molecular_function', 'GO:0043739', ('107', '110'))	('DOX', 'Chemical', 'MESH:D004317', (95, 98))	('IC50', 'Var', (157, 161))
3603	32824649	The genetic and epigenetic changes cooperatively produce intratumoral heterogeneity, which may promote the development of competitive cancer cell phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('epigenetic changes', 'Var', (16, 34))	('promote', 'PosReg', (95, 102))	('competitive cancer', 'Disease', 'MESH:D009369', (122, 140))	('competitive cancer', 'Disease', (122, 140))	('tumor', 'Disease', (62, 67))	('rat', 'Species', '10116', (60, 63))	('rat', 'Species', '10116', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('produce', 'Reg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
3614	32824649	As a consequence, even when the tumor mass is reduced, CSCs enriched in mutations, may accumulate within the remainder of the tumor.	('mutations', 'Var', (72, 81))	('accumulate', 'PosReg', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (126, 131))
3687	32824649	CAF-derived sEV miR-92a-3p caused an increased nuclear beta-catenin expression in colorectal carcinoma cells with the appearance of CSC markers and several processes associated with EMT, such as the E-cadherin to N-cadherin switch.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('beta-catenin', 'Gene', (55, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('215', '223'))	('N-cadherin', 'Gene', (213, 223))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('beta-catenin', 'Gene', '1499', (55, 67))	('N-cadherin', 'Gene', '1000', (213, 223))	('E-cadherin', 'Gene', (199, 209))	('miR-92a-3p', 'Var', (16, 26))	('CAF', 'Gene', (0, 3))	('colorectal carcinoma', 'Disease', (82, 102))	('increased', 'PosReg', (37, 46))	('E-cadherin', 'Gene', '999', (199, 209))	('CAF', 'Gene', '8850', (0, 3))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (82, 102))	('EMT', 'biological_process', 'GO:0001837', ('182', '185'))
3827	32323497	In a study by Wang et al., a DL algorithm could predict the mutation of epidermal growth factor receptor from CT images, with an AUC of 0.81 in an independent cohort, outperforming the conventional method of using hand-crafted CT features.	('epidermal growth factor receptor', 'Gene', '1956', (72, 104))	('mutation', 'Var', (60, 68))	('epidermal growth factor receptor', 'Gene', (72, 104))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('72', '95'))
3847	32236608	This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild-type NSCLC cells to cisplatin and how it affects wild-type EGFR in NSCLC cells.	('NSCLC', 'Disease', (192, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('184', '188'))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('epidermal growth factor receptor', 'Gene', (80, 112))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('80', '103'))	('epidermal growth factor receptor', 'Gene', '1956', (80, 112))	('sensitivity', 'MPA', (65, 76))	('inhibition', 'Var', (41, 51))	('EGFR', 'Gene', (184, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('improves', 'PosReg', (52, 60))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('NSCLC', 'Disease', (130, 135))	('CD44', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (184, 188))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('EGFR', 'Gene', '1956', (114, 118))
3855	32236608	Although targeted molecular therapy has achieved great success in treatment of NSCLC, it is usually limited to a group of patients harboring drug-sensitive epidermal growth factor receptor (EGFR) mutations.	('epidermal growth factor receptor', 'Gene', '1956', (156, 188))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('EGFR', 'Gene', '1956', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('156', '179'))	('mutations', 'Var', (196, 205))	('patients', 'Species', '9606', (122, 130))	('EGFR', 'Gene', (190, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('epidermal growth factor receptor', 'Gene', (156, 188))	('NSCLC', 'Disease', (79, 84))
3864	32236608	On the other hand, it was indicated that CD44 is a promoting modulator for EGFR activation.	('cat', 'Gene', (30, 33))	('CD44', 'Var', (41, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('cat', 'Gene', '847', (30, 33))	('EGFR', 'Gene', (75, 79))	('activation', 'PosReg', (80, 90))
3867	32236608	Recently, it has been shown that CD44s, a splicing isoform of CD44, could stabilize protein level of receptor tyrosine kinases (RTKs) through interaction with Rab7A and the absence of CD44 facilitated Rab7A-mediated trafficking of EGFR to lysosomes in glioblastoma cells, contributing to EGFR degradation.	('glioblastoma', 'Disease', 'MESH:D005909', (252, 264))	('protein level of receptor tyrosine kinases', 'MPA', (84, 126))	('interaction', 'Interaction', (142, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('231', '235'))	('Rab7A', 'Gene', (201, 206))	('EGFR', 'Gene', (288, 292))	('CD44', 'Gene', (184, 188))	('contributing', 'Reg', (272, 284))	('glioblastoma', 'Disease', (252, 264))	('Rab7A', 'Gene', (159, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (252, 264))	('degradation', 'biological_process', 'GO:0009056', ('293', '304'))	('EGFR', 'Gene', (231, 235))	('absence', 'Var', (173, 180))	('CD44s', 'Var', (33, 38))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('Rab7A', 'Gene', '7879', (201, 206))	('EGFR', 'Gene', '1956', (288, 292))	('Rab7A', 'Gene', '7879', (159, 164))	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('EGFR', 'Gene', '1956', (231, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('288', '292'))	('facilitated', 'PosReg', (189, 200))
3872	32236608	The present study hypothesized that blocking CD44 may result in altered EGFR signaling and increase sensitivity of wild-type EGFR NSCLC cells to chemotherapeutics such as cisplatin.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', '1956', (72, 76))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('sensitivity', 'MPA', (100, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('increase', 'PosReg', (91, 99))	('EGFR', 'Gene', (72, 76))	('EGFR', 'Gene', (125, 129))	('CD44', 'Gene', (45, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('blocking', 'Var', (36, 44))	('NSCLC', 'Disease', (130, 135))	('altered', 'Reg', (64, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))
3892	32236608	Primary antibodies against phosphorylated (p)-EGFR (Tyr1173; cat.	('cat', 'molecular_function', 'GO:0004096', ('61', '64'))	('EGFR', 'Gene', '1956', (46, 50))	('cat', 'Gene', (61, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('Tyr1173', 'Chemical', '-', (52, 59))	('Tyr1173;', 'Var', (52, 60))	('cat', 'Gene', '847', (61, 64))
3895	32236608	6943; 1:1,000), CD44 (cat.	('CD44', 'Var', (16, 20))	('cat', 'Gene', '847', (22, 25))	('cat', 'Gene', (22, 25))	('cat', 'molecular_function', 'GO:0004096', ('22', '25'))
3921	32236608	The cBioPortal (http://www.cbioportal.org/) for Cancer Genomics provides information on EGFR mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('EGFR', 'Gene', '1956', (88, 92))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutation', 'Var', (93, 101))	('EGFR', 'Gene', (88, 92))
3926	32236608	It was confirmed that, compared with blank cells, transfection with sictr did not significantly affect CD44 expression and cell growth of H460 cells (Fig.	('H460', 'CellLine', 'CVCL:0459', (138, 142))	('sictr', 'Gene', (68, 73))	('CD44', 'Protein', (103, 107))	('cell growth', 'CPA', (123, 134))	('cell growth', 'biological_process', 'GO:0016049', ('123', '134'))	('transfection', 'Var', (50, 62))
3928	32236608	1B, after knockdown of CD44, cisplatin significantly inhibited cell growth of H460 at concentration of 2.5, 5 and 10 microM when compared with the sictr group and 10 microM for cisplatin was selected following in vitro studies.	('cisplatin', 'Var', (29, 38))	('cell growth of H460', 'CPA', (63, 82))	('inhibited', 'NegReg', (53, 62))	('cell growth', 'biological_process', 'GO:0016049', ('63', '74'))	('CD44', 'Gene', (23, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('knockdown', 'Var', (10, 19))	('H460', 'CellLine', 'CVCL:0459', (78, 82))
3929	32236608	The proliferative curve of H460 was further detected after silencing CD44 combined with cisplatin treatment (10 microM).	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('CD44', 'Gene', (69, 73))	('silencing', 'Var', (59, 68))	('H460', 'CellLine', 'CVCL:0459', (27, 31))
3930	32236608	1C, knockdown of CD44 significantly inhibited cell growth of H460.	('inhibited', 'NegReg', (36, 45))	('H460', 'CellLine', 'CVCL:0459', (61, 65))	('CD44', 'Gene', (17, 21))	('cell growth of H460', 'CPA', (46, 65))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('knockdown', 'Var', (4, 13))
3936	32236608	It was further observed that knockdown of CD44 in H460 cells led to a significant G0/G1 cell cycle arrest compared with the control (Fig.	('knockdown', 'Var', (29, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('88', '105'))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('H460', 'CellLine', 'CVCL:0459', (50, 54))	('CD44', 'Gene', (42, 46))	('arrest', 'Disease', (99, 105))
3940	32236608	Its combination with CD44 silencing resulted in a significant increase of G0/G1 populations in H460 cells (Fig.	('H460', 'CellLine', 'CVCL:0459', (95, 99))	('CD44', 'Gene', (21, 25))	('silencing', 'Var', (26, 35))	('G0/G1 populations', 'CPA', (74, 91))	('increase', 'PosReg', (62, 70))
3943	32236608	The cell cycle arrest is believed to be mainly relying on the downregulation of CDKs as well as other cyclins, such as cyclin C. Flow cytometry results indicated that knockdown of CD44 significantly increased the apoptotic population from 5.8 to 13.2% (Fig.	('apoptotic population', 'CPA', (213, 233))	('cyclins', 'Gene', '892', (102, 109))	('cat', 'Gene', (156, 159))	('increased', 'PosReg', (199, 208))	('CDKs', 'Gene', '983;1017;1018;1019;1021', (80, 84))	('cyclin', 'molecular_function', 'GO:0016538', ('119', '125'))	('cyclin C', 'Gene', (119, 127))	('cyclins', 'Gene', (102, 109))	('arrest', 'Disease', 'MESH:D006323', (15, 21))	('knockdown', 'Var', (167, 176))	('cat', 'Gene', '847', (156, 159))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('4', '21'))	('CDKs', 'Gene', (80, 84))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (4, 21))	('cyclin C', 'Gene', '892', (119, 127))	('arrest', 'Disease', (15, 21))	('CD44', 'Gene', (180, 184))
3945	32236608	Western-blot analysis showed that expression of the pro-apoptotic protein Bax was increased while that of anti-apoptotic protein Bcl-2 was decreased after knockdown of CD44 in H460 cells (Fig.	('knockdown', 'Var', (155, 164))	('expression', 'MPA', (34, 44))	('Bax', 'Gene', (74, 77))	('Bcl-2', 'Gene', (129, 134))	('Bcl-2', 'Gene', '596', (129, 134))	('Bcl-2', 'molecular_function', 'GO:0015283', ('129', '134'))	('decreased', 'NegReg', (139, 148))	('H460', 'CellLine', 'CVCL:0459', (176, 180))	('Bax', 'Gene', '581', (74, 77))	('increased', 'PosReg', (82, 91))	('CD44', 'Gene', (168, 172))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
3948	32236608	The results demonstrated that suppression of CD44 promoted cell cycle arrest and cell apoptosis of EGFR wild-type NSCLC cells and further increased the antitumor effect of cisplatin.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('arrest', 'Disease', (70, 76))	('tumor', 'Disease', (156, 161))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', (99, 103))	('increased', 'PosReg', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cell apoptosis', 'CPA', (81, 95))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('59', '76'))	('arrest', 'Disease', 'MESH:D006323', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('CD44', 'Gene', (45, 49))	('EGFR', 'Gene', '1956', (99, 103))	('promoted', 'PosReg', (50, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('suppression', 'Var', (30, 41))	('NSCLC', 'Disease', (114, 119))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (59, 76))
3949	32236608	In order to investigate the effect of silencing CD44 on EGFR signaling in H460 cells, western blotting was performed to discover the expression level of EGFR, AKT and ERK as well as their phosphorylated form.	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('AKT', 'Gene', (159, 162))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', '1956', (153, 157))	('ERK', 'Gene', '2048', (167, 170))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('ERK', 'Gene', (167, 170))	('AKT', 'Gene', '207', (159, 162))	('H460', 'CellLine', 'CVCL:0459', (74, 78))	('CD44', 'Gene', (48, 52))	('silencing', 'Var', (38, 47))	('ERK', 'molecular_function', 'GO:0004707', ('167', '170'))
3951	32236608	4A, EGF-mediated activation of EGFR in H460 cells was reduced in the siCD44 group, as reflected by protein expression of p-EGFR (Tyr1068 and Tyr1173) within 60 min.	('EGFR', 'Gene', (123, 127))	('EGF', 'Gene', (31, 34))	('EGF', 'Gene', '1950', (123, 126))	('EGF', 'Gene', '1950', (4, 7))	('protein expression', 'MPA', (99, 117))	('Tyr1173', 'Chemical', '-', (141, 148))	('EGFR', 'Gene', '1956', (31, 35))	('Tyr1068', 'Chemical', '-', (129, 136))	('siCD44', 'Var', (69, 75))	('activation', 'PosReg', (17, 27))	('EGFR', 'Gene', '1956', (123, 127))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('Tyr1173', 'Var', (141, 148))	('EGF', 'Gene', (123, 126))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('EGF', 'Gene', (4, 7))	('reduced', 'NegReg', (54, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('EGF', 'Gene', '1950', (31, 34))	('EGFR', 'Gene', (31, 35))	('EGF', 'molecular_function', 'GO:0005154', ('4', '7'))	('Tyr1068', 'Var', (129, 136))	('H460', 'CellLine', 'CVCL:0459', (39, 43))
3954	32236608	The results indicated that knockdown of CD44 attenuated EGF-mediated stimulation of EGFR signaling in H460 cells.	('knockdown', 'Var', (27, 36))	('cat', 'Gene', (16, 19))	('CD44', 'Gene', (40, 44))	('H460', 'CellLine', 'CVCL:0459', (102, 106))	('EGF', 'Gene', (84, 87))	('EGF', 'Gene', '1950', (56, 59))	('stimulation', 'MPA', (69, 80))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('attenuated', 'NegReg', (45, 55))	('EGF', 'Gene', '1950', (84, 87))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('cat', 'Gene', '847', (16, 19))	('EGF', 'Gene', (56, 59))	('EGF', 'molecular_function', 'GO:0005154', ('56', '59'))
3955	32236608	It is further confirmed that siCD44 led to direct inhibition of EGFR signaling (Fig.	('inhibition', 'NegReg', (50, 60))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('siCD44', 'Var', (29, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))
3957	32236608	The current study demonstrated that EGFR signaling pathway was attenuated after silencing of CD44 in H460 cells (Fig.	('silencing', 'Var', (80, 89))	('attenuated', 'NegReg', (63, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('36', '58'))	('EGFR', 'Gene', '1956', (36, 40))	('H460', 'CellLine', 'CVCL:0459', (101, 105))	('EGFR', 'Gene', (36, 40))	('CD44', 'Gene', (93, 97))
3959	32236608	In order to confirm that, the EGFR signaling activation including the phosphorylation of EGFR, SRC, AKT and ERK was observed after knockdown of CD44 as well as in combination with cisplatin.	('EGFR', 'Gene', (30, 34))	('ERK', 'Gene', (108, 111))	('SRC', 'Gene', '6714', (95, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('ERK', 'molecular_function', 'GO:0004707', ('108', '111'))	('ERK', 'Gene', '2048', (108, 111))	('knockdown', 'Var', (131, 140))	('AKT', 'Gene', (100, 103))	('SRC', 'Gene', (95, 98))	('phosphorylation', 'MPA', (70, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('CD44', 'Gene', (144, 148))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (89, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('AKT', 'Gene', '207', (100, 103))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('activation', 'PosReg', (45, 55))	('EGFR', 'Gene', '1956', (89, 93))
3960	32236608	While cisplatin alone had a limited effect on EGFR signaling, as revealed by the unchanged protein expression levels of p-EGFR (Tyr1068 and Tyr1173), p-SRC (Tyr416), p-AKT (Ser473), and p-ERK (Tyr204), cisplatin plus CD44 knockdown led to significantly repressed phosphorylation of these proteins (Fig.	('SRC', 'Gene', '6714', (152, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (202, 211))	('Tyr416', 'Chemical', '-', (157, 163))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('phosphorylation', 'biological_process', 'GO:0016310', ('263', '278'))	('EGFR', 'Gene', '1956', (46, 50))	('Ser', 'cellular_component', 'GO:0005790', ('173', '176'))	('repressed', 'NegReg', (253, 262))	('ERK', 'Gene', '2048', (188, 191))	('AKT', 'Gene', '207', (168, 171))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('Tyr1068', 'Var', (128, 135))	('CD44', 'Gene', (217, 221))	('EGFR', 'Gene', (122, 126))	('phosphorylation', 'MPA', (263, 278))	('SRC', 'Gene', (152, 155))	('Tyr1068', 'Chemical', '-', (128, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (6, 15))	('Tyr1173', 'Chemical', '-', (140, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('ERK', 'molecular_function', 'GO:0004707', ('188', '191'))	('EGFR', 'Gene', '1956', (122, 126))	('Tyr204', 'Chemical', '-', (193, 199))	('AKT', 'Gene', (168, 171))	('Ser473', 'Chemical', '-', (173, 179))	('knockdown', 'Var', (222, 231))	('ERK', 'Gene', (188, 191))	('Tyr1173', 'Var', (140, 147))
3962	32236608	A previous study suggested that CD44 may interfere with EGFR degradation.	('EGFR', 'Gene', '1956', (56, 60))	('CD44', 'Var', (32, 36))	('degradation', 'biological_process', 'GO:0009056', ('61', '72'))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('interfere', 'NegReg', (41, 50))
3967	32236608	6D, after knockdown of CD44, EGFR IF staining was significantly decreased, which suggested that siCD44 promoted EGFR degradation, thereby resulting in deactivation of EGFR downstream signaling.	('EGFR', 'Gene', (112, 116))	('degradation', 'MPA', (117, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('degradation', 'biological_process', 'GO:0009056', ('117', '128'))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('siCD44', 'Var', (96, 102))	('CD44', 'Gene', (23, 27))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('deactivation', 'NegReg', (151, 163))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (167, 171))	('promoted', 'PosReg', (103, 111))	('knockdown', 'Var', (10, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))	('EGFR', 'Gene', (167, 171))	('decreased', 'NegReg', (64, 73))
3971	32236608	EGFR mutations or hyperactivation is common among lung cancer patients.	('lung cancer', 'Disease', (50, 61))	('EGFR', 'Gene', (0, 4))	('hyperactivation', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('patients', 'Species', '9606', (62, 70))	('EGFR', 'Gene', '1956', (0, 4))
3972	32236608	While EGFR TKIs achieved a favorable outcome in EGFR-mutant patients and were recommended as first-line treatment for patients with positive EGFR mutation, chemotherapeutics including cisplatin, carboplatin, etoposide and docetaxel were used as the first line of treatment for EGFR-wild-type patients.	('EGFR', 'Gene', '1956', (48, 52))	('carboplatin', 'Chemical', 'MESH:D016190', (195, 206))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('EGFR', 'Gene', '1956', (277, 281))	('patients', 'Species', '9606', (292, 300))	('mutation', 'Var', (146, 154))	('EGFR', 'Gene', '1956', (6, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('EGFR', 'Gene', '1956', (141, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('patients', 'Species', '9606', (60, 68))	('docetaxel', 'Chemical', 'MESH:D000077143', (222, 231))	('EGFR', 'Gene', (48, 52))	('EGFR', 'Gene', (277, 281))	('EGFR', 'molecular_function', 'GO:0005006', ('277', '281'))	('EGFR', 'Gene', (6, 10))	('etoposide', 'Chemical', 'MESH:D005047', (208, 217))	('EGFR', 'Gene', (141, 145))	('patients', 'Species', '9606', (118, 126))
3979	32236608	A previous finding showed that the absence of CD44 in lung cancer cells could result in suppression of cancer stem cell properties including downregulation of tumor occurrence and reversing multi-drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (196, 211))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('downregulation', 'NegReg', (141, 155))	('suppression', 'NegReg', (88, 99))	('cancer', 'Disease', (103, 109))	('lung cancer', 'Disease', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('reversing', 'Reg', (180, 189))	('CD44', 'Gene', (46, 50))	('drug resistance', 'biological_process', 'GO:0009315', ('196', '211'))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('tumor', 'Disease', (159, 164))	('drug resistance', 'biological_process', 'GO:0042493', ('196', '211'))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('absence', 'Var', (35, 42))	('cancer', 'Disease', (59, 65))	('multi-drug resistance', 'MPA', (190, 211))
3980	32236608	Knockdown of CD44 might benefit numerous chemotherapeutic treatments in wild-type EGFR NSCLC.	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', (82, 86))	('NSCLC', 'Disease', (87, 92))	('benefit', 'PosReg', (24, 31))	('Knockdown', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('CD44', 'Gene', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('EGFR', 'Gene', '1956', (82, 86))
3982	32236608	Additionally, cell cycle arrest and cell apoptosis were induced by knockdown of CD44 and the effects were enhanced when in combination with cisplatin.	('CD44', 'Gene', (80, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('cell apoptosis', 'CPA', (36, 50))	('arrest', 'Disease', (25, 31))	('enhanced', 'PosReg', (106, 114))	('knockdown', 'Var', (67, 76))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('14', '31'))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (14, 31))	('induced', 'Reg', (56, 63))	('arrest', 'Disease', 'MESH:D006323', (25, 31))
3985	32236608	It was also reported that a CD44 isoform could attenuate Rab7-induced EGFR degradation by lysosomes in glioblastoma, which provides a novel mechanism for CD44 activated the EGFR signaling pathway.	('Rab7', 'Gene', '7879', (57, 61))	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('CD44', 'Var', (154, 158))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('173', '195'))	('Rab7', 'Gene', (57, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('EGFR', 'Gene', (70, 74))	('glioblastoma', 'Disease', (103, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('EGFR', 'Gene', (173, 177))	('attenuate', 'NegReg', (47, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
3986	32236608	The current study further investigated the related mechanism and found that EGF-mediated activation of EGFR signaling was restrained by CD44 silencing.	('EGFR', 'Gene', '1956', (103, 107))	('silencing', 'Var', (141, 150))	('EGF', 'Gene', '1950', (103, 106))	('CD44', 'Protein', (136, 140))	('EGF', 'Gene', '1950', (76, 79))	('EGFR', 'Gene', (103, 107))	('EGF', 'molecular_function', 'GO:0005154', ('76', '79'))	('signaling', 'biological_process', 'GO:0023052', ('108', '117'))	('activation', 'PosReg', (89, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('restrained', 'NegReg', (122, 132))	('EGF', 'Gene', (103, 106))	('EGF', 'Gene', (76, 79))
3987	32236608	In addition, knockdown of CD44 augments EGFR degradation in CHX in the treatment group, indicating the mechanism underlying the relationship between CD44 and EGFR was consistent with previous findings.	('cat', 'Gene', '847', (92, 95))	('EGFR', 'Gene', (158, 162))	('degradation', 'biological_process', 'GO:0009056', ('45', '56'))	('CHX', 'Chemical', 'MESH:D003513', (60, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('augments', 'PosReg', (31, 39))	('cat', 'Gene', (92, 95))	('CD44', 'Gene', (26, 30))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', '1956', (158, 162))	('knockdown', 'Var', (13, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))
3992	32236608	The current results demonstrated that CD44 inhibition enhanced cisplatin sensitivity in H460 cells, which might be due to the downregulating of EGFR signaling activation.	('signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('EGFR', 'Gene', (144, 148))	('inhibition', 'Var', (43, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('cisplatin sensitivity', 'MPA', (63, 84))	('CD44', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (144, 148))	('enhanced', 'PosReg', (54, 62))	('H460', 'CellLine', 'CVCL:0459', (88, 92))	('downregulating', 'NegReg', (126, 140))
4011	32181043	A search of the electronic medical records at Kings County Hospital Center and SUNY Downstate Medical Center was completed looking for patients with both bronchiectasis and HIV infection identified by either ICD-9 (042 for HIV and 494.0 for bronchiectasis) or ICD-10 codes (B20 for HIV and J47 for bronchiectasis).	('patients', 'Species', '9606', (135, 143))	('bronchiectasis', 'Disease', (298, 312))	('bronchiectasis', 'Disease', (154, 168))	('HIV', 'Disease', 'MESH:D015658', (223, 226))	('bronchiectasis', 'Disease', 'MESH:D001987', (298, 312))	('bronchiectasis', 'Disease', 'MESH:D001987', (154, 168))	('HIV', 'Disease', 'MESH:D015658', (173, 176))	('bronchiectasis', 'Disease', (241, 255))	('bronchiectasis', 'Disease', 'MESH:D001987', (241, 255))	('B20', 'Var', (274, 277))	('HIV', 'Disease', (223, 226))	('HIV', 'Disease', (173, 176))	('bronchiectasis', 'Phenotype', 'HP:0002110', (154, 168))	('bronchiectasis and HIV infection', 'Disease', 'MESH:D001987', (154, 186))	('J47', 'Var', (290, 293))	('J47', 'CellLine', 'CVCL:L675', (290, 293))	('bronchiectasis', 'Phenotype', 'HP:0002110', (298, 312))	('HIV', 'Disease', 'MESH:D015658', (282, 285))	('bronchiectasis', 'Phenotype', 'HP:0002110', (241, 255))	('HIV', 'Disease', (282, 285))
4128	32181043	It has been hypothesized that defective B lymphocyte and neutrophil function leads to decreased response to antigenic stimuli, which may predispose patients to increased lung infections that consequently act as a trigger for the above-mentioned cycle.	('lung infections', 'Phenotype', 'HP:0006532', (170, 185))	('patients', 'Species', '9606', (148, 156))	('lung infections', 'Disease', (170, 185))	('defective B lymphocyte', 'Phenotype', 'HP:0010976', (30, 52))	('defective', 'Var', (30, 39))	('lung infections', 'Disease', 'MESH:D008171', (170, 185))	('increased', 'PosReg', (160, 169))	('decreased', 'NegReg', (86, 95))	('response to antigenic stimuli', 'MPA', (96, 125))
4161	30938103	Nanoparticle albumin-bound paclitaxel (nab-PTX) showed a significantly higher overall response rate (ORR) than solvent-based paclitaxel (sb-PTX) in combination with carboplatin for patients with non-small cell lung cancer (NSCLC) as first-line treatment (33% vs 25%, P = 0.001).	('higher', 'PosReg', (71, 77))	('paclitaxel', 'Chemical', 'MESH:D017239', (27, 37))	('NSCLC', 'Disease', (223, 228))	('paclitaxel', 'Chemical', 'MESH:D017239', (125, 135))	('PTX', 'Chemical', 'MESH:C051905', (140, 143))	('Nanoparticle', 'Var', (0, 12))	('carboplatin', 'Chemical', 'MESH:D016190', (165, 176))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (195, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('patients', 'Species', '9606', (181, 189))	('non-small cell lung cancer', 'Disease', (195, 221))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (195, 221))	('PTX', 'Chemical', 'MESH:C051905', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (199, 221))	('response', 'MPA', (86, 94))
4162	30938103	The frequency of some serious adverse events (AEs) in the nab-PTX arm, such as peripheral neuropathy and neutropenia, was less than that in the sb-PTX arm.1 A 4-week cycle treatment (days 1, 8 and 15) of 125 mg/m2 of nab-PTX for patients with naive advanced NSCLC demonstrated efficacy and tolerability in phase I/II of the study; ORR and median time to progression were 30% and 5 months, respectively.2 In addition, a phase II study of weekly nab-PTX in patients previously treated for advanced NSCLC demonstrated acceptable toxicity and promising activity; ORR and median progression-free survival (mPFS) were 31.7% (95% confidence interval [CI] of 19.3-44.1%) and 4.9 months (95% CI, 2.4-7.4 months), respectively.3   Epidermal growth factor receptor (EGFR) mutations may be predictive biomarkers for the effects of cytotoxic chemotherapy, according to some phase III randomized studies comparing the efficacy of EGFR-tyrosine kinase inhibitors with cytotoxic chemotherapies in NSCLC patients.	('patients', 'Species', '9606', (229, 237))	('PTX', 'Chemical', 'MESH:C051905', (147, 150))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (79, 100))	('peripheral neuropathy', 'Disease', (79, 100))	('toxicity', 'Disease', (526, 534))	('PTX', 'Chemical', 'MESH:C051905', (448, 451))	('NSCLC', 'Disease', 'MESH:D002289', (981, 986))	('EGFR', 'Gene', (916, 920))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('neutropenia', 'Disease', (105, 116))	('Epidermal growth factor receptor', 'Gene', (721, 753))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (79, 100))	('NSCLC', 'Disease', (981, 986))	('mutations', 'Var', (761, 770))	('NSCLC', 'Disease', 'MESH:D002289', (496, 501))	('EGFR', 'Gene', (755, 759))	('NSCLC', 'Disease', (258, 263))	('patients', 'Species', '9606', (455, 463))	('patients', 'Species', '9606', (987, 995))	('PTX', 'Chemical', 'MESH:C051905', (62, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (981, 986))	('PTX', 'Chemical', 'MESH:C051905', (221, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('EGFR', 'Gene', '1956', (916, 920))	('NSCLC', 'Disease', (496, 501))	('neutropenia', 'Disease', 'MESH:D009503', (105, 116))	('tyrosine', 'Chemical', 'None', (921, 929))	('neutropenia', 'Phenotype', 'HP:0001875', (105, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (496, 501))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('721', '744'))	('toxicity', 'Disease', 'MESH:D064420', (526, 534))	('EGFR', 'molecular_function', 'GO:0005006', ('916', '920'))	('neuropathy', 'Phenotype', 'HP:0009830', (90, 100))	('Epidermal growth factor receptor', 'Gene', '1956', (721, 753))	('EGFR', 'Gene', '1956', (755, 759))	('EGFR', 'molecular_function', 'GO:0005006', ('755', '759'))
4169	30938103	The driver mutation status for each patient was also confirmed; EGFR mutation was negative and ALK fusion status was negative or unknown.	('ALK', 'Gene', (95, 98))	('mutation', 'Var', (69, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('ALK', 'Gene', '238', (95, 98))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('patient', 'Species', '9606', (36, 43))	('negative', 'NegReg', (82, 90))
4226	30938103	We performed a prospective, multicenter phase I/II study of weekly nab-PTX therapy in patients with advanced NSCLC without EGFR mutations or ALK rearrangement who were previously treated with platinum-doublet chemotherapy.	('EGFR', 'Gene', (123, 127))	('ALK', 'Gene', '238', (141, 144))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('mutations', 'Var', (128, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('rearrangement', 'Var', (145, 158))	('ALK', 'Gene', (141, 144))	('EGFR', 'Gene', '1956', (123, 127))	('platinum', 'Chemical', 'MESH:D010984', (192, 200))	('PTX', 'Chemical', 'MESH:C051905', (71, 74))	('NSCLC', 'Disease', (109, 114))	('patients', 'Species', '9606', (86, 94))
4233	30938103	Although the prescribed DI was 75 mg/m2/week, skipping treatment or dose reduction of nab-PTX may have resulted in the reduction of the RDI to 83.3%.	('nab-PTX', 'Gene', (86, 93))	('PTX', 'Chemical', 'MESH:C051905', (90, 93))	('skipping', 'Var', (46, 54))	('RDI', 'MPA', (136, 139))	('reduction', 'NegReg', (119, 128))
4240	30938103	The weekly nab-PTX was not a promising treatment for NSCLC patients without EGFR or ALK mutations as a second- or third-line treatment setting.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('ALK', 'Gene', (84, 87))	('EGFR', 'Gene', '1956', (76, 80))	('mutations', 'Var', (88, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('ALK', 'Gene', '238', (84, 87))	('EGFR', 'Gene', (76, 80))	('patients', 'Species', '9606', (59, 67))	('NSCLC', 'Disease', (53, 58))	('PTX', 'Chemical', 'MESH:C051905', (15, 18))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
4249	31451693	For example, the clinical decision making of EGFR-TKI is normally based upon tumor genotyping to identify the existence of EGFR sensitive mutations.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', (45, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('EGFR', 'Gene', '1956', (123, 127))	('tumor', 'Disease', (77, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('clinical', 'Species', '191496', (17, 25))	('mutations', 'Var', (138, 147))
4250	31451693	But at least 20-30% of NSCLC patients with EGFR sensitive mutations do not respond or develop resistance rapidly to EGFR-TKI treatment.	('resistance', 'MPA', (94, 104))	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('develop', 'Reg', (86, 93))	('respond', 'MPA', (75, 82))	('NSCLC', 'Disease', (23, 28))	('not', 'NegReg', (71, 74))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', (116, 120))
4277	31451693	Prior reports have shown that 2-NBDG enters a cell via glucose transporters and is phosphorylated at the C-6 position by hexokinases I-II.	('glucose', 'Chemical', 'MESH:D005947', (55, 62))	('glucose transporters', 'MPA', (55, 75))	('2-NBDG', 'Chemical', 'MESH:C098340', (30, 36))	('2-NBDG', 'Var', (30, 36))
4291	31451693	Taken together, these results indicate that 2-NBDG and C12R can be used as robust surrogates for assessing cellular glucose uptake and mitochondrial oxidation activity, respectively without mutual interference (Supplementary Fig.	('cellular glucose uptake', 'CPA', (107, 130))	('C12R', 'Chemical', '-', (55, 59))	('2-NBDG', 'Chemical', 'MESH:C098340', (44, 50))	('mitochondrial oxidation activity', 'MPA', (135, 167))	('C12R', 'Var', (55, 59))	('glucose uptake', 'biological_process', 'GO:0046323', ('116', '130'))	('glucose', 'Chemical', 'MESH:D005947', (116, 123))
4295	31451693	Target cells are retrieved individually by a micromanipulator based upon recorded addresses for single-cell sequencing of driver mutations, copy number variation (CNV), and transcriptome profiles (Supplementary Fig.	('mutations', 'Var', (129, 138))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('copy number variation', 'Var', (140, 161))
4303	31451693	Measurement of CD45pos leukocytes was used to generate the cut-offs for identification of 2-NBDGhigh and C12Rhigh cells (See Methods).	('2-NBDGhigh', 'Var', (90, 100))	('C12R', 'Chemical', '-', (105, 109))	('2-NBDG', 'Chemical', 'MESH:C098340', (90, 96))	('C12Rhigh', 'Var', (105, 113))
4307	31451693	Among these 34 cells, 18 out of 20 (90%) 2-NBDGhigh cells, 7 out of 10 (70%) C12Rhigh cells, and 3 out of 4 (75%) double positive cells were found to harbor an in-frame deletion (p. E746_A750del) in exon 19 of EGFR, consistent with the mutation status found in the primary lesion (Supplementary Fig.	('p. E746_A750del', 'Mutation', 'p.746,750delA', (179, 194))	('p. E746_A750del', 'Var', (179, 194))	('EGFR', 'Gene', (210, 214))	('2-NBDG', 'Chemical', 'MESH:C098340', (41, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('C12R', 'Chemical', '-', (77, 81))	('EGFR', 'Gene', '1956', (210, 214))
4311	31451693	The CD45neg, metabolically active cells in the MPEs are either highly glycolytic (2-NBDGhigh cells) or having a high mitochondrial oxidation activity (C12Rhigh cells) with few cells in double positive phenotype (Fig.	('glycolytic', 'MPA', (70, 80))	('2-NBDG', 'Chemical', 'MESH:C098340', (82, 88))	('mitochondrial oxidation activity', 'MPA', (117, 149))	('C12R', 'Chemical', '-', (151, 155))	('CD45neg', 'Var', (4, 11))
4333	31451693	For example, in newly diagnosed patients with mutations that confer sensitivity to EGFR-TKIs, the established clinical factors may not effectively distinguish patients who bear EGFR sensitive mutations but do not respond to EGFR-TKIs.	('EGFR', 'Gene', '1956', (83, 87))	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (46, 55))	('clinical', 'Species', '191496', (110, 118))	('EGFR', 'Gene', (224, 228))	('EGFR', 'molecular_function', 'GO:0005006', ('177', '181'))	('EGFR', 'Gene', (83, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('224', '228'))	('EGFR', 'Gene', '1956', (177, 181))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('patients', 'Species', '9606', (159, 167))	('mutations', 'Var', (192, 201))	('EGFR', 'Gene', (177, 181))	('EGFR', 'Gene', '1956', (224, 228))
4338	31451693	In contrast, patients with predominantly mitochondrial oxidation cells (N/R <= 0.5) in their effusions were all partial responders with reduced tumor sizes upon follow-up.	('tumor', 'Disease', (144, 149))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('patients', 'Species', '9606', (13, 21))	('effusion', 'Disease', 'MESH:D010996', (93, 101))	('R', 'Chemical', 'MESH:D019344', (74, 75))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('reduced', 'NegReg', (136, 143))	('effusion', 'Disease', (93, 101))	('mitochondrial oxidation', 'Var', (41, 64))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
4340	31451693	The segregation capability of the N/R ratio holds for patients with EGFR mutations (Fig.	('patients', 'Species', '9606', (54, 62))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('EGFR', 'Gene', '1956', (68, 72))	('R', 'Chemical', 'MESH:D019344', (71, 72))	('R', 'Chemical', 'MESH:D019344', (36, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
4341	31451693	11b), other driver mutations, or WT tumors (Fig.	('WT tumors', 'Disease', (33, 42))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('WT tumors', 'Disease', 'MESH:C536751', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
4346	31451693	This holds true regardless if we evaluated all the patients, or the newly diagnosed patients, or the patients with EGFR mutations (Fig.	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (120, 129))
4350	31451693	For example, although P15 had the highest SUVmax in PET imaging and the highest relative 2-NBDG intensity of 2-NBDGhigh cell population among the three patients, this patient had more C12Rhigh tumor cells present in the MPE and consequently a lower N/R ratio and better response and survival (Fig.	('P15', 'Gene', '1030', (22, 25))	('patient', 'Species', '9606', (152, 159))	('N', 'Chemical', 'MESH:D009584', (249, 250))	('lower', 'NegReg', (243, 248))	('2-NBDG', 'Chemical', 'MESH:C098340', (109, 115))	('patient', 'Species', '9606', (167, 174))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('better', 'PosReg', (263, 269))	('tumor', 'Disease', (193, 198))	('survival', 'CPA', (283, 291))	('N/R ratio', 'MPA', (249, 258))	('P15', 'Gene', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('C12R', 'Chemical', '-', (184, 188))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('C12Rhigh', 'Var', (184, 192))	('patients', 'Species', '9606', (152, 160))	('R', 'Chemical', 'MESH:D019344', (251, 252))	('response', 'CPA', (270, 278))	('more', 'PosReg', (179, 183))	('2-NBDG', 'Chemical', 'MESH:C098340', (89, 95))	('R', 'Chemical', 'MESH:D019344', (187, 188))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
4355	31451693	We first sought to identify if different driver oncogene mutations are associated with different metabolic phenotypes, and thus subsequently predictive for patients' drug response and performance.	('patients', 'Species', '9606', (156, 164))	('metabolic', 'MPA', (97, 106))	('mutations', 'Var', (57, 66))	('predictive', 'Reg', (141, 151))	('associated', 'Reg', (71, 81))
4360	31451693	The diverse metabolic phenotypes were also observed for patients with ALK fusion alteration (Table 1).	('alteration', 'Var', (81, 91))	('ALK', 'Gene', (70, 73))	('patients', 'Species', '9606', (56, 64))	('ALK', 'Gene', '238', (70, 73))
4364	31451693	A small number of nonsynonymous mutations were found in certain metabolic phenotype across 4 out of 5 patients.	('metabolic phenotype', 'MPA', (64, 83))	('patients', 'Species', '9606', (102, 110))	('found', 'Reg', (47, 52))	('nonsynonymous mutations', 'Var', (18, 41))
4391	31451693	Consistent with our expectation, R428 treatment led to significant cell killing in the 2-NBDGhigh phenotype for all three patients (Fig.	('cell killing', 'CPA', (67, 79))	('R', 'Chemical', 'MESH:D019344', (33, 34))	('patients', 'Species', '9606', (122, 130))	('cell killing', 'biological_process', 'GO:0001906', ('67', '79'))	('2-NBDGhigh', 'Disease', (87, 97))	('2-NBDG', 'Chemical', 'MESH:C098340', (87, 93))	('R428', 'Var', (33, 37))
4405	31451693	Specifically, a patient with a high N/R ratio is likely to have a poor therapy response and physiological performance upon follow-up 5-7 months later after MPE draw, as well as a shorter survival time (Figs.	('R', 'Chemical', 'MESH:D019344', (38, 39))	('shorter', 'NegReg', (179, 186))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('high N/R ratio', 'Var', (31, 45))	('patient', 'Species', '9606', (16, 23))	('physiological performance', 'CPA', (92, 117))	('survival time', 'CPA', (187, 200))	('poor', 'NegReg', (66, 70))
4418	31451693	13 and 14), which points to a possibility that patients with high N/R ratios may have higher AXL and checkpoint ligand expression in their tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('ligand', 'molecular_function', 'GO:0005488', ('112', '118'))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('higher', 'PosReg', (86, 92))	('high N/R ratios', 'Var', (61, 76))	('R', 'Chemical', 'MESH:D019344', (68, 69))
4419	31451693	Given the observation that patients with high N/R ratios are less likely to get benefit from traditional chemo- or targeted therapies, alternative treatment strategies, such as inhibition of AXL in combination with the drugs that target the driver oncogenes or first-line checkpoint immunotherapy (anti-PD1, anti-PDL1, etc.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('R', 'Chemical', 'MESH:D019344', (48, 49))	('inhibition', 'Var', (177, 187))	('PD1', 'Gene', '5133', (303, 306))	('PDL1', 'Gene', '29126', (313, 317))	('PD1', 'Gene', (303, 306))	('patients', 'Species', '9606', (27, 35))	('PDL1', 'Gene', (313, 317))
4423	31451693	Although we did not see any exception in our dataset, the robustness and generality of the predictive capability of the N/R ratio in lung cancer requires further examination in a larger patient population before clinical translation, particularly for patients with low frequency driver oncogene mutations, patients receiving checkpoint inhibitors, and other tumor subtypes.	('translation', 'biological_process', 'GO:0006412', ('221', '232'))	('lung cancer', 'Disease', (133, 144))	('tumor', 'Disease', 'MESH:D009369', (358, 363))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('patient', 'Species', '9606', (251, 258))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('driver oncogene', 'Gene', (279, 294))	('tumor', 'Disease', (358, 363))	('mutations', 'Var', (295, 304))	('patients', 'Species', '9606', (251, 259))	('clinical', 'Species', '191496', (212, 220))	('R', 'Chemical', 'MESH:D019344', (122, 123))	('patient', 'Species', '9606', (186, 193))	('patient', 'Species', '9606', (306, 313))	('patients', 'Species', '9606', (306, 314))
4429	31451693	Metabolically active tumor cells with distinct metabolic signatures were retrieved individually by a micromanipulator for single-cell sequencing of driver mutations, CNVs, and transcriptome profiles.	('N', 'Chemical', 'MESH:D009584', (167, 168))	('mutations', 'Var', (155, 164))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
4455	31451693	The numbers of three metabolically active subsets (CD45neg/2-NBDGhigh/C12Rhigh, CD45neg/2-NBDGlow/C12Rhigh, CD45neg/2-NBDGhigh/C12Rlow) were recorded for each patient involved in this study.	('CD45neg/2-NBDGhigh/C12Rhigh', 'Var', (51, 78))	('2-NBDG', 'Chemical', 'MESH:C098340', (116, 122))	('CD45neg/2-NBDGhigh/C12Rlow', 'Var', (108, 134))	('C12R', 'Chemical', '-', (70, 74))	('patient', 'Species', '9606', (159, 166))	('C12Rlow', 'CellLine', 'CVCL:0188', (127, 134))	('CD45neg/2-NBDGlow/C12Rhigh', 'Var', (80, 106))	('2-NBDG', 'Chemical', 'MESH:C098340', (59, 65))	('C12R', 'Chemical', '-', (127, 131))	('C12R', 'Chemical', '-', (98, 102))	('2-NBDG', 'Chemical', 'MESH:C098340', (88, 94))
4466	31451693	Libraries were prepared by NEBNext Ultra  II DNA Library Prep Kit for Illumina (New England Biolabs), fragments end-repair, 3' adenylation and ligation according to the manufacturer's instructions.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('end-repair', 'Var', (112, 122))	("3' adenylation", 'Var', (124, 138))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('fragments end-repair', 'Var', (102, 122))	('ligation', 'Var', (143, 151))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('N', 'Chemical', 'MESH:D009584', (80, 81))
4477	31451693	For identifying tumor-specific protein-altering mutations, RNA-sequencing reads from one phenotype of the same patient were merged and aligned to the major chromosomes of human (hg19) using BWA (v0.7.16) with default options.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('tumor', 'Disease', (16, 21))	('patient', 'Species', '9606', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('human', 'Species', '9606', (171, 176))
4508	31451693	Remnant tumor tissue samples obtained from bronchoscopy were immediately transported to the laboratory in the F12K/DMEM (1:1, Corning) medium, followed by enzymatic digestion with collagenase type I (170 mg L-1, Gibco) and elastase (25 mg L-1, Sigma-Aldrich) at 37  C for 30-45 min.	('L-1', 'Gene', '28938', (239, 242))	('digestion', 'biological_process', 'GO:0007586', ('165', '174'))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('F12K', 'SUBSTITUTION', 'None', (110, 114))	('F12K', 'Var', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('DMEM', 'Chemical', '-', (115, 119))	('L-1', 'Gene', (207, 210))	('tumor', 'Disease', (8, 13))	('L-1', 'Gene', '28938', (207, 210))	('R', 'Chemical', 'MESH:D019344', (0, 1))	('L-1', 'Gene', (239, 242))
4522	31451693	After on-chip cell fixation (2% PFA, 10 min) and blocking (3% BSA and 10% Normal Goat Serum), the chip was imaged again to confirm the disappearance of fluorescence of 2-NBDG and C12R.	('C12R', 'Var', (179, 183))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('Goat', 'Species', '9925', (81, 85))	('2-NBDG', 'Chemical', 'MESH:C098340', (168, 174))	('fluorescence', 'MPA', (152, 164))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('2-NBDG', 'Gene', (168, 174))	('PFA', 'Chemical', 'MESH:D017245', (32, 35))	('C12R', 'Chemical', '-', (179, 183))
4527	31451693	PE Annexin V Apoptosis Detection Kit I was used to measure the apoptosis of cells on the chips for calculating percentages of apoptosis in metabolically active subpopulations (C12Rhigh and 2-NBDGhigh).	('Annexin V', 'Gene', '308', (3, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('Annexin V', 'Gene', (3, 12))	('C12R', 'Chemical', '-', (176, 180))	('C12Rhigh', 'Var', (176, 184))	('2-NBDG', 'Chemical', 'MESH:C098340', (189, 195))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('2-NBDGhigh', 'Var', (189, 199))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
4561	31179236	Similarly, fractionation can sensitize tumor cells to RT by inducing reoxygenation or shifting the tumor cells to a radiation-sensitive phase of the cell cycle.	('tumor', 'Disease', (99, 104))	('reoxygenation', 'MPA', (69, 82))	('sensitize', 'Reg', (29, 38))	('cell cycle', 'biological_process', 'GO:0007049', ('149', '159'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('inducing', 'Reg', (60, 68))	('fractionation', 'Var', (11, 24))
4587	31179236	Cytotoxic CD8+ T cells migrate to the irradiated tumor and eliminate the residual cancer cells as well as to distant metastatic sites which can lead to a systemic tumor regression, the abscopal effect.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Cytotoxic', 'Disease', 'MESH:D064420', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', (163, 168))	('lead to', 'Reg', (144, 151))	('Cytotoxic', 'Disease', (0, 9))	('CD8+', 'Var', (10, 14))
4594	31179236	Similarly, some RT regimens lead to upregulation of DNA exonuclease three-prime repair exonuclease 1 (TREX1) which cleaves RT-induced dsDNA and limits the cGAS/STING/IFN-beta pathway induction.	('cleaves', 'Var', (115, 122))	('three-prime repair exonuclease 1', 'Gene', (68, 100))	('TREX1', 'Gene', (102, 107))	('upregulation', 'PosReg', (36, 48))	('three-prime repair exonuclease 1', 'Gene', '11277', (68, 100))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('TREX1', 'Gene', '11277', (102, 107))	('IFN-beta', 'Gene', '3456', (166, 174))	('limits', 'NegReg', (144, 150))	('induction', 'MPA', (183, 192))	('IFN-beta', 'Gene', (166, 174))
4624	31179236	Currently, there are two ongoing phase II studies to assess the treatment with SABR in combination with a high dose IL-2 regimen for patients with metastatic renal carcinoma (NCT01896271, NCT02306954), one phase II trial for patients with metastatic melanoma (NCT01416831) and one phase II study for both patients with metastatic melanoma and renal cell carcinoma (NCT01884961).	('patients', 'Species', '9606', (133, 141))	('melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (330, 363))	('NCT01416831', 'Var', (260, 271))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (343, 363))	('NCT02306954', 'Var', (188, 199))	('melanoma', 'Phenotype', 'HP:0002861', (330, 338))	('metastatic renal carcinoma', 'Disease', (147, 173))	('melanoma', 'Disease', (330, 338))	('SABR', 'Chemical', '-', (79, 83))	('patients', 'Species', '9606', (225, 233))	('metastatic renal carcinoma', 'Disease', 'MESH:C538445', (147, 173))	('patients', 'Species', '9606', (305, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('IL-2', 'molecular_function', 'GO:0005134', ('116', '120'))	('carcinoma', 'Phenotype', 'HP:0030731', (354, 363))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('renal carcinoma', 'Phenotype', 'HP:0005584', (158, 173))	('melanoma', 'Disease', 'MESH:D008545', (330, 338))	('NCT01896271', 'Var', (175, 186))
4627	31179236	Nivolumab and Ipilimumab with IL-2 and RT will be tested in pilot phase I trial for patients with metastatic NSCLC (NCT03224871) and pembrolizumab in phase I/II trial for patients with various metastatic tumors (NCT03474497).	('NCT03224871', 'Var', (116, 127))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (14, 24))	('patients', 'Species', '9606', (84, 92))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('patients', 'Species', '9606', (171, 179))	('pembrolizumab', 'Chemical', 'MESH:C582435', (133, 146))	('IL-2', 'molecular_function', 'GO:0005134', ('30', '34'))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('NSCLC', 'Disease', (109, 114))
4635	31179236	These preclinical findings set base for the initiation of phase I clinical trial in patients with metastatic solid tumors (NCT02086721), and phase II trial for stage IV NSCLC patients (currently withdrawn) (NCT02735850) (Table 2).	('solid tumors', 'Disease', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (84, 92))	('NCT02735850', 'Var', (207, 218))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('NSCLC', 'Disease', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (175, 183))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('NCT02086721', 'Var', (123, 134))
4639	31179236	Tumor regression was observed in 80% of mice when treated with RT and NHS-IL2 and in almost 100% mice when treated with the triple combination.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NHS-IL2', 'Var', (70, 77))	('mice', 'Species', '10090', (97, 101))	('Tumor regression', 'CPA', (0, 16))	('IL2', 'molecular_function', 'GO:0005134', ('74', '77'))	('mice', 'Species', '10090', (40, 44))
4651	31179236	ALT-803 is a mutated IL-15 (N72D) to enhance its biological activity bound to an IL-15RalphaSu/Fc fusion protein.	('IL-15Ralpha', 'Gene', (81, 92))	('biological activity', 'MPA', (49, 68))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('IL-15', 'molecular_function', 'GO:0016170', ('21', '26'))	('ALT', 'molecular_function', 'GO:0004021', ('0', '3'))	('N72D', 'Mutation', 'p.N72D', (28, 32))	('ALT', 'Gene', (0, 3))	('N72D', 'Var', (28, 32))	('IL-15', 'molecular_function', 'GO:0016170', ('81', '86'))	('IL-15Ralpha', 'Gene', '3601', (81, 92))	('ALT', 'Gene', '76282', (0, 3))	('enhance', 'PosReg', (37, 44))
4657	31179236	GM-CSF was also shown to stimulate the capacity of neutrophils, macrophages and monocytes to mediate antibody-dependent cytotoxicity.	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('cytotoxicity', 'Disease', (120, 132))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('stimulate', 'PosReg', (25, 34))	('GM-CSF', 'Var', (0, 6))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))
4665	31179236	Similarly, in glioblastoma there is a study planning the intratumoral addition of polyI:C together with GM-CSF and RT (NCT03392545).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('glioblastoma', 'Disease', (14, 26))	('glioblastoma', 'Disease', 'MESH:D005909', (14, 26))	('polyI:C', 'Var', (82, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('polyI:C', 'Chemical', 'MESH:D011070', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
4699	31179236	The receptor for IL-12 consists of IL-12Rbeta1 and IL-12Rbeta2.	('IL-12Rbeta1', 'Gene', (35, 46))	('IL-12', 'molecular_function', 'GO:0005143', ('17', '22'))	('IL-12Rbeta1', 'Gene', '3594', (35, 46))	('IL-12', 'Gene', (17, 22))	('IL-12', 'molecular_function', 'GO:0005143', ('51', '56'))	('IL-12', 'molecular_function', 'GO:0005143', ('35', '40'))	('receptor', 'Gene', '3480', (4, 12))	('receptor', 'Gene', (4, 12))	('IL-12Rbeta2', 'Var', (51, 62))
4732	30771618	In conclusion, TFAP2C-activated MALAT1 modulated the chemoresistance of LUAD cells by sponging miR-200b to upregulate E2F3 and ZEB1.	('TFAP2C', 'Gene', (15, 21))	('TFAP2C', 'Gene', '7022', (15, 21))	('miR-200b', 'Gene', (95, 103))	('chemoresistance of LUAD cells', 'CPA', (53, 82))	('LUAD', 'Phenotype', 'HP:0030078', (72, 76))	('sponging', 'Var', (86, 94))	('E2F3', 'Protein', (118, 122))	('modulated', 'Reg', (39, 48))	('ZEB1', 'Gene', '6935', (127, 131))	('ZEB1', 'Gene', (127, 131))	('upregulate', 'PosReg', (107, 117))	('miR-200b', 'Gene', '406984', (95, 103))	('MALAT1', 'Gene', (32, 38))
4741	30771618	An increasing number of studies have indicated that the aberrant expression of lncRNAs is closely associated with tumor sprouting, cancer cell growth, apoptosis, metastasis, and chemoresistance.	('lncRNAs', 'Gene', (79, 86))	('metastasis', 'CPA', (162, 172))	('cancer', 'Disease', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cell growth', 'biological_process', 'GO:0016049', ('138', '149'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (114, 119))	('chemoresistance', 'CPA', (178, 193))	('apoptosis', 'CPA', (151, 160))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('aberrant expression', 'Var', (56, 75))	('associated', 'Reg', (98, 108))
4745	30771618	For examples, lncRNA H19 can regulate the stemness and chemoresistance of colorectal cancer; lncRNA LBCS inhibits chemoresistance of bladder cancer stem cells by epigenetically silencing SOX2.	('H19', 'Gene', '283120', (21, 24))	('chemoresistance', 'CPA', (55, 70))	('chemoresistance', 'CPA', (114, 129))	('inhibits', 'NegReg', (105, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('SOX2', 'Gene', '6657', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SOX2', 'Gene', (187, 191))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('epigenetically silencing', 'Var', (162, 186))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('stemness', 'Disease', 'MESH:D020295', (42, 50))	('bladder cancer', 'Disease', (133, 147))	('stemness', 'Disease', (42, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('colorectal cancer', 'Disease', (74, 91))	('H19', 'Gene', (21, 24))
4756	30771618	As illustrated in Figure 1A and Figure S4A, three lncRNAs had a fold change >= 2.0 in SPC-A1/DTX, H1299/DTX, and A549/DTX cells compared with parental SPC-A1, H1299, and A549 cells.	('SPC-A1', 'Gene', (86, 92))	('SPC-A1/DTX', 'Gene', '27032', (86, 96))	('H1299/DTX', 'Var', (98, 107))	('DTX', 'Chemical', 'MESH:D000077143', (104, 107))	('A549/DTX', 'Var', (113, 121))	('H1299', 'CellLine', 'CVCL:0060', (159, 164))	('DTX', 'Chemical', 'MESH:D000077143', (93, 96))	('DTX', 'Chemical', 'MESH:D000077143', (118, 121))	('H1299', 'CellLine', 'CVCL:0060', (98, 103))	('SPC', 'molecular_function', 'GO:0009004', ('86', '89'))	('A549', 'CellLine', 'CVCL:0023', (170, 174))	('SPC-A1', 'Gene', (151, 157))	('SPC-A1', 'Gene', '27032', (151, 157))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('SPC-A1', 'Gene', '27032', (86, 92))	('SPC-A1/DTX', 'Gene', (86, 96))	('SPC', 'molecular_function', 'GO:0009004', ('151', '154'))
4758	30771618	qRT-PCR examination showed that only silencing of MALAT1 led to the significant upregulation of miR-200b (Figure 1B).	('upregulation', 'PosReg', (80, 92))	('miR-200b', 'Gene', '406984', (96, 104))	('silencing', 'Var', (37, 46))	('miR-200b', 'Gene', (96, 104))	('MALAT1', 'Gene', (50, 56))
4760	30771618	Furthermore, we assessed the levels of pri-miR-200b and pre-miR-200b in DTX-resistant LUAD cells transfected with MALAT1-specific siRNAs and found that MALAT1 knockdown didn't affect the levels of both pri-miR-200b and pre-miR-200b (Figure S1D), indicating that MALAT1 might regulate miR-200b in DTX-resistant LUAD cells at the post-transcription level.	('knockdown', 'Var', (159, 168))	('miR-200b', 'Gene', (284, 292))	('pre', 'molecular_function', 'GO:0003904', ('56', '59'))	('miR-200b', 'Gene', (43, 51))	('miR-200b', 'Gene', (60, 68))	('DTX', 'Chemical', 'MESH:D000077143', (72, 75))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('miR-200b', 'Gene', '406984', (206, 214))	('miR-200b', 'Gene', '406984', (223, 231))	('LUAD', 'Phenotype', 'HP:0030078', (310, 314))	('miR-200b', 'Gene', (206, 214))	('pre', 'molecular_function', 'GO:0003904', ('219', '222'))	('transcription', 'biological_process', 'GO:0006351', ('333', '346'))	('miR-200b', 'Gene', (223, 231))	('miR-200b', 'Gene', '406984', (284, 292))	('miR-200b', 'Gene', '406984', (43, 51))	('miR-200b', 'Gene', '406984', (60, 68))	('DTX', 'Chemical', 'MESH:D000077143', (296, 299))
4765	30771618	To validate whether these two binding sequences were responsible for the interaction between MALAT1 and miR-200b, we mutated binding sequence 1 (Mut1) and binding sequence 2 (Mut2), respectively.	('mutated', 'Var', (117, 124))	('interaction', 'Interaction', (73, 84))	('binding', 'molecular_function', 'GO:0005488', ('155', '162'))	('miR-200b', 'Gene', '406984', (104, 112))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('binding', 'Interaction', (125, 132))	('binding', 'molecular_function', 'GO:0005488', ('125', '132'))	('miR-200b', 'Gene', (104, 112))
4767	30771618	The results showed that miR-200b mimics significantly decreased the luciferase activity of the WT reporter, Mut1 reporter, and Mut2 reporter, but not that of Mut1/2 reporter (Figure 1G), indicating that these two binding sequences were synergistically responsible for the interaction of MALAT1 and miR-200b.	('activity', 'MPA', (79, 87))	('miR-200b', 'Gene', '406984', (298, 306))	('miR-200b', 'Gene', '406984', (24, 32))	('miR-200b', 'Gene', (298, 306))	('binding', 'molecular_function', 'GO:0005488', ('213', '220'))	('luciferase', 'Enzyme', (68, 78))	('luciferase activity', 'molecular_function', 'GO:0047077', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('68', '87'))	('decreased', 'NegReg', (54, 63))	('miR-200b', 'Gene', (24, 32))	('luciferase activity', 'molecular_function', 'GO:0050397', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('68', '87'))	('mimics', 'Var', (33, 39))
4771	30771618	In addition, the half maximal inhibitory concentration (IC50) value of A549/DTX was higher that that of A549 (Figure S4B).	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('half maximal inhibitory concentration', 'MPA', (17, 54))	('DTX', 'Chemical', 'MESH:D000077143', (76, 79))	('A549/DTX', 'Var', (71, 79))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('higher', 'PosReg', (84, 90))
4772	30771618	Then, we detected the effect of MALAT1 overexpression or knockdown on IC50 in parental or DTX-resistant LUAD cells.	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('overexpression', 'PosReg', (39, 53))	('knockdown', 'Var', (57, 66))	('DTX', 'Chemical', 'MESH:D000077143', (90, 93))
4774	30771618	However, overexpression of mutant type of MALAT1 (MALAT1-MUT) and knockdown of MALAT1-MUT could not affect the IC50 of SPC-A1 and SPC-A1/DTX cells (Figure S4F).	('SPC', 'molecular_function', 'GO:0009004', ('119', '122'))	('mutant', 'Var', (27, 33))	('SPC', 'molecular_function', 'GO:0009004', ('130', '133'))	('IC50', 'MPA', (111, 115))	('SPC-A1', 'Gene', (130, 136))	('SPC-A1', 'Gene', '27032', (130, 136))	('SPC-A1/DTX', 'Gene', (130, 140))	('SPC-A1', 'Gene', (119, 125))	('SPC-A1', 'Gene', '27032', (119, 125))	('SPC-A1/DTX', 'Gene', '27032', (130, 140))
4775	30771618	Then, we detected the effects of MALAT1 overexpression or knockdown on the biological processes of parental or DTX-resistant LUAD cells under the condition with or without DTX.	('DTX', 'Chemical', 'MESH:D000077143', (172, 175))	('LUAD', 'Phenotype', 'HP:0030078', (125, 129))	('DTX', 'Chemical', 'MESH:D000077143', (111, 114))	('MALAT1', 'Gene', (33, 39))	('knockdown', 'Var', (58, 67))
4778	30771618	In contrast, knockdown of MALAT1 significantly inhibited the colony-forming ability of DTX-resistant LUAD cells treated with or without DTX (0 or 100 mug/L) (Figure 2C; Figure S2A).	('inhibited', 'NegReg', (47, 56))	('DTX', 'Chemical', 'MESH:D000077143', (87, 90))	('MALAT1', 'Gene', (26, 32))	('mug', 'molecular_function', 'GO:0043739', ('150', '153'))	('colony-forming ability of', 'CPA', (61, 86))	('LUAD', 'Phenotype', 'HP:0030078', (101, 105))	('knockdown', 'Var', (13, 22))	('DTX', 'Chemical', 'MESH:D000077143', (136, 139))
4779	30771618	Consistently, similar positive effects of MALAT1 overexpression on the proliferation of parental cells, as well as the negative effect of MALAT1 knockdown on the proliferation of DTX-resistant LUAD cells, were validated by 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays (Figure 2D; Figure S3A).	('EdU', 'Chemical', 'MESH:C031086', (250, 253))	('knockdown', 'Var', (145, 154))	('MALAT1', 'Gene', (42, 48))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (223, 248))	('MALAT1', 'Gene', (138, 144))	('DTX', 'Chemical', 'MESH:D000077143', (179, 182))
4780	30771618	The results indicated that overexpression of MALAT1 led to decreased apoptosis rate in parental cells, while MALAT1 knockdown increased the apoptosis rate in DTX-resistant LUAD cells (Figure 3A; Figure S2B).	('MALAT1', 'Gene', (109, 115))	('apoptosis rate', 'CPA', (69, 83))	('LUAD', 'Phenotype', 'HP:0030078', (172, 176))	('decreased', 'NegReg', (59, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('knockdown', 'Var', (116, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('increased', 'PosReg', (126, 135))	('DTX', 'Chemical', 'MESH:D000077143', (158, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
4781	30771618	Overexpression of MALAT1 promoted the cell-cycle progress in parental cells, while knockdown of MALAT1 induced cell-cycle arrest at the G0/G1 phase in DTX-resistant LUAD cells (Figure 3B; Figure S2C).	('LUAD', 'Phenotype', 'HP:0030078', (165, 169))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('111', '128'))	('cell-cycle progress', 'CPA', (38, 57))	('MALAT1', 'Gene', (96, 102))	('promoted', 'PosReg', (25, 33))	('cell-cycle', 'biological_process', 'GO:0007049', ('38', '48'))	('G1 phase', 'biological_process', 'GO:0051318', ('139', '147'))	('DTX', 'Chemical', 'MESH:D000077143', (151, 154))	('knockdown', 'Var', (83, 92))	('cell-cycle arrest at the G0/G1 phase', 'CPA', (111, 147))
4783	30771618	In contrast, the levels were increased by the knockdown of MALAT1 in DTX-resistant LUAD cells.	('DTX', 'Chemical', 'MESH:D000077143', (69, 72))	('LUAD', 'Phenotype', 'HP:0030078', (83, 87))	('knockdown', 'Var', (46, 55))	('MALAT1', 'Gene', (59, 65))	('increased', 'PosReg', (29, 38))	('levels', 'MPA', (17, 23))
4786	30771618	As presented in Figure 4A, the morphology of DTX-resistant cells was distinctly different from that of parental cells because of loss of cell polarity, intercellular adhesion, and formation of pseudopodia.	('intercellular adhesion', 'CPA', (152, 174))	('DTX', 'Chemical', 'MESH:D000077143', (45, 48))	('cell polarity', 'biological_process', 'GO:0007163', ('137', '150'))	('pseudopodia', 'CPA', (193, 204))	('loss', 'NegReg', (129, 133))	('formation', 'biological_process', 'GO:0009058', ('180', '189'))	('different', 'Reg', (80, 89))	('cell polarity', 'CPA', (137, 150))	('DTX-resistant', 'Var', (45, 58))
4789	30771618	In contrast, knockdown of MALAT1 in DTX-resistant cells led to the opposite results (Figure 4B; Figure S3C).	('DTX', 'Chemical', 'MESH:D000077143', (36, 39))	('MALAT1', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))
4792	30771618	Then, cells were injected into nude mice to assess the effect of MALAT1 knockdown on cell growth in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('85', '96'))	('knockdown', 'Var', (72, 81))	('nude mice', 'Species', '10090', (31, 40))	('MALAT1', 'Gene', (65, 71))
4793	30771618	Without DTX treatment, tumors derived from SPC-A1/DTX cells stably transfected with shMALAT1 grew slower than those derived from control cells, and this phenomenon was more significant in tumors treated with DTX (Figures 5A-5C).	('grew', 'CPA', (93, 97))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', (188, 194))	('SPC-A1/DTX', 'Gene', (43, 53))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('shMALAT1', 'Var', (84, 92))	('DTX', 'Chemical', 'MESH:D000077143', (8, 11))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('slower', 'NegReg', (98, 104))	('DTX', 'Chemical', 'MESH:D000077143', (208, 211))	('SPC-A1/DTX', 'Gene', '27032', (43, 53))	('DTX', 'Chemical', 'MESH:D000077143', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SPC', 'molecular_function', 'GO:0009004', ('43', '46'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
4795	30771618	The inhibition of MALAT1 knockdown on Ki-67 and PCNA positivity was more efficient when treating with DTX.	('PCNA', 'molecular_function', 'GO:0003892', ('48', '52'))	('MALAT1', 'Gene', (18, 24))	('PCNA', 'Gene', (48, 52))	('DTX', 'Chemical', 'MESH:D000077143', (102, 105))	('PCNA', 'Gene', '5111', (48, 52))	('knockdown', 'Var', (25, 34))
4800	30771618	As shown in Figure 5G, ectopic MALAT1 knockdown reduced the number of metastatic cells compared with the control group; the result was confirmed by testing H&E-stained lung sections.	('ectopic', 'Var', (23, 30))	('reduced', 'NegReg', (48, 55))	('number of metastatic cells', 'CPA', (60, 86))	('MALAT1', 'Gene', (31, 37))	('knockdown', 'Var', (38, 47))	('H&E', 'Chemical', 'MESH:D006371', (156, 159))
4801	30771618	In all experimental results shown in Figure 5, the effect of MALAT1 knockdown on tumor growth was more significant when treating with DTX.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('knockdown', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('DTX', 'Chemical', 'MESH:D000077143', (134, 137))	('MALAT1', 'Gene', (61, 67))
4807	30771618	Furthermore, we found that the levels of E2F3 and ZEB1 were positively regulated by MALAT1, while miR-200b mimics or inhibitors partially attenuated the effects of MALAT1 overexpression or knockdown on the expression levels of E2F3 and ZEB1 (Figures 6C and 6D; Figure S4I), indicating that MALAT1 regulates E2F3 and ZEB1 expression in a miR-200b-dependent manner.	('ZEB1', 'Gene', '6935', (316, 320))	('miR-200b', 'Gene', '406984', (98, 106))	('ZEB1', 'Gene', '6935', (50, 54))	('ZEB1', 'Gene', (316, 320))	('ZEB1', 'Gene', (50, 54))	('ZEB1', 'Gene', (236, 240))	('attenuated', 'NegReg', (138, 148))	('miR-200b', 'Gene', (98, 106))	('ZEB1', 'Gene', '6935', (236, 240))	('MALAT1', 'Gene', (84, 90))	('miR-200b', 'Gene', '406984', (337, 345))	('miR-200b', 'Gene', (337, 345))	('knockdown', 'Var', (189, 198))
4809	30771618	In addition, we applied dual-luciferase reporter assays and observed that miR-200b mimics inhibited firefly luciferase activity of WT ZEB1 or E2F3 3' UTRs, but not that of mutant type; this effect was abolished by the introduction of MALAT1 (Figure 6F).	('firefly luciferase activity', 'molecular_function', 'GO:0047077', ('100', '127'))	('firefly luciferase', 'Enzyme', (100, 118))	('miR-200b', 'Gene', (74, 82))	('ZEB1', 'Gene', '6935', (134, 138))	('ZEB1', 'Gene', (134, 138))	('activity', 'MPA', (119, 127))	('inhibited', 'NegReg', (90, 99))	('E2F3', 'Var', (142, 146))	('miR-200b', 'Gene', '406984', (74, 82))
4811	30771618	As presented in Figure 7A, the increased IC50 value in parental cell was partially attenuated by the overexpression of miR-200b or the knockdown of E2F3.	('overexpression', 'PosReg', (101, 115))	('knockdown', 'Var', (135, 144))	('E2F3', 'Gene', (148, 152))	('miR-200b', 'Gene', (119, 127))	('attenuated', 'NegReg', (83, 93))	('IC50 value', 'MPA', (41, 51))	('miR-200b', 'Gene', '406984', (119, 127))
4813	30771618	Furthermore, knockdown of MALAT1 weakened proliferative ability and increased apoptosis rate, which could be abolished largely by the introduction of miR-200b inhibitors or E2F3, but not ZEB1 (Figures 7C and 7D).	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('proliferative ability', 'CPA', (42, 63))	('ZEB1', 'Gene', (187, 191))	('ZEB1', 'Gene', '6935', (187, 191))	('miR-200b', 'Gene', '406984', (150, 158))	('weakened', 'NegReg', (33, 41))	('apoptosis rate', 'CPA', (78, 92))	('miR-200b', 'Gene', (150, 158))	('knockdown', 'Var', (13, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('MALAT1', 'Gene', (26, 32))	('increased', 'PosReg', (68, 77))
4816	30771618	Therefore, we confirmed that miR-200b and E2F3 are involved in MALAT1-mediated chemoresistance in LUAD.	('miR-200b', 'Gene', (29, 37))	('involved', 'Reg', (51, 59))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('E2F3', 'Var', (42, 46))	('miR-200b', 'Gene', '406984', (29, 37))	('LUAD', 'Disease', (98, 102))
4822	30771618	Based on online bioinformatics analysis (http://genome.ucsc.edu/index.html), we found the binding region of transcription factor AP-2 gamma (TFAP2C) on the promoters of MALAT1 and ZEB1 (> hg19 dna range = chr11:65264902-65265225;strand = + and > hg19 dna range = chr10:31607523-31608038;strand = +), as well as the binding region of ZEB1 on the promoter of MALAT1 (> hg19 dna range = chr11:65263903-65264418;strand = +) (Figure 8B).	('AP-2 gamma', 'Gene', '7022', (129, 139))	('ZEB1', 'Gene', '6935', (180, 184))	('chr11:65263903-65264418', 'STRUCTURAL_ABNORMALITY', 'None', (384, 407))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('chr11:65264902-65265225', 'STRUCTURAL_ABNORMALITY', 'None', (205, 228))	('ZEB1', 'Gene', (180, 184))	('MALAT1', 'Gene', (357, 363))	('chr10:31607523-31608038', 'STRUCTURAL_ABNORMALITY', 'None', (263, 286))	('transcription factor', 'molecular_function', 'GO:0000981', ('108', '128'))	('AP-2', 'cellular_component', 'GO:0005908', ('129', '133'))	('AP-2 gamma', 'Gene', (129, 139))	('TFAP2C', 'Gene', (141, 147))	('TFAP2C', 'Gene', '7022', (141, 147))	('ZEB1', 'Gene', '6935', (333, 337))	('binding', 'molecular_function', 'GO:0005488', ('315', '322'))	('ZEB1', 'Gene', (333, 337))	('> hg19 dna', 'Var', (365, 375))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))
4826	30771618	As shown in Figure 8D, knockdown of TFAP2C or ZEB1 efficiently reduced the level of MALAT1 both in SPC-A1/DTX and H1299/DTX cells.	('TFAP2C', 'Gene', '7022', (36, 42))	('ZEB1', 'Gene', (46, 50))	('H1299', 'CellLine', 'CVCL:0060', (114, 119))	('reduced', 'NegReg', (63, 70))	('ZEB1', 'Gene', '6935', (46, 50))	('knockdown', 'Var', (23, 32))	('SPC-A1/DTX', 'Gene', (99, 109))	('SPC-A1/DTX', 'Gene', '27032', (99, 109))	('level of MALAT1', 'MPA', (75, 90))	('SPC', 'molecular_function', 'GO:0009004', ('99', '102'))	('DTX', 'Chemical', 'MESH:D000077143', (106, 109))	('DTX', 'Chemical', 'MESH:D000077143', (120, 123))	('TFAP2C', 'Gene', (36, 42))
4827	30771618	In addition, knockdown of TFAP2C could reduce the mRNA and protein levels of ZEB1 (Figure 8E).	('reduce', 'NegReg', (39, 45))	('TFAP2C', 'Gene', (26, 32))	('TFAP2C', 'Gene', '7022', (26, 32))	('ZEB1', 'Gene', (77, 81))	('ZEB1', 'Gene', '6935', (77, 81))	('knockdown', 'Var', (13, 22))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
4832	30771618	The dysregulation of lncRNAs is closely related to the tumorigenesis of various cancer types, which provides new perspectives for the treatment of malignant cancers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('related', 'Reg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('malignant cancers', 'Disease', (147, 164))	('lncRNAs', 'Protein', (21, 28))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancer', 'Disease', (157, 163))	('malignant cancers', 'Disease', 'MESH:D009369', (147, 164))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
4840	30771618	Our study uncovered that inhibiting MALAT1 expression could sensitize LUAD cells to DTX, suppressing proliferation and EMT phenotype of DTX-resistant LUAD cells.	('inhibiting', 'Var', (25, 35))	('suppressing', 'NegReg', (89, 100))	('EMT', 'biological_process', 'GO:0001837', ('119', '122'))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('proliferation', 'CPA', (101, 114))	('DTX', 'Chemical', 'MESH:D000077143', (84, 87))	('sensitize', 'Reg', (60, 69))	('MALAT1', 'Gene', (36, 42))	('expression', 'MPA', (43, 53))	('DTX', 'Chemical', 'MESH:D000077143', (136, 139))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('EMT phenotype', 'CPA', (119, 132))
4841	30771618	What's more, rescue assays demonstrated that knockdown of MALAT1 inhibited LUAD cell proliferation through the miR-200b/E2F3 axis, while knockdown of MALAT1 inhibited EMT progression through the miR-200b/ZEB1 axis.	('ZEB1', 'Gene', '6935', (204, 208))	('inhibited', 'NegReg', (157, 166))	('ZEB1', 'Gene', (204, 208))	('MALAT1', 'Gene', (58, 64))	('LUAD', 'Phenotype', 'HP:0030078', (75, 79))	('EMT progression', 'CPA', (167, 182))	('LUAD cell proliferation', 'CPA', (75, 98))	('knockdown', 'Var', (45, 54))	('miR-200b', 'Gene', '406984', (195, 203))	('knockdown', 'Var', (137, 146))	('miR-200b', 'Gene', (195, 203))	('inhibited', 'NegReg', (65, 74))	('miR-200b', 'Gene', '406984', (111, 119))	('EMT', 'biological_process', 'GO:0001837', ('167', '170'))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('miR-200b', 'Gene', (111, 119))	('MALAT1', 'Gene', (150, 156))
4842	30771618	To confirm whether MALAT1 regulated miR-200b expression on the transcription level or on the post-transcription level, we established a luciferase reporter system and found that the dysregulation of MALAT1 had no effect on the miR-200b promoter, indicating that MALAT1 could regulate miR-200b on the post-transcription level.	('MALAT1', 'Gene', (199, 205))	('miR-200b', 'Gene', (284, 292))	('miR-200b', 'Gene', (36, 44))	('miR-200b', 'Gene', '406984', (36, 44))	('transcription', 'biological_process', 'GO:0006351', ('305', '318'))	('dysregulation', 'Var', (182, 195))	('miR-200b', 'Gene', '406984', (227, 235))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('miR-200b', 'Gene', '406984', (284, 292))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('miR-200b', 'Gene', (227, 235))
4921	30515212	Fifty-six percent of the tumors had NSCLC-like molecular features, such as lack of RB1+TP53 coalteration and presence of NSCLC-type common mutations including STK11, KRAS, KEAP1, and NFE2L2, while 40% showed SCLC-like molecular features, with RB1+TP53 coalteration, complete absence of mutations in STK11 and KRAS, and exclusive or enriched occurrence of MYCL, SOX2, and FGFR1 amplifications and mutation and/or loss of PTEN .	('NFE2L2', 'Gene', (183, 189))	('NSCLC-type', 'Disease', 'MESH:D017827', (121, 131))	('STK11', 'Gene', '6794', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('SOX2', 'Gene', '6657', (361, 365))	('STK11', 'molecular_function', 'GO:0033868', ('299', '304'))	('SOX2', 'Gene', (361, 365))	('PTEN', 'Gene', '5728', (420, 424))	('FGFR1', 'Gene', '2260', (371, 376))	('STK11', 'Gene', '6794', (299, 304))	('SCLC', 'Phenotype', 'HP:0030357', (37, 41))	('TP53', 'Gene', '7157', (87, 91))	('mutations', 'Var', (286, 295))	('FGFR', 'molecular_function', 'GO:0005007', ('371', '375'))	('absence', 'NegReg', (275, 282))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('SCLC', 'Gene', '7864', (37, 41))	('SCLC', 'Gene', (37, 41))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('TP53', 'Gene', (247, 251))	('KRAS', 'Gene', '3845', (309, 313))	('MYCL', 'Gene', (355, 359))	('FGFR1', 'Gene', (371, 376))	('KRAS', 'Gene', '3845', (166, 170))	('STK11', 'Gene', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('SCLC', 'Phenotype', 'HP:0030357', (208, 212))	('NSCLC', 'Disease', (36, 41))	('NFE2L2', 'Gene', '4780', (183, 189))	('mutation', 'Var', (396, 404))	('SCLC', 'Gene', '7864', (122, 126))	('SCLC', 'Gene', (122, 126))	('MYCL', 'Gene', '4610', (355, 359))	('STK11', 'molecular_function', 'GO:0033868', ('159', '164'))	('NSCLC-type', 'Disease', (121, 131))	('KRAS', 'Gene', (309, 313))	('mutations', 'Var', (139, 148))	('KEAP1', 'Gene', '9817', (172, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', (87, 91))	('KRAS', 'Gene', (166, 170))	('STK11', 'Gene', (299, 304))	('PTEN', 'Gene', (420, 424))	('NSCLC', 'Disease', (121, 126))	('SCLC', 'Gene', '7864', (208, 212))	('KEAP1', 'Gene', (172, 177))	('SCLC', 'Gene', (208, 212))	('TP53', 'Gene', '7157', (247, 251))	('loss', 'NegReg', (412, 416))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
4970	30197847	Finally, a randomized, double-blind placebo-controlled study at the Penn State College of Medicine (PSU) focusing on Crohn's disease (CD) determined that 88% of the patients receiving LDN versus the control group had a 70-point decline in Crohn's Disease Activity Index Score (CDAI) .	('CD', 'Phenotype', 'HP:0100280', (134, 136))	('LDN', 'Chemical', '-', (184, 187))	("Crohn's disease", 'Disease', (117, 132))	('CD', 'Disease', 'MESH:D006223', (134, 136))	("Crohn's disease", 'Disease', 'MESH:D003424', (117, 132))	("Crohn's Disease", 'Disease', 'MESH:D003424', (239, 254))	("Crohn's Disease", 'Disease', (239, 254))	('CD', 'Disease', 'MESH:D006223', (277, 279))	('decline', 'NegReg', (228, 235))	('CD', 'Phenotype', 'HP:0100280', (277, 279))	('LDN', 'Var', (184, 187))	('patients', 'Species', '9606', (165, 173))	("Crohn's disease", 'Phenotype', 'HP:0100280', (117, 132))	("Crohn's Disease", 'Phenotype', 'HP:0100280', (239, 254))
5037	29782069	We obtained clinical data of participating patients from the electronic medical records of each institution, including: age, gender, smoking history, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), histology, any existing driver gene mutations, prior therapies (including surgery and radiotherapy), and the comorbidity of autoimmune diseases.	('autoimmune diseases', 'Disease', 'MESH:D001327', (339, 358))	('mutations', 'Var', (251, 260))	('autoimmune diseases', 'Disease', (339, 358))	('patients', 'Species', '9606', (43, 51))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (339, 358))	('Oncology', 'Phenotype', 'HP:0002664', (170, 178))
5054	29782069	There were significant differences between the groups regarding the number of patients carrying a positive EGFR mutation (0% vs. 22%; P = 0.003), with RA (27% vs. 2%; P < 0.001), or who had undergone prior thoracic radiotherapy (11% vs. 32%; P = 0.039).	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'Gene', '1956', (107, 111))	('mutation', 'Var', (112, 120))	('patients', 'Species', '9606', (78, 86))	('EGFR', 'Gene', (107, 111))	('RA', 'Phenotype', 'HP:0001370', (151, 153))	('RA', 'Disease', 'MESH:D001172', (151, 153))
5226	29967723	On the other hand, F-actin modification reagents usually decrease cell migration, and apoptotic cells are less stiff than normal cells.	('F-actin', 'Protein', (19, 26))	('decrease', 'NegReg', (57, 65))	('actin modification', 'biological_process', 'GO:0030047', ('21', '39'))	('cell migration', 'CPA', (66, 80))	('F-actin', 'cellular_component', 'GO:0031941', ('19', '26'))	('modification', 'Var', (27, 39))	('rat', 'Species', '10116', (74, 77))	('less', 'NegReg', (106, 110))	('cell migration', 'biological_process', 'GO:0016477', ('66', '80'))
5253	29868476	In patients with driver mutations of non-small cell lung cancer (NSCLC), systemic therapies have become more effective in patients with metastatic disease, resulting in longer overall survival (OS).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('overall survival', 'MPA', (176, 192))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('non-small cell lung cancer', 'Disease', (37, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (3, 11))	('OS', 'Chemical', '-', (194, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('mutations', 'Var', (24, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('longer', 'PosReg', (169, 175))	('NSCLC', 'Disease', (65, 70))
5286	29868476	There are several remarks with respect to clinical application of the results: patients were only included if the patient or the multidisciplinary team had doubts if WBRT should be applied, favorable prognostic patients (RPA class I) did have a survival benefit of WBRT, and the effect on symptom control such as seizures or headache were not described in detail.	('WBRT', 'Var', (265, 269))	('patients', 'Species', '9606', (211, 219))	('headache', 'Disease', 'MESH:D006261', (325, 333))	('seizures', 'Disease', 'MESH:D012640', (313, 321))	('RPA', 'cellular_component', 'GO:0005662', ('221', '224'))	('headache', 'Phenotype', 'HP:0002315', (325, 333))	('patient', 'Species', '9606', (79, 86))	('survival benefit', 'CPA', (245, 261))	('headache', 'Disease', (325, 333))	('patients', 'Species', '9606', (79, 87))	('patient', 'Species', '9606', (114, 121))	('seizures', 'Phenotype', 'HP:0001250', (313, 321))	('seizures', 'Disease', (313, 321))	('patient', 'Species', '9606', (211, 218))
5302	29868476	For patients with an EGFR targetable mutated NSCLC, an alternative first line of treatment consists of an EGFR inhibitor like erlotinib, gefitinib, osimertinib, or afatinib with a response rate of approximately 60-70%.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('afatinib', 'Chemical', 'MESH:D000077716', (164, 172))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('osimertinib', 'Chemical', 'MESH:C000603933', (148, 159))	('EGFR', 'Gene', '1956', (106, 110))	('patients', 'Species', '9606', (4, 12))	('mutated', 'Var', (37, 44))	('erlotinib', 'Chemical', 'MESH:D000069347', (126, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('gefitinib', 'Chemical', 'MESH:D000077156', (137, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('EGFR', 'Gene', (106, 110))
5308	29868476	Patients who are tyrosine kinase inhibitors (TKI) naive and have an EGFR mutation had a better survival than patients who were treated with primary systemic therapy.	('better', 'PosReg', (88, 94))	('patients', 'Species', '9606', (109, 117))	('survival', 'MPA', (95, 103))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))
5344	29868476	They used two separate cut-points of DS-GPA, >=2.0 vs <2.0 and >=2.5 vs <2.5 in a study population consisting of 126 NSCLC patients with 1-3 BM.	('NSCLC', 'Disease', (117, 122))	('>=2.5', 'Var', (63, 68))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('DS-GPA', 'Chemical', '-', (37, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))
5357	29868476	The trial population consisted of favorable prognostic patients with low volume BM, three-quarters originate from primary lung cancer, the majority had an RPA 2 and KPS >= 80 (largest tumor <10 mL in volume, <3 cm in longest diameter; total cumulative volume <=15 mL).	('KPS >= 80', 'Var', (165, 174))	('RPA 2', 'Gene', (155, 160))	('originate from', 'Reg', (99, 113))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('RPA', 'cellular_component', 'GO:0005662', ('155', '158'))	('tumor', 'Disease', (184, 189))	('primary lung cancer', 'Disease', (114, 133))	('patients', 'Species', '9606', (55, 63))	('RPA 2', 'Gene', '6118', (155, 160))	('primary lung cancer', 'Disease', 'MESH:D008175', (114, 133))
5375	29868476	In the Netherlands a randomized phase III trial (NCT02353000, ) is enrolling patients with 4-10 BM, KPS >= 70, and any primary solid tumor including NSCLC.	('NSCLC', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('solid tumor', 'Disease', (127, 138))	('solid tumor', 'Disease', 'MESH:D009369', (127, 138))	('patients', 'Species', '9606', (77, 85))	('KPS >= 70', 'Var', (100, 109))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
5380	29868476	Several other trials are currently being initiated to evaluate the role of SRS in patients with multiple BM, such as Heidelberg (NCT0329778) and Boston (NTC03075072), among others.	('SRS', 'Disease', (75, 78))	('patients', 'Species', '9606', (82, 90))	('NCT0329778', 'Var', (129, 139))	('NTC', 'cellular_component', 'GO:0000974', ('153', '156'))	('NTC03075072', 'Var', (153, 164))	('SRS', 'Disease', 'MESH:C536678', (75, 78))
5381	29868476	Another treatment option for patients with multiple BM, especially in patients with asymptomatic BM of a driver mutation, is to only treat the larger and worrisome BM with SRS (Figure 1).	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (29, 37))	('SRS', 'Disease', 'MESH:C536678', (172, 175))	('mutation', 'Var', (112, 120))	('SRS', 'Disease', (172, 175))
5416	29868476	randomized 80 NSCLC patients with KPS >= 70 and multiple BM to erlotinib or placebo arms, both concurrent with WBRT.	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('KPS >= 70', 'Var', (34, 43))	('patients', 'Species', '9606', (20, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('erlotinib', 'Chemical', 'MESH:D000069347', (63, 72))
5419	29868476	More grade 3/4 toxicity was found in the erlotinib arm compared with the placebo arm for fatigue and rash and there was no reported difference in the QoL.	('rash', 'Disease', (101, 105))	('fatigue', 'Phenotype', 'HP:0012378', (89, 96))	('rash', 'Phenotype', 'HP:0000988', (101, 105))	('erlotinib', 'Var', (41, 50))	('rash', 'Disease', 'MESH:D005076', (101, 105))	('fatigue', 'Disease', 'MESH:D005221', (89, 96))	('toxicity', 'Disease', 'MESH:D064420', (15, 23))	('toxicity', 'Disease', (15, 23))	('erlotinib', 'Chemical', 'MESH:D000069347', (41, 50))	('fatigue', 'Disease', (89, 96))
5424	29868476	The performance status was inferior in the group with erlotinib or temozolomide compared with the group treated with WBRT plus SRS.	('temozolomide', 'Chemical', 'MESH:D000077204', (67, 79))	('performance', 'MPA', (4, 15))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('WBRT plus SRS', 'Disease', (117, 130))	('inferior', 'NegReg', (27, 35))	('WBRT plus SRS', 'Disease', 'MESH:C536678', (117, 130))	('erlotinib', 'Var', (54, 63))
5425	29868476	They found more grade 3-5 toxicity in the patients treated with targeted therapy concurrent with radiation.	('targeted', 'Var', (64, 72))	('patients', 'Species', '9606', (42, 50))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('toxicity', 'Disease', (26, 34))
5430	29868476	The median survival was 9.3 months for EGFR wild-type patients and 19.1 months for patients with an EGFR mutation.	('EGFR', 'Gene', '1956', (100, 104))	('mutation', 'Var', (105, 113))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (83, 91))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
5467	29868476	At present, patients having NSCLC with driver mutations are treated with multiple lines of systemic therapy leading to an increasing importance of the management of BM.	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Disease', (28, 33))	('mutations', 'Var', (46, 55))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))
5516	29456881	Resectable disease typically includes T4N0 tumours for which complete (R0) resection is considered by a multi-disciplinary team (MDT) to be feasible, or N2 disease with single nodal station involvement.	('nodal', 'Gene', (176, 181))	('nodal', 'Gene', '4838', (176, 181))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('Resectable disease', 'Disease', (0, 18))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', (43, 50))	('MDT', 'Disease', (129, 132))	('MDT', 'Disease', 'None', (129, 132))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('T4N0', 'Var', (38, 42))
5537	29456881	Several studies have shown that single-station N2 disease is associated with a longer survival (from 40 to 67% in the absence of concomitant pN1 disease).	('N1 disease', 'Disease', (142, 152))	('N1 disease', 'Disease', 'MESH:D004194', (142, 152))	('single-station', 'Var', (32, 46))	('N2 disease', 'Disease', (47, 57))	('longer', 'PosReg', (79, 85))	('pN1', 'Gene', '5270', (141, 144))	('pN1', 'Gene', (141, 144))
5542	29456881	Whilst there is now good evidence for the utility of adjuvant chemotherapy in NSCLC, a meta-analysis of early trials undertaken during the 1990s suggested that the use of alkylating-agents was detrimental to overall survival.	('detrimental', 'NegReg', (193, 204))	('alkylating-agents', 'Var', (171, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('NSCLC', 'Disease', (78, 83))	('overall', 'MPA', (208, 215))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
5556	29456881	Additional therapeutic options to reduce the rate of disease progression include targeted inhibition of anaplastic lymphoma kinase (ALK) and EGFR, in addition to a raft of immune-checkpoint inhibitors.	('lymphoma', 'Phenotype', 'HP:0002665', (115, 123))	('anaplastic lymphoma kinase', 'Gene', (104, 130))	('EGFR', 'Gene', '1956', (141, 145))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (104, 123))	('ALK', 'Gene', '238', (132, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('anaplastic lymphoma kinase', 'Gene', '238', (104, 130))	('EGFR', 'Gene', (141, 145))	('ALK', 'Gene', (132, 135))	('targeted inhibition', 'Var', (81, 100))
5594	29456881	In the context of lung metastases, sublobar resection may deliver reduced toxicity compared with lobectomy or pneumonectomy.	('reduced', 'NegReg', (66, 73))	('toxicity', 'Disease', (74, 82))	('lung metastases', 'Disease', (18, 33))	('lung metastases', 'Disease', 'MESH:D009362', (18, 33))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('sublobar resection', 'Var', (35, 53))
5628	29456881	Generating a risk-model, the authors identified nodal involvement and synchronous, as oppose to metachronous, metastases as predictive of worse overall survival.	('synchronous', 'Var', (70, 81))	('metastases', 'Disease', (110, 120))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('nodal', 'Gene', (48, 53))	('nodal', 'Gene', '4838', (48, 53))
5649	29235457	However, gene abnormalities are uncommon and virtually all patients develop resistance to the corresponding target therapy.	('gene abnormalities', 'Var', (9, 27))	('develop', 'Reg', (68, 75))	('patients', 'Species', '9606', (59, 67))	('resistance', 'MPA', (76, 86))
5719	29235457	However, treatment with the heat shock protein (HSP) 90 inhibitor was reported to cause an increase in PC in several cancer models.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('shock', 'Phenotype', 'HP:0031273', (33, 38))	('inhibitor', 'Var', (56, 65))	('increase', 'PosReg', (91, 99))	('heat shock protein (HSP) 90', 'Gene', '3320', (28, 55))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('PC', 'Chemical', '-', (103, 105))	('cancer', 'Disease', (117, 123))	('heat shock protein (HSP) 90', 'Gene', (28, 55))
5765	28961214	Elevated exposure to cadmium is associated with reduced pulmonary function, obstructive lung disease, bronchogenic carcinoma, cardiovascular diseases including myocardial infarction, peripheral arterial disease, prostate cancer, cervical cancer, pancreatic cancer, and various oral pathologies.	('obstructive lung disease', 'Disease', (76, 100))	('bronchogenic carcinoma', 'Disease', 'MESH:D002283', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('bronchogenic carcinoma', 'Disease', (102, 124))	('peripheral arterial disease', 'Disease', 'MESH:D058729', (183, 210))	('myocardial infarction', 'Disease', (160, 181))	('pancreatic cancer', 'Disease', (246, 263))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (126, 148))	('myocardial infarction', 'Phenotype', 'HP:0001658', (160, 181))	('cervical cancer', 'Disease', (229, 244))	('cervical cancer', 'Disease', 'MESH:D002583', (229, 244))	('cardiovascular diseases', 'Disease', (126, 149))	('reduced pulmonary function', 'Phenotype', 'HP:0005952', (48, 74))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (126, 149))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('lung disease', 'Phenotype', 'HP:0002088', (88, 100))	('myocardial infarction', 'Disease', 'MESH:D009203', (160, 181))	('cadmium', 'Var', (21, 28))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (246, 263))	('reduced', 'NegReg', (48, 55))	('oral pathologies', 'Disease', (277, 293))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('obstructive lung disease', 'Phenotype', 'HP:0006536', (76, 100))	('prostate cancer', 'Disease', 'MESH:D011471', (212, 227))	('cadmium', 'Chemical', 'MESH:D002104', (21, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (212, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (126, 149))	('pulmonary function', 'Disease', (56, 74))	('prostate cancer', 'Disease', (212, 227))	('peripheral arterial disease', 'Phenotype', 'HP:0004950', (183, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (246, 263))	('peripheral arterial disease', 'Disease', (183, 210))	('obstructive lung disease', 'Disease', 'MESH:D008173', (76, 100))
5779	28961214	Strong evidence exists supporting cadmium as an inducer of proinflammatory cytokines, as a carcinogen, and as a substance that causes disease in many tissues in the body including the lungs and the kidneys.	('cadmium', 'Chemical', 'MESH:D002104', (34, 41))	('causes', 'Reg', (127, 133))	('disease', 'Disease', (134, 141))	('proinflammatory cytokines', 'MPA', (59, 84))	('cadmium', 'Var', (34, 41))
5783	28961214	In addition to inhibiting DNA repair enzymes, cadmium exposure causes an inflammatory response by stimulating reactive oxygen species production by human polymorphonuclear leukocytes and phagocytic cells.	('DNA repair', 'biological_process', 'GO:0006281', ('26', '36'))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('inflammatory response', 'CPA', (73, 94))	('stimulating', 'PosReg', (98, 109))	('cadmium', 'Var', (46, 53))	('human', 'Species', '9606', (148, 153))	('inflammatory response', 'biological_process', 'GO:0006954', ('73', '94'))	('cadmium', 'Chemical', 'MESH:D002104', (46, 53))	('reactive oxygen species production', 'MPA', (110, 144))	('causes', 'Reg', (63, 69))	('inhibiting', 'NegReg', (15, 25))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (110, 133))
5866	28961214	They concluded that cadmium exposure is a risk factor for cardiovascular disease with 1084 cardiovascular events, including 400 deaths among 3348 study subjects.	('deaths', 'Disease', (128, 134))	('cardiovascular disease', 'Disease', (58, 80))	('cadmium', 'Chemical', 'MESH:D002104', (20, 27))	('deaths', 'Disease', 'MESH:D003643', (128, 134))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (58, 80))	('cardiovascular', 'Disease', (91, 105))	('cardiovascular disease', 'Disease', 'MESH:D002318', (58, 80))	('cardiovascular events', 'Phenotype', 'HP:0001626', (91, 112))	('cadmium', 'Var', (20, 27))
5937	28961214	Both changes facilitate angiogenesis and cell migratory properties and are likely indicative of cell transformation to an early stage of cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('facilitate', 'PosReg', (13, 23))	('changes', 'Var', (5, 12))	('cell migratory properties', 'CPA', (41, 66))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('angiogenesis', 'biological_process', 'GO:0001525', ('24', '36'))	('angiogenesis', 'CPA', (24, 36))
5967	28961214	Collectively these factors are consistent with cadmium exposure as a risk factor for pancreatic cancer and for smoking as the most commonly associated risk factor for pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('cadmium', 'Var', (47, 54))	('pancreatic cancer', 'Disease', (167, 184))	('cadmium', 'Chemical', 'MESH:D002104', (47, 54))
6005	28961214	Some studies suggest that cadmium exposure may increase the risk of vascular and heart disease.	('cadmium', 'Chemical', 'MESH:D002104', (26, 33))	('cadmium', 'Var', (26, 33))	('heart disease', 'Disease', 'MESH:D006331', (81, 94))	('heart disease', 'Disease', (81, 94))
6040	28322105	Multivariate logistic regression analysis showed that levels of D-dimer, CA125 and CA199 were independently related to lung cancer-associated stroke.	('stroke', 'Disease', 'MESH:D020521', (142, 148))	('lung cancer', 'Disease', (119, 130))	('CA125', 'Gene', (73, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CA199', 'Var', (83, 88))	('CA125', 'Gene', '94025', (73, 78))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('stroke', 'Phenotype', 'HP:0001297', (142, 148))	('CA199', 'Chemical', '-', (83, 88))	('stroke', 'Disease', (142, 148))	('related', 'Reg', (108, 115))	('D-dimer', 'MPA', (64, 71))
6041	28322105	Elevated plasma D-dimer, CA125 and CA199 may be independent risk factors for and biomarkers of lung cancer-associated stroke.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('stroke', 'Disease', 'MESH:D020521', (118, 124))	('CA199', 'Chemical', '-', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('plasma D-dimer', 'MPA', (9, 23))	('CA125', 'Gene', '94025', (25, 30))	('Elevated', 'PosReg', (0, 8))	('stroke', 'Phenotype', 'HP:0001297', (118, 124))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('stroke', 'Disease', (118, 124))	('CA199', 'Var', (35, 40))	('CA125', 'Gene', (25, 30))
6075	28322105	The medical records of the patients were scanned for relevant information, including demographic data, routine laboratory investigations, D-dimer levels, presence of cancer markers such as CA125, CA153 and CA199, presence of conventional risk factors for stroke, relevant clinical data, imaging reports (CT scan, MRI, transcranial Doppler, magnetic resonance angiography, computed tomography angiography, and digital subtraction angiography).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('CA125', 'Gene', '94025', (189, 194))	('CA153', 'Gene', '4582', (196, 201))	('stroke', 'Phenotype', 'HP:0001297', (255, 261))	('D-dimer levels', 'MPA', (138, 152))	('patients', 'Species', '9606', (27, 35))	('stroke', 'Disease', (255, 261))	('CA199', 'Chemical', '-', (206, 211))	('CA199', 'Var', (206, 211))	('CA125', 'Gene', (189, 194))	('stroke', 'Disease', 'MESH:D020521', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CA153', 'Gene', (196, 201))
6078	28322105	For variables exhibiting a non-normal distribution (e.g., D-dimer, CA125, CA155 and CA199 levels), inter-group differences were evaluated using Mann - Whitney U tests.	('CA125', 'Gene', '94025', (67, 72))	('D-dimer', 'MPA', (58, 65))	('CA199', 'Chemical', '-', (84, 89))	('CA125', 'Gene', (67, 72))	('CA199 levels', 'Var', (84, 96))	('CA155', 'Var', (74, 79))
6092	28322105	High blood levels of D-dimer, CA155 and CA199 were independently associated with stroke risk.	('stroke', 'Disease', (81, 87))	('CA155', 'Var', (30, 35))	('D-dimer', 'MPA', (21, 28))	('CA199', 'Var', (40, 45))	('stroke', 'Disease', 'MESH:D020521', (81, 87))	('associated', 'Reg', (65, 75))	('CA199', 'Chemical', '-', (40, 45))	('stroke', 'Phenotype', 'HP:0001297', (81, 87))
6094	28322105	The risk of cerebral infarction increased by 0.6% (OR 1.006; 95% CI 1.001, 1.010; P = 0.017) with an increase in CA125 of 1 U/mL, and by 2.1% (OR 1.021; 95% CI 1.011, 1.024; P = 0.000) with an increase in CA199 of 1 U/mL (Table 3).	('cerebral infarction', 'Disease', 'MESH:D002544', (12, 31))	('CA125', 'Gene', '94025', (113, 118))	('CA199', 'Var', (205, 210))	('CA199', 'Chemical', '-', (205, 210))	('CA125', 'Gene', (113, 118))	('cerebral infarction', 'Disease', (12, 31))
6110	28322105	Further analysis showed that elevated levels of plasma D-dimer, plasma CA125 and CA199 were all independent risk factors for stroke in patients with active lung cancer.	('plasma D-dimer', 'MPA', (48, 62))	('elevated', 'PosReg', (29, 37))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CA199', 'Var', (81, 86))	('CA125', 'Gene', (71, 76))	('CA199', 'Chemical', '-', (81, 86))	('stroke', 'Phenotype', 'HP:0001297', (125, 131))	('active lung cancer', 'Disease', 'MESH:D008175', (149, 167))	('stroke', 'Disease', (125, 131))	('active lung cancer', 'Disease', (149, 167))	('stroke', 'Disease', 'MESH:D020521', (125, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('CA125', 'Gene', '94025', (71, 76))
6115	28322105	The present study showed that elevated plasma levels of D-dimer, CD125 and CA199 were independent risk factors for stroke in patients with active lung cancer, and that D-dimer levels were positively associated with CA125 and CA199 levels.	('stroke', 'Disease', 'MESH:D020521', (115, 121))	('CA199', 'Chemical', '-', (225, 230))	('CA199', 'Chemical', '-', (75, 80))	('plasma levels', 'MPA', (39, 52))	('elevated', 'PosReg', (30, 38))	('active lung cancer', 'Disease', 'MESH:D008175', (139, 157))	('stroke', 'Disease', (115, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('CA125', 'Gene', '94025', (215, 220))	('patients', 'Species', '9606', (125, 133))	('CA199', 'Var', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('D-dimer levels', 'MPA', (168, 182))	('associated', 'Interaction', (199, 209))	('D-dimer', 'MPA', (56, 63))	('CD125', 'MPA', (65, 70))	('CA125', 'Gene', (215, 220))	('stroke', 'Phenotype', 'HP:0001297', (115, 121))	('active lung cancer', 'Disease', (139, 157))
6116	28322105	We therefore concluded that elevated plasma levels of CA125 and CA199 not only act as biomarkers of lung cancer, but may also play a role in increasing the hypercoagulable state in lung cancer patients.	('patients', 'Species', '9606', (193, 201))	('CA125', 'Gene', '94025', (54, 59))	('hypercoagulable state', 'Phenotype', 'HP:0100724', (156, 177))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('CA125', 'Gene', (54, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('plasma levels', 'MPA', (37, 50))	('CA199', 'Var', (64, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('lung cancer', 'Disease', (100, 111))	('CA199', 'Chemical', '-', (64, 69))	('increasing', 'PosReg', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('elevated', 'PosReg', (28, 36))	('hypercoagulable state', 'MPA', (156, 177))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
6118	28322105	However, the mechanisms whereby elevated plasma levels of CA125 and CA199 enhance the coagulation state in lung cancer patients, leading to stroke, need further investigation.	('stroke', 'Phenotype', 'HP:0001297', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('stroke', 'Disease', (140, 146))	('patients', 'Species', '9606', (119, 127))	('CA125', 'Gene', '94025', (58, 63))	('coagulation', 'biological_process', 'GO:0050817', ('86', '97'))	('leading to', 'Reg', (129, 139))	('stroke', 'Disease', 'MESH:D020521', (140, 146))	('CA199', 'Var', (68, 73))	('lung cancer', 'Disease', (107, 118))	('CA199', 'Chemical', '-', (68, 73))	('coagulation state', 'MPA', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CA125', 'Gene', (58, 63))	('enhance', 'PosReg', (74, 81))
6121	28460475	Triptolide reduced the viability of five non-small cell lung cancer (NSCLC) cells, the proliferation and self-renewal of pulmospheres, and levels of HA synthase 2 (HAS2), HAS3, HA, CD44, RHAMM, EGFR, Akt and ERK, but increased the cleavage of caspase 3 and PARP.	('reduced', 'NegReg', (11, 18))	('Akt', 'Gene', '207', (200, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (45, 67))	('proliferation', 'CPA', (87, 100))	('HA synthase 2', 'Gene', (149, 162))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('HA', 'Chemical', 'MESH:D006820', (149, 151))	('EGFR', 'Gene', (194, 198))	('PARP', 'Gene', '142', (257, 261))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (41, 67))	('HA', 'Chemical', 'MESH:D006820', (164, 166))	('viability', 'CPA', (23, 32))	('HA', 'Chemical', 'MESH:D006820', (188, 190))	('HAS3', 'Var', (171, 175))	('rat', 'Species', '10116', (94, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('194', '198'))	('NSCLC', 'Disease', (69, 74))	('ERK', 'Gene', '5594', (208, 211))	('PARP', 'Gene', (257, 261))	('ERK', 'molecular_function', 'GO:0004707', ('208', '211'))	('Triptolide', 'Chemical', 'MESH:C001899', (0, 10))	('cleavage', 'MPA', (231, 239))	('increased', 'PosReg', (217, 226))	('CD44', 'MPA', (181, 185))	('HA', 'Chemical', 'MESH:D006820', (171, 173))	('non-small cell lung cancer', 'Disease', (41, 67))	('ERK', 'Gene', (208, 211))	('caspase 3', 'Gene', (243, 252))	('EGFR', 'Gene', '1956', (194, 198))	('HA', 'Chemical', 'MESH:D006820', (177, 179))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('caspase 3', 'Gene', '836', (243, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('HA synthase 2', 'Gene', '3037', (149, 162))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (41, 67))	('Akt', 'Gene', (200, 203))
6122	28460475	Addition of excess HA to the culture media completely abrogated the effects of triptolide and siRNAs targeting HAS2, CD44, or RHAMM.	('HA', 'Chemical', 'MESH:D006820', (19, 21))	('HA', 'Chemical', 'MESH:D006820', (127, 129))	('triptolide', 'Chemical', 'MESH:C001899', (79, 89))	('abrogated', 'NegReg', (54, 63))	('HA', 'Chemical', 'MESH:D006820', (111, 113))	('CD44', 'Var', (117, 121))	('triptolide', 'MPA', (79, 89))	('siRNAs', 'Gene', (94, 100))
6140	28460475	We then examined the efficacy of triptolide to inhibit the growth of NSCLC cells in vitro and in vivo and if targeting of HA-CD44/RHAMM contributes to the growth inhibitory effects of the drug.	('HA-CD44/RHAMM', 'Var', (122, 135))	('triptolide', 'Chemical', 'MESH:C001899', (33, 43))	('growth inhibitory effects', 'MPA', (155, 180))	('NSCLC', 'Disease', (69, 74))	('growth', 'CPA', (59, 65))	('HA', 'Chemical', 'MESH:D006820', (131, 133))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('inhibit', 'NegReg', (47, 54))	('HA', 'Chemical', 'MESH:D006820', (122, 124))
6142	28460475	Furthermore, intranasal instillation of liposomal triptolide to rats inhibited the growth of orthotopically xenografted NSCLC cells and these effects involved suppression of HA-CD44/RHAMM signaling.	('rats', 'Species', '10116', (64, 68))	('triptolide', 'Chemical', 'MESH:C001899', (50, 60))	('HA', 'Chemical', 'MESH:D006820', (174, 176))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('suppression', 'NegReg', (159, 170))	('growth', 'CPA', (83, 89))	('liposomal', 'Var', (40, 49))	('HA', 'Chemical', 'MESH:D006820', (183, 185))	('NSCLC', 'Disease', (120, 125))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('inhibited', 'NegReg', (69, 78))	('HA-CD44/RHAMM', 'MPA', (174, 187))
6151	28460475	Consistent with these results, measurement of HA accumulation in the culture media showed that A549, H1299, H520 and H1975 cells secreted a 2-3 fold higher level of HA as compared to the amount secreted by BEAS-2B cells (Figure 2A-iv); the level of HA in H1650 cells was lower than that of BEAS-2B cells.	('H1975', 'CellLine', 'CVCL:1511', (117, 122))	('BEAS-2B', 'CellLine', 'CVCL:0168', (290, 297))	('H1299', 'Var', (101, 106))	('H1975', 'Var', (117, 122))	('A549', 'Var', (95, 99))	('HA', 'Chemical', 'MESH:D006820', (165, 167))	('H1299', 'CellLine', 'CVCL:0060', (101, 106))	('BEAS-2B', 'CellLine', 'CVCL:0168', (206, 213))	('H1650', 'CellLine', 'CVCL:1483', (255, 260))	('HA', 'Chemical', 'MESH:D006820', (46, 48))	('higher', 'PosReg', (149, 155))	('HA', 'Chemical', 'MESH:D006820', (249, 251))	('H520', 'Var', (108, 112))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
6166	28460475	In order to further assess the role of the HA-CD44/RHAMM signaling in the growth and survival of NSCLC cells, we transfected the cells with HAS2, CD44 or RHAMM specific siRNAs or scrambled siRNA and effects on cell viability and expression of cell proliferation- and apoptosis-related proteins were determined.	('HA', 'Chemical', 'MESH:D006820', (140, 142))	('NSCLC', 'Disease', (97, 102))	('HA', 'Chemical', 'MESH:D006820', (155, 157))	('HA', 'Chemical', 'MESH:D006820', (52, 54))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('CD44', 'Var', (146, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('267', '276'))	('rat', 'Species', '10116', (255, 258))	('apoptosis', 'biological_process', 'GO:0006915', ('267', '276'))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('HA', 'Chemical', 'MESH:D006820', (43, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('243', '261'))
6167	28460475	Transfection of NSCLC cells with HAS2, CD44, or RHAMM siRNA significantly reduced the expression of the respective genes (data not shown) and reduced the viability of NSCLC cells (Figure 3A), albeit with different efficiency.	('CD44', 'Var', (39, 43))	('HAS2', 'Var', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('viability', 'CPA', (154, 163))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('reduced', 'NegReg', (142, 149))	('expression', 'MPA', (86, 96))	('NSCLC', 'Disease', (16, 21))	('reduced', 'NegReg', (74, 81))	('NSCLC', 'Disease', (167, 172))
6170	28460475	As shown in Figure 3C, silencing of HAS2 reduced accumulation of HA in the culture media by 60%.	('reduced', 'NegReg', (41, 48))	('HAS2', 'Gene', (36, 40))	('accumulation of HA in the culture media', 'MPA', (49, 88))	('HA', 'Chemical', 'MESH:D006820', (65, 67))	('silencing', 'Var', (23, 32))	('HA', 'Chemical', 'MESH:D006820', (36, 38))
6171	28460475	Consistent with the reduction in HA synthesis, the viability of A549 cells was reduced by 56%, whereas concurrent exposure of the cells to HAS2 siRNA and HA (2.5 mg/mL) not only completely rescued the cells from the cytotoxic effects of HAS2 silencing, but also increased cell viability by 1.6-fold (Figure 3D).	('increased', 'PosReg', (262, 271))	('HA synthesis', 'MPA', (33, 45))	('HA', 'Chemical', 'MESH:D006820', (154, 156))	('reduced', 'NegReg', (79, 86))	('HA', 'Chemical', 'MESH:D006820', (237, 239))	('HA (2', 'cellular_component', 'GO:0030122', ('154', '159'))	('synthesis', 'biological_process', 'GO:0009058', ('36', '45'))	('cell viability', 'CPA', (272, 286))	('silencing', 'Var', (242, 251))	('HA', 'Chemical', 'MESH:D006820', (33, 35))	('HA', 'Chemical', 'MESH:D006820', (139, 141))	('reduction', 'NegReg', (20, 29))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('cytotoxic', 'CPA', (216, 225))
6173	28460475	Similar to the results observed with HAS2 siRNA, siRNAs targeting CD44, RHAMM and CD44 + RHAMM reduced the viability of A549 cells by 43, 66, and 73%, while co-treatment with HA and siRNAs targeting CD44, RHAMM or CD44 + RHAMM increased cell viability by 1.4-, 1.5- and 1.3-fold, respectively, compared to the cell viability in control cells (Figure 3E).	('increased', 'PosReg', (227, 236))	('HA', 'Chemical', 'MESH:D006820', (175, 177))	('cell viability', 'CPA', (237, 251))	('HA', 'Chemical', 'MESH:D006820', (206, 208))	('HA', 'Chemical', 'MESH:D006820', (222, 224))	('CD44', 'Var', (199, 203))	('viability', 'CPA', (107, 116))	('HA', 'Chemical', 'MESH:D006820', (90, 92))	('HA', 'Chemical', 'MESH:D006820', (73, 75))	('CD44 + RHAMM', 'Var', (214, 226))	('CD44', 'Var', (66, 70))	('CD44 + RHAMM', 'Var', (82, 94))	('HA', 'Chemical', 'MESH:D006820', (37, 39))	('reduced', 'NegReg', (95, 102))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
6174	28460475	In line with the cell viability results, silencing of HAS2, CD44 and RHAMM in A549 cells suppressed the level of CD44, RHAMM, EGFR and phospho- EGFR, albeit to different degrees, and caused PARP cleavage and these effects were reversed upon co-treatment with HA and the siRNAs (Figure 3F).	('silencing', 'Var', (41, 50))	('suppressed', 'NegReg', (89, 99))	('HA', 'Chemical', 'MESH:D006820', (70, 72))	('HA', 'Chemical', 'MESH:D006820', (259, 261))	('HA', 'Chemical', 'MESH:D006820', (54, 56))	('RHAMM', 'MPA', (119, 124))	('EGFR', 'Gene', '1956', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('caused', 'Reg', (183, 189))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('EGFR', 'Gene', (144, 148))	('HAS2', 'Gene', (54, 58))	('level', 'MPA', (104, 109))	('HA', 'Chemical', 'MESH:D006820', (120, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('EGFR', 'Gene', (126, 130))	('PARP', 'Gene', '142', (190, 194))	('CD44', 'Gene', (60, 64))	('CD44', 'MPA', (113, 117))	('EGFR', 'Gene', '1956', (144, 148))	('PARP', 'Gene', (190, 194))
6180	28460475	Similarly, transfection of A549 cells with CD44 siRNA significantly reduced the number of primary, secondary and tertiary pulmospheres (Figure 4C) and images of these spheres are shown in Figure 4D.	('reduced', 'NegReg', (68, 75))	('CD44 siRNA', 'Var', (43, 53))	('A549', 'CellLine', 'CVCL:0023', (27, 31))
6183	28460475	Also, analysis of tumor burden indicated that triptolide significantly reduced tumor burden (2.38 in the triptolide group versus 3.08 in the vehicle group, Table 1).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('triptolide', 'Chemical', 'MESH:C001899', (105, 115))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (18, 23))	('reduced', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('triptolide', 'Var', (105, 115))	('triptolide', 'Chemical', 'MESH:C001899', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
6200	28460475	We observed that silencing HAS2, CD44 or RHAMM genes suppressed the expression and activation of EGFR, Akt, and ERK and activated the pro-apoptotic proteins caspase 3 and PARP, indicating that the interaction between HA and CD44/RHAMM regulate the EGFR/Akt/ERK pathway and thereby enhancing cell proliferation and survival.	('rat', 'Species', '10116', (303, 306))	('HA', 'Chemical', 'MESH:D006820', (230, 232))	('EGFR', 'molecular_function', 'GO:0005006', ('248', '252'))	('expression', 'MPA', (68, 78))	('Akt', 'Gene', (103, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('291', '309'))	('interaction', 'Interaction', (197, 208))	('Akt', 'Gene', (253, 256))	('Akt', 'Gene', '207', (103, 106))	('PARP', 'Gene', '142', (171, 175))	('ERK', 'Gene', (257, 260))	('activation', 'PosReg', (83, 93))	('Akt', 'Gene', '207', (253, 256))	('regulate', 'Reg', (235, 243))	('CD44', 'Gene', (33, 37))	('ERK', 'molecular_function', 'GO:0004707', ('112', '115'))	('PARP', 'Gene', (171, 175))	('EGFR', 'Gene', (248, 252))	('ERK', 'Gene', '5594', (112, 115))	('RHAMM', 'Gene', (41, 46))	('EGFR', 'Gene', (97, 101))	('caspase 3', 'Gene', (157, 166))	('caspase 3', 'Gene', '836', (157, 166))	('suppressed', 'NegReg', (53, 63))	('HA', 'Chemical', 'MESH:D006820', (217, 219))	('HA', 'Chemical', 'MESH:D006820', (42, 44))	('HA', 'Chemical', 'MESH:D006820', (27, 29))	('activated', 'PosReg', (120, 129))	('ERK', 'Gene', (112, 115))	('survival', 'CPA', (314, 322))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('cell proliferation', 'CPA', (291, 309))	('EGFR', 'Gene', '1956', (248, 252))	('enhancing', 'PosReg', (281, 290))	('EGFR', 'Gene', '1956', (97, 101))	('ERK', 'molecular_function', 'GO:0004707', ('257', '260'))	('ERK', 'Gene', '5594', (257, 260))	('HAS2', 'Gene', (27, 31))	('silencing', 'Var', (17, 26))
6201	28460475	These results are consistent with previous reports in malignant colon, prostate, and breast carcinoma cells, in which HA-CD44 interaction activated multiple RTKs including EGFR as well as assembly of lipid-raft-integrated signaling complexes containing activated RTKs, CD44, ezrin, PI3-kinase (PI3K) and the chaperone molecules HSP90 and CDC37.	('HSP90', 'Gene', '3320', (328, 333))	('EGFR', 'Gene', (172, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('CDC37', 'Gene', (338, 343))	('HA', 'Chemical', 'MESH:D006820', (118, 120))	('ezrin', 'Gene', '7430', (275, 280))	('breast carcinoma', 'Phenotype', 'HP:0003002', (85, 101))	('lipid-raft', 'cellular_component', 'GO:0045121', ('200', '210'))	('activated', 'PosReg', (138, 147))	('breast carcinoma', 'Disease', (85, 101))	('malignant colon', 'Disease', 'MESH:D009369', (54, 69))	('HA-CD44 interaction', 'Var', (118, 137))	('lipid', 'Chemical', 'MESH:D008055', (200, 205))	('CDC37', 'Gene', '11140', (338, 343))	('interaction', 'Var', (126, 137))	('EGFR', 'Gene', '1956', (172, 176))	('malignant colon', 'Disease', (54, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('294', '298'))	('HSP90', 'Gene', (328, 333))	('signaling', 'biological_process', 'GO:0023052', ('222', '231'))	('CD44', 'Gene', (269, 273))	('breast carcinoma', 'Disease', 'MESH:D001943', (85, 101))	('PI3-kinase', 'Gene', (282, 292))	('PI3-kinase', 'Gene', '5294', (282, 292))	('ezrin', 'Gene', (275, 280))	('rat', 'Species', '10116', (216, 219))
6204	28460475	Indeed, HA has been shown to promote the proliferation and migration of cancer cells by interacting with TLR4 and knockdown of TLR4 inhibited these effects of HA.	('promote', 'PosReg', (29, 36))	('inhibited', 'NegReg', (132, 141))	('rat', 'Species', '10116', (48, 51))	('knockdown', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HA', 'Chemical', 'MESH:D006820', (159, 161))	('TLR4', 'Gene', '7099', (105, 109))	('interacting', 'Interaction', (88, 99))	('HA', 'Chemical', 'MESH:D006820', (8, 10))	('TLR4', 'Gene', '7099', (127, 131))	('TLR4', 'Gene', (105, 109))	('rat', 'Species', '10116', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('migration', 'CPA', (59, 68))	('TLR4', 'Gene', (127, 131))	('proliferation', 'CPA', (41, 54))	('cancer', 'Disease', (72, 78))
6207	28460475	Similar observations were made in bladder cancer cells in which silencing of HAS1 suppressed the level of CD44 variant isoforms.	('level of CD44 variant isoforms', 'MPA', (97, 127))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('suppressed', 'NegReg', (82, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('HAS1', 'Gene', (77, 81))	('bladder cancer', 'Disease', (34, 48))	('silencing', 'Var', (64, 73))
6211	28460475	Assessment of the expression of CD44 in 12 human lung cancer cell lines and 23 paraffin-embedded lung cancers showed that CD44s is the predominant isoform.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('paraffin', 'Chemical', 'MESH:D010232', (79, 87))	('CD44', 'Gene', (32, 36))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('lung cancers', 'Disease', (97, 109))	('lung cancers', 'Disease', 'MESH:D008175', (97, 109))	('lung cancer', 'Disease', (49, 60))	('CD44s', 'Var', (122, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('human', 'Species', '9606', (43, 48))	('lung cancers', 'Phenotype', 'HP:0100526', (97, 109))
6212	28460475	In line with this, among 6 lung cell lines used in the present study, H1650 expressed both CD44s and CD44v, whereas BEAS-2B, A549, H1299 and H520 cells expressed only CD44s; H1975 cells expressed neither of the CD44 isoforms.	('CD44v', 'Var', (101, 106))	('H1299', 'CellLine', 'CVCL:0060', (131, 136))	('CD44s', 'Var', (91, 96))	('A549', 'CellLine', 'CVCL:0023', (125, 129))	('BEAS-2B', 'CellLine', 'CVCL:0168', (116, 123))	('H1650', 'CellLine', 'CVCL:1483', (70, 75))	('H1975', 'CellLine', 'CVCL:1511', (174, 179))
6214	28460475	For instance, acute myeloid leukemia (AML) and Glioblastoma express solely CD44s, whereas in colorectal cancer more than 75% of patients express CD44v8-v10 as the predominant isoform.	('AML', 'Disease', (38, 41))	('Glioblastoma', 'Disease', (47, 59))	('Glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CD44s', 'Var', (75, 80))	('CD44v8-v10', 'Var', (145, 155))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (14, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (20, 36))	('colorectal cancer', 'Disease', (93, 110))	('acute myeloid leukemia', 'Disease', (14, 36))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('patients', 'Species', '9606', (128, 136))	('Glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (14, 36))
6216	28460475	In a study involving 37 tumor xenografts, models using cell lines expressing predominantly CD44s were found to be responsive to RG7356 treatment (8/19, 42%), whereas none of the models with predominant CD44v tumor cells responded to RG7356.	('responsive', 'MPA', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (24, 29))	('CD44s', 'Var', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
6219	28460475	However, with the exception of some anti-CD44 antibodies, which were found to be highly toxic, none of the agents have so far been tested in cancer patients.	('patients', 'Species', '9606', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('anti-CD44', 'Var', (36, 45))	('cancer', 'Disease', (141, 147))
6233	28460475	Abrogation of EGFR signaling through pharmacological or genetic inhibitors suppressed the self-renewal growth and expansion of cancer stem cells.	('suppressed', 'NegReg', (75, 85))	('EGFR', 'Gene', '1956', (14, 18))	('Abrogation', 'Var', (0, 10))	('EGFR', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('self-renewal growth', 'CPA', (90, 109))	('cancer', 'Disease', (127, 133))
6234	28460475	These results indicate that targeting HA-CD44-mediated enhancement of EGFR expression and activation in cancer stem cells could be a promising approach to suppress the progression of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('enhancement', 'PosReg', (55, 66))	('activation', 'PosReg', (90, 100))	('HA', 'Chemical', 'MESH:D006820', (38, 40))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('EGFR', 'Gene', '1956', (70, 74))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('EGFR', 'Gene', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (188, 194))	('HA-CD44-mediated', 'Var', (38, 54))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('cancer', 'Disease', (104, 110))	('suppress', 'NegReg', (155, 163))	('expression', 'MPA', (75, 85))
6238	28460475	H1650 (EGFR tyrosine kinase domain DeltaE746-A750, exon 19 mutant, adenocarcinoma) and H1975 (L858R kinase domain mutation in exon 21 and a second mutation at T790M, P53 mutation, adenocarcinoma) cell lines were obtained from Dr. Shujun Liu (Hormel Institute, University of Minnesota).	('adenocarcinoma', 'Disease', (67, 81))	('P53', 'Gene', '7157', (166, 169))	('T790M', 'Mutation', 'rs121434569', (159, 164))	('DeltaE746-A750', 'Var', (35, 49))	('H1975', 'CellLine', 'CVCL:1511', (87, 92))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('7', '11'))	('EGFR', 'Gene', (7, 11))	('H1650', 'CellLine', 'CVCL:1483', (0, 5))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))	('adenocarcinoma', 'Disease', (180, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('L858R', 'Mutation', 'rs121434568', (94, 99))	('P53', 'Gene', (166, 169))	('EGFR', 'Gene', '1956', (7, 11))
6243	28460475	Anti-CD44, anti-phospho-Akt (Ser 478), anti-total Akt, anti-phospho-ERK (T202/Y204), anti-total ERK, anti-phospho-EGFR (Y1068), anti-total EGFR, anti-caspase 3, anti-beta-actin and goat anti-rabbit IgG secondary antibody were from Cell Signaling Technology (Beverly, MA).	('beta-actin', 'Gene', (166, 176))	('antibody', 'cellular_component', 'GO:0019814', ('212', '220'))	('Y1068', 'Var', (120, 125))	('ERK', 'Gene', '5594', (96, 99))	('Akt', 'Gene', '207', (24, 27))	('ERK', 'Gene', (68, 71))	('Ser', 'Chemical', 'MESH:D012694', (29, 32))	('EGFR', 'Gene', (139, 143))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('antibody', 'molecular_function', 'GO:0003823', ('212', '220'))	('caspase 3', 'Gene', (150, 159))	('antibody', 'cellular_component', 'GO:0042571', ('212', '220'))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('Signaling', 'biological_process', 'GO:0023052', ('236', '245'))	('ERK', 'Gene', (96, 99))	('caspase 3', 'Gene', '836', (150, 159))	('beta-actin', 'Gene', '728378', (166, 176))	('rabbit', 'Species', '9986', (191, 197))	('goat', 'Species', '9925', (181, 185))	('Akt', 'Gene', (50, 53))	('EGFR', 'Gene', '1956', (139, 143))	('antibody', 'cellular_component', 'GO:0019815', ('212', '220'))	('Akt', 'Gene', '207', (50, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('ERK', 'molecular_function', 'GO:0004707', ('96', '99'))	('ERK', 'Gene', '5594', (68, 71))	('EGFR', 'Gene', '1956', (114, 118))	('ERK', 'molecular_function', 'GO:0004707', ('68', '71'))	('Akt', 'Gene', (24, 27))
6303	27442681	The present study firstly assessed the clinical background of patients and found that CPFE obviously affected early surgical outcomes.	('affected', 'Reg', (101, 109))	('patients', 'Species', '9606', (62, 70))	('CPFE', 'Var', (86, 90))	('CPFE', 'Chemical', '-', (86, 90))
6325	27442681	Squamous cell carcinoma was the most frequent histological type (50%) followed by adenocarcinoma (38%) among patients with CPFE (Table 2), which differed from those without CPFE.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('CPFE', 'Chemical', '-', (123, 127))	('patients', 'Species', '9606', (109, 117))	('adenocarcinoma', 'Disease', (82, 96))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('CPFE', 'Var', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('adenocarcinoma', 'Disease', 'MESH:D000230', (82, 96))	('Squamous cell carcinoma', 'Disease', (0, 23))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('CPFE', 'Chemical', '-', (173, 177))
6368	27900363	Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('PDL1', 'Gene', '29126', (131, 135))	('amplification', 'Var', (136, 149))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PDL1', 'Gene', (131, 135))
6371	27900363	Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3).	('TP53', 'Gene', (171, 175))	('mutation/deletion', 'Var', (176, 193))	('JAK2', 'Gene', '3717', (298, 302))	('GATA3', 'Gene', '2625', (323, 328))	('JAK', 'molecular_function', 'GO:0004713', ('298', '301'))	('PDL1', 'Gene', (281, 285))	('G12S', 'Mutation', 'rs121913530', (134, 138))	('CD274', 'Gene', (287, 292))	('JAK2', 'Gene', (298, 302))	('CD274', 'Gene', '29126', (287, 292))	('KRAS', 'Gene', (129, 133))	('KRAS', 'Gene', '3845', (129, 133))	('GATA3', 'Gene', (323, 328))	('TP53', 'Gene', '7157', (171, 175))	('PDL1', 'Gene', '29126', (281, 285))
6375	27900363	We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA expression in 24% of cases.	('PDL1', 'Gene', (118, 122))	('gains', 'PosReg', (86, 91))	('copy number', 'Var', (74, 85))	('mRNA expression', 'MPA', (123, 138))	('Cancer Genome Atlas', 'Disease', (38, 57))	('PDL1', 'Gene', '29126', (69, 73))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (38, 57))	('PDL1', 'Gene', '29126', (118, 122))	('PDL1', 'Gene', (69, 73))
6376	27900363	Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('PDL1', 'Gene', (301, 305))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('tumor', 'Disease', (70, 75))	('PDL1', 'Gene', '29126', (176, 180))	('amplification', 'Var', (181, 194))	('PDL1', 'Gene', '29126', (301, 305))	('Chromosome', 'cellular_component', 'GO:0005694', ('283', '293'))	('cancers', 'Disease', (316, 323))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancers', 'Disease', 'MESH:D009369', (316, 323))	('PDL1', 'Gene', (176, 180))
6381	27900363	Compared to targeted sequencing of selected cancer genes, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) allow for superior detection of coding sequence variants, amplifications, deletions, and structural rearrangements of chromosomes as well as their consequences on mRNA transcription.	('consequences', 'Reg', (263, 275))	('amplifications', 'Var', (174, 188))	('variants', 'Var', (164, 172))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('structural rearrangements', 'Var', (205, 230))	('mRNA transcription', 'biological_process', 'GO:0009299', ('279', '297'))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('mRNA transcription', 'MPA', (279, 297))	('deletions', 'Var', (190, 199))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
6394	27900363	Known driver mutations were detected in TP53 (p.E135fs) and KRAS (p.G12S), the latter also being highly expressed on the RNA level because of a focal amplification on Chromosome 12p (Table 1).	('Chromosome', 'cellular_component', 'GO:0005694', ('167', '177'))	('TP53', 'Gene', '7157', (40, 44))	('p.E135fs', 'Var', (46, 54))	('KRAS', 'Gene', (60, 64))	('TP53', 'Gene', (40, 44))	('p.G12S', 'Mutation', 'rs121913530', (66, 72))	('KRAS', 'Gene', '3845', (60, 64))	('RNA', 'cellular_component', 'GO:0005562', ('121', '124'))	('p.E135fs', 'Mutation', 'p.E135fsX', (46, 54))
6395	27900363	Mutations of unknown significance occurred in other cancer-related genes (e.g., PIK3CD, CDKN2A, NCOA1, FAT2, EGFR, MSH3, ARID1A, MDC1, SETD1A, SETD3, and TET1) (Supplemental Table S1).	('MDC1', 'Gene', '9656', (129, 133))	('SETD1A', 'Gene', (135, 141))	('ARID1A', 'Gene', (121, 127))	('EGFR', 'Gene', '1956', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('TET1', 'Gene', (154, 158))	('occurred', 'Reg', (34, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('CDKN2A', 'Gene', (88, 94))	('NCOA1', 'Gene', (96, 101))	('SETD3', 'Gene', '84193', (143, 148))	('ARID1A', 'Gene', '8289', (121, 127))	('Mutations', 'Var', (0, 9))	('NCOA1', 'Gene', '8648', (96, 101))	('MSH3', 'Gene', (115, 119))	('SETD1A', 'Gene', '9739', (135, 141))	('CDKN2A', 'Gene', '1029', (88, 94))	('FAT2', 'Gene', '2196', (103, 107))	('MSH3', 'Gene', '4437', (115, 119))	('PIK3CD', 'Gene', '5293', (80, 86))	('SETD3', 'Gene', (143, 148))	('cancer', 'Disease', (52, 58))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TET1', 'Gene', '80312', (154, 158))	('MDC1', 'Gene', (129, 133))	('FAT2', 'Gene', (103, 107))	('PIK3CD', 'Gene', (80, 86))
6400	27900363	A query of publicly available databases for matching cancer mutational profiles comprising TP53 inactivation and amplification of Chromosomes 9p (PDL1, JAK2), 10p (GATA3), and 12p (mutant KRAS) as well as review of the literature suggested lung adenocarcinoma, triple-negative breast cancer (TNBC), or gastric adenocarcinoma as the most probable diagnoses.	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (302, 324))	('JAK', 'molecular_function', 'GO:0004713', ('152', '155'))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('JAK2', 'Gene', (152, 156))	('breast cancer', 'Disease', (277, 290))	('PDL1', 'Gene', (146, 150))	('GATA3', 'Gene', '2625', (164, 169))	('TP53', 'Gene', (91, 95))	('lung adenocarcinoma', 'Disease', (240, 259))	('cancer', 'Disease', (53, 59))	('inactivation', 'Var', (96, 108))	('cancer', 'Disease', (284, 290))	('PDL1', 'Gene', '29126', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('gastric adenocarcinoma', 'Disease', (302, 324))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('GATA3', 'Gene', (164, 169))	('KRAS', 'Gene', '3845', (188, 192))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (240, 259))	('KRAS', 'Gene', (188, 192))	('JAK2', 'Gene', '3717', (152, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (240, 259))	('TP53', 'Gene', '7157', (91, 95))
6408	27900363	In the context of poor differentiation, negativity for TTF1 and napsin does not rule out the differential diagnosis of lung adenocarcinoma but is not supportive either.	('negativity', 'Var', (40, 50))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('TTF1', 'Gene', '7270', (55, 59))	('TTF1', 'Gene', (55, 59))	('lung adenocarcinoma', 'Disease', (119, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))
6411	27900363	To this end, we analyzed PDL1 copy number variation in a TCGA cohort of 937 breast carcinomas (Fig.	('PDL1', 'Gene', '29126', (25, 29))	('copy number variation', 'Var', (30, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('PDL1', 'Gene', (25, 29))	('breast carcinomas', 'Disease', 'MESH:D001943', (76, 93))	('breast carcinomas', 'Disease', (76, 93))	('breast carcinomas', 'Phenotype', 'HP:0003002', (76, 93))
6412	27900363	Copy number gains were more frequent in TNBC (43.3%) compared to hormone receptor (HR)+/HER2-, HR+/HER2+, and HR-/HER2+ breast cancer (10.9%, 10.3%, and 26.3%; p = 0.00045).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HR', 'Gene', '3164', (95, 97))	('breast cancer', 'Disease', (120, 133))	('Copy number gains', 'Var', (0, 17))	('HER2', 'Gene', (114, 118))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('HER2', 'Gene', (88, 92))	('hormone receptor', 'Gene', (65, 81))	('HER2', 'Gene', '2064', (114, 118))	('hormone receptor', 'Gene', '3164', (65, 81))	('TNBC', 'Disease', (40, 44))	('HER2', 'Gene', '2064', (88, 92))	('HER2', 'Gene', (99, 103))	('HR', 'Gene', '3164', (110, 112))	('HR', 'Gene', '3164', (83, 85))	('HER2', 'Gene', '2064', (99, 103))
6415	27900363	3B) and revealed significantly higher PDL1 levels in tumors with PDL1 copy number gains compared to tumors that were diploid for the PDL1 locus (fold change, 1.25; p = 0.019).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PDL1', 'Gene', '29126', (38, 42))	('PDL1', 'Gene', '29126', (65, 69))	('PDL1', 'Gene', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (100, 106))	('PDL1', 'Gene', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('copy number gains', 'Var', (70, 87))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('PDL1', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('higher', 'PosReg', (31, 37))	('tumors', 'Disease', (53, 59))	('PDL1', 'Gene', '29126', (133, 137))
6433	27900363	Furthermore, novel data-sharing initiatives, such as AACR (American Association for Cancer Research) Project GENIE (Genomics, Evidence, Neoplasia, Information Exchange; ), as well as innovative interventional clinical trials, such as NCI-MATCH (National Cancer Institute-Molecular Analysis for Therapy Choice; ), are expected to broaden the basis for greater individualization of therapy, particularly in the case of rare cancers and rare mutations in common cancers.	('cancers', 'Disease', 'MESH:D009369', (459, 466))	('Neoplasia', 'Disease', 'MESH:D009369', (136, 145))	('cancers', 'Phenotype', 'HP:0002664', (422, 429))	('cancers', 'Disease', (422, 429))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancers', 'Phenotype', 'HP:0002664', (459, 466))	('NCI-MATCH', 'Disease', (234, 243))	('Neoplasia', 'Phenotype', 'HP:0002664', (136, 145))	('Cancer', 'Disease', (254, 260))	('cancers', 'Disease', (459, 466))	('Neoplasia', 'Disease', (136, 145))	('cancers', 'Disease', 'MESH:D009369', (422, 429))	('NCI-MATCH', 'Disease', 'None', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', 'MESH:D009369', (254, 260))	('mutations', 'Var', (439, 448))	('Cancer', 'Disease', (84, 90))
6434	27900363	In our patient, the finding of PDL1 amplification and overexpression in conjunction with the high mutational load, and the failure of previous conventional chemotherapeutic approaches, prompted us to administer off-label immunotherapy.	('patient', 'Species', '9606', (7, 14))	('overexpression', 'PosReg', (54, 68))	('PDL1', 'Gene', '29126', (31, 35))	('amplification', 'Var', (36, 49))	('PDL1', 'Gene', (31, 35))
6438	27900363	The choice of immunotherapy in our patient was supported by the high density of tumor-infiltrating lymphocytes, PDL1 amplification resulting in strong intratumoral PDL1 expression both on the RNA and protein level, and a high mutational load, which was reported as being predictive for response to ICI in a range of cancers.	('PDL1', 'Gene', '29126', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression', 'MPA', (169, 179))	('tumor', 'Disease', (156, 161))	('mutational load', 'Var', (226, 241))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('PDL1', 'Gene', (164, 168))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))	('cancers', 'Disease', (316, 323))	('tumoral', 'Disease', (156, 163))	('tumoral', 'Disease', 'MESH:D009369', (156, 163))	('PDL1', 'Gene', '29126', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PDL1', 'Gene', (112, 116))	('patient', 'Species', '9606', (35, 42))	('RNA', 'cellular_component', 'GO:0005562', ('192', '195'))	('amplification', 'Var', (117, 130))	('cancers', 'Disease', 'MESH:D009369', (316, 323))
6439	27900363	Although future studies are needed to further establish robust and reliable determinants of response to ICI, PDL1 amplification might serve as a rapidly available and inexpensive surrogate marker across histologic entities, as supported by the striking therapeutic activity of PD1 blockade in TNBC (this study) and refractory classical Hodgkin lymphoma characterized by Chromosome 9p24.1 gain.	('Hodgkin lymphoma', 'Disease', (336, 352))	('gain', 'PosReg', (388, 392))	('PDL1', 'Gene', (109, 113))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (336, 352))	('blockade', 'Var', (281, 289))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (336, 352))	('TNBC', 'Gene', (293, 297))	('PD1', 'Gene', '5133', (277, 280))	('Chromosome', 'cellular_component', 'GO:0005694', ('370', '380'))	('PDL1', 'Gene', '29126', (109, 113))	('lymphoma', 'Phenotype', 'HP:0002665', (344, 352))	('PD1', 'Gene', (277, 280))
6443	27900363	Inactivating JAK2 mutations have recently been implicated in acquired resistance to PD1 inhibitor treatment and immune evasion of cancer cells, possibly related to down-regulation of PDL1 and antigen presentation as a consequence of abolished interferon signaling due to loss-of-function alterations in JAK2.	('antigen presentation', 'MPA', (192, 212))	('abolished', 'NegReg', (233, 242))	('JAK', 'molecular_function', 'GO:0004713', ('13', '16'))	('signaling', 'biological_process', 'GO:0023052', ('254', '263'))	('JAK2', 'Gene', (303, 307))	('immune evasion', 'MPA', (112, 126))	('JAK2', 'Gene', '3717', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('loss-of-function', 'NegReg', (271, 287))	('Inactivating', 'Var', (0, 12))	('interferon signaling', 'MPA', (243, 263))	('down-regulation', 'NegReg', (164, 179))	('PD1', 'Gene', (84, 87))	('antigen presentation', 'biological_process', 'GO:0019882', ('192', '212'))	('JAK', 'molecular_function', 'GO:0004713', ('303', '306'))	('regulation', 'biological_process', 'GO:0065007', ('169', '179'))	('implicated', 'Reg', (47, 57))	('JAK2', 'Gene', (13, 17))	('PDL1', 'Gene', (183, 187))	('immune evasion', 'biological_process', 'GO:0042783', ('112', '126'))	('immune evasion', 'biological_process', 'GO:0051842', ('112', '126'))	('cancer', 'Disease', (130, 136))	('PDL1', 'Gene', '29126', (183, 187))	('PD1', 'Gene', '5133', (84, 87))	('JAK2', 'Gene', '3717', (303, 307))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mutations', 'Var', (18, 27))
6454	27900363	After antigen retrieval, the following primary antibodies were used: AE1/3: 1:100 dilution, DAKO (#M3515); GATA3: ready to use, Ventana (#760-4897); CK7: 1:50 dilution, DAKO (#M7018); PDL1: 1:100 dilution, Spring (#07309457001); CD4 mouse monoclonal antibody: 1:20 dilution, Novocastra/Leica (clone 1F6); napsin: 1:400 dilution, Novacastra/Leica (clone IP64, #NCL-L-Napsin A); TTF1: 1:100 dilution, Novocastra/Leica (clone SPT24, #NCL-L-TTF1).	('CD4', 'Gene', (229, 232))	('TTF1', 'Gene', '7270', (437, 441))	('Napsin A', 'Gene', '9476', (366, 374))	('AE1/3', 'Gene', '6521;6508', (69, 74))	('antibody', 'molecular_function', 'GO:0003823', ('250', '258'))	('TTF1', 'Gene', (377, 381))	('antibody', 'cellular_component', 'GO:0042571', ('250', '258'))	('AE1/3', 'Gene', (69, 74))	('NCL', 'Gene', '4691', (431, 434))	('CK7', 'Gene', (149, 152))	('NCL', 'Gene', '4691', (360, 363))	('SPT', 'molecular_function', 'GO:0004760', ('423', '426'))	('GATA3', 'Gene', '2625', (107, 112))	('Napsin A', 'Gene', (366, 374))	('TTF1', 'Gene', (437, 441))	('antibody', 'cellular_component', 'GO:0019815', ('250', '258'))	('NCL', 'Gene', (431, 434))	('GATA3', 'Gene', (107, 112))	('PDL1', 'Gene', (184, 188))	('CK7', 'Gene', '3855', (149, 152))	('NCL', 'Gene', (360, 363))	('TTF1', 'Gene', '7270', (377, 381))	('mouse', 'Species', '10090', (233, 238))	('SPT', 'molecular_function', 'GO:0004758', ('423', '426'))	('PDL1', 'Gene', '29126', (184, 188))	('#07309457001', 'Var', (214, 226))	('CD4', 'Gene', '920', (229, 232))	('antibody', 'cellular_component', 'GO:0019814', ('250', '258'))
6460	27900363	Point substitution variants were submitted to the Catalogue of Somatic Mutations in Cancer (COSMIC; , identifier COSP41747).	('Point substitution variants', 'Var', (0, 27))	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', (84, 90))
6536	34007391	TTF-1 positivity suggested the possibility of a lung primary, and absence of CDX-2 made a gastrointestinal primary less likely.	('CDX-2', 'Gene', '1045', (77, 82))	('CDX-2', 'Gene', (77, 82))	('TTF-1', 'Gene', '7270', (0, 5))	('positivity', 'Var', (6, 16))	('absence', 'NegReg', (66, 73))	('gastrointestinal primary', 'Disease', (90, 114))	('lung primary', 'Disease', (48, 60))	('TTF-1', 'Gene', (0, 5))
6585	33718595	It has a very aggressive course and is characterized by genomic instability, almost universal inactivation of the genes TP53 and RB1, rapid tumor growth, increased vascularity, and high metastatic potential.	('vascularity', 'CPA', (164, 175))	('RB1', 'Gene', '5925', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('RB1', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('inactivation', 'Var', (94, 106))	('increased', 'PosReg', (154, 163))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))	('tumor', 'Disease', (140, 145))
6587	33718595	Most SCLC patients are current or former heavy smokers resulting in a high tumor mutational burden (TMB) (with C:G>A:T transversions being the most common type of base substitutions).	('TMB', 'Chemical', '-', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('SCLC', 'Gene', '7864', (5, 9))	('C:G>A:T transversions', 'Var', (111, 132))	('SCLC', 'Gene', (5, 9))	('SCLC', 'Phenotype', 'HP:0030357', (5, 9))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
6615	33718595	SCLCs are likely to gain various genetic alterations as they evolve or as they metastasize outside the chest.	('SCLC', 'Gene', '7864', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (0, 4))	('gain', 'PosReg', (20, 24))	('genetic alterations', 'Var', (33, 52))	('SCLC', 'Gene', (0, 4))
6630	33718595	It has also been hypothesized that MYC amplification appears during tumor progression and is connected to CHT resistance.	('tumor', 'Disease', (68, 73))	('MYC', 'Gene', (35, 38))	('amplification', 'Var', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CHT resistance', 'Disease', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MYC', 'Gene', '4609', (35, 38))	('connected', 'Reg', (93, 102))
6637	33718595	A subset of SCLCs is associated with the amplification of the fibroblast-growth factor receptor 1 (FGFR1) gene that displays a target for FGFR1 inhibitor therapy.	('fibroblast-growth factor receptor 1', 'Gene', (62, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('fibroblast-growth factor receptor 1', 'Gene', '2260', (62, 97))	('FGFR1', 'Gene', (99, 104))	('associated', 'Reg', (21, 31))	('fibroblast-growth factor', 'molecular_function', 'GO:0005104', ('62', '86'))	('SCLC', 'Gene', '7864', (12, 16))	('FGFR1', 'Gene', (138, 143))	('SCLC', 'Gene', (12, 16))	('FGFR1', 'Gene', '2260', (99, 104))	('amplification', 'Var', (41, 54))	('SCLC', 'Phenotype', 'HP:0030357', (12, 16))	('FGFR1', 'Gene', '2260', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))
6639	33718595	Important aberrations in the SCLC-A subtype comprise amplifications of BCL2, EZH2, and the decrease of CREBBP, whereas SCLC-Y is associated with mutations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway.	('BCL2', 'Gene', (71, 75))	('associated', 'Reg', (129, 139))	('AKT', 'Gene', (199, 202))	('mutations', 'Var', (145, 154))	('signaling pathway', 'biological_process', 'GO:0007165', ('208', '225'))	('SCLC', 'Phenotype', 'HP:0030357', (29, 33))	('decrease', 'NegReg', (91, 99))	('mTOR', 'Gene', '2475', (203, 207))	('SCLC', 'Gene', '7864', (29, 33))	('SCLC', 'Gene', (29, 33))	('AKT', 'Gene', '207', (199, 202))	('CREBBP', 'Gene', (103, 109))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (162, 191))	('BCL2', 'Gene', '596', (71, 75))	('SCLC', 'Phenotype', 'HP:0030357', (119, 123))	('EZH2', 'Gene', '2146', (77, 81))	('EZH2', 'Gene', (77, 81))	('BCL2', 'molecular_function', 'GO:0015283', ('71', '75'))	('phosphatidylinositol 3-kinase', 'Gene', (162, 191))	('CREBBP', 'Gene', '1387', (103, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('193', '197'))	('SCLC', 'Gene', '7864', (119, 123))	('SCLC', 'Gene', (119, 123))	('mTOR', 'Gene', (203, 207))
6652	33718595	SLFN11 expression, therefore, correlates with sensitivity to various DNA-damaging chemotherapeutics, but in many cases it is silenced in SCLC by methylation or acetylation.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('correlates', 'Reg', (30, 40))	('SLFN11', 'Gene', '91607', (0, 6))	('silenced', 'NegReg', (125, 133))	('acetylation', 'Var', (160, 171))	('SCLC', 'Gene', '7864', (137, 141))	('SCLC', 'Gene', (137, 141))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('methylation', 'Var', (145, 156))	('SLFN11', 'Gene', (0, 6))	('SCLC', 'Phenotype', 'HP:0030357', (137, 141))
6653	33718595	On the contrary, the upregulation of EZH2 mediates chemoresistance based on SLFN11 downregulation via histone methylation and modification.	('histone', 'MPA', (102, 109))	('SLFN11', 'Gene', (76, 82))	('mediates', 'Reg', (42, 50))	('downregulation', 'NegReg', (83, 97))	('modification', 'Var', (126, 138))	('SLFN11', 'Gene', '91607', (76, 82))	('upregulation', 'PosReg', (21, 33))	('EZH2', 'Gene', (37, 41))	('EZH2', 'Gene', '2146', (37, 41))	('histone methylation', 'biological_process', 'GO:0016571', ('102', '121'))	('chemoresistance', 'CPA', (51, 66))
6697	33718595	In addition, PARP inhibitors also enhance the effects of CHT and ionizing radiation both in vivo and in vitro.	('PARP', 'Gene', (13, 17))	('enhance', 'PosReg', (34, 41))	('PARP', 'Gene', '142', (13, 17))	('effects', 'MPA', (46, 53))	('inhibitors', 'Var', (18, 28))
6701	33718595	PARP inhibitor combinations might thus be attractive therapeutic approaches for SCLC patients, but predictive biomarkers are required to maximize their clinical efficacy.	('PARP', 'Gene', (0, 4))	('SCLC', 'Gene', '7864', (80, 84))	('SCLC', 'Phenotype', 'HP:0030357', (80, 84))	('SCLC', 'Gene', (80, 84))	('patients', 'Species', '9606', (85, 93))	('PARP', 'Gene', '142', (0, 4))	('combinations', 'Var', (15, 27))
6728	33718595	The histone demethylase LSD1 activity has been described to be dependent on the disruption of INSM1, which is linked to the NE subtypes SCLC-A and SCLC-N.	('SCLC', 'Gene', '7864', (147, 151))	('SCLC-N', 'Disease', 'MESH:D018288', (147, 153))	('SCLC', 'Phenotype', 'HP:0030357', (147, 151))	('LSD1', 'Gene', '23028', (24, 28))	('SCLC', 'Gene', '7864', (136, 140))	('SCLC-N', 'Disease', (147, 153))	('linked', 'Reg', (110, 116))	('LSD1', 'Gene', (24, 28))	('dependent', 'Reg', (63, 72))	('activity', 'MPA', (29, 37))	('INSM1', 'Gene', '3642', (94, 99))	('INSM1', 'Gene', (94, 99))	('disruption', 'Var', (80, 90))	('SCLC', 'Phenotype', 'HP:0030357', (136, 140))	('SCLC', 'Gene', (147, 151))	('SCLC', 'Gene', (136, 140))
6729	33718595	Recent data also indicate that LSD1 inhibition leads to NOTCH1 activation, resulting in ASCL1 suppression in SCLC.	('suppression', 'NegReg', (94, 105))	('ASCL1', 'Gene', '429', (88, 93))	('inhibition', 'Var', (36, 46))	('LSD1', 'Gene', '23028', (31, 35))	('LSD1', 'Gene', (31, 35))	('SCLC', 'Gene', (109, 113))	('ASCL1', 'Gene', (88, 93))	('SCLC', 'Gene', '7864', (109, 113))	('SCLC', 'Phenotype', 'HP:0030357', (109, 113))	('NOTCH1', 'Gene', '4851', (56, 62))	('NOTCH1', 'Gene', (56, 62))	('activation', 'PosReg', (63, 73))
6737	33718595	Finally, based on recent in vivo studies, "NEUROD1-high" tumor cells are also suspected to be sensitive to arginine depletion caused by pegylated arginine deaminase (ADI-PEG 20), which leads to the inhibition of tumor cell growth.	('arginine depletion', 'MPA', (107, 125))	('inhibition', 'NegReg', (198, 208))	('NEUROD1', 'Gene', (43, 50))	('cell growth', 'biological_process', 'GO:0016049', ('216', '227'))	('pegylated', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('arginine', 'Chemical', 'MESH:D001120', (107, 115))	('arginine', 'Chemical', 'MESH:D001120', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (212, 217))	('NEUROD1', 'Gene', '4760', (43, 50))
6738	33718595	Based on the results of CRISPR screens, the SCLC-P subtype possesses a unique vulnerability to IGF-1R deficiency.	('SCLC-P', 'Disease', (44, 50))	('SCLC-P', 'Disease', 'MESH:D018288', (44, 50))	('IGF-1R', 'Gene', '3480', (95, 101))	('deficiency', 'Var', (102, 112))	('IGF-1R', 'Gene', (95, 101))	('SCLC', 'Phenotype', 'HP:0030357', (44, 48))
6754	33718595	Genetic alterations lead to the development of SCLC subtypes and therapeutic resistance.	('Genetic alterations', 'Var', (0, 19))	('therapeutic resistance', 'CPA', (65, 87))	('lead to', 'Reg', (20, 27))	('SCLC', 'Gene', (47, 51))	('SCLC', 'Gene', '7864', (47, 51))	('SCLC', 'Phenotype', 'HP:0030357', (47, 51))
6758	33718595	As for the SCLC-Y subtype, YAP1 expression is linked with poor prognosis and decreased survival plus increased chemoresistance.	('YAP1', 'Gene', (27, 31))	('YAP1', 'Gene', '10413', (27, 31))	('SCLC', 'Gene', '7864', (11, 15))	('increased', 'PosReg', (101, 110))	('SCLC', 'Gene', (11, 15))	('expression', 'Var', (32, 42))	('chemoresistance', 'CPA', (111, 126))	('SCLC', 'Phenotype', 'HP:0030357', (11, 15))	('survival', 'CPA', (87, 95))	('decreased', 'NegReg', (77, 86))
6795	30879091	The modulation of lncRNAs by phytochemicals can produce therapeutic effects in some cancer types (Table 2).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('modulation', 'Var', (4, 14))	('cancer', 'Disease', (84, 90))
6798	30879091	Moreover, the modulation of lncRNAs by phytochemicals can lead to the inhibition of survival, proliferation, migration, invasion, metastasis, and epithelial-to-mesenchymal transition (Fig.	('inhibition', 'NegReg', (70, 80))	('rat', 'Species', '10116', (101, 104))	('modulation', 'Var', (14, 24))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('146', '182'))	('epithelial-to-mesenchymal transition', 'CPA', (146, 182))	('metastasis', 'CPA', (130, 140))	('invasion', 'CPA', (120, 128))	('proliferation', 'CPA', (94, 107))	('migration', 'CPA', (109, 118))	('rat', 'Species', '10116', (112, 115))	('survival', 'CPA', (84, 92))
6799	30879091	The modulation of lncRNAs expression by phytochemicals can also lead to chemosensitization and radiosensitization of cancer cells (Fig.	('lncRNAs', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('modulation', 'Var', (4, 14))	('lead to', 'Reg', (64, 71))	('radiosensitization', 'CPA', (95, 113))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('chemosensitization', 'CPA', (72, 90))	('cancer', 'Disease', (117, 123))
6805	30879091	The common lncRNAs modulated by curcumin include AF086415, AK056098, AK095147, AK294004, FLJ36000, GUCY2GP, H19, H2BFXP, HOTAIR, LINC00623, LOC100506835, MEG3, MUDENG, PANDAR, PVT1, RP1-179N16.3, and ZRANB2-AS2.	('AK095147', 'Var', (69, 77))	('PVT1', 'Gene', '5820', (176, 180))	('LINC00623', 'Gene', '728855', (129, 138))	('HOTAIR', 'Gene', '100124700', (121, 127))	('ZRANB2-AS2', 'Gene', (200, 210))	('HOTAIR', 'Gene', (121, 127))	('MEG3', 'Gene', '55384', (154, 158))	('ZRANB2-AS2', 'Gene', '100852410;9406', (200, 210))	('PANDAR', 'Gene', '101154753', (168, 174))	('PANDAR', 'Gene', (168, 174))	('RA', 'Phenotype', 'HP:0001370', (201, 203))	('LINC00623', 'Gene', (129, 138))	('curcumin', 'Chemical', 'MESH:D003474', (32, 40))	('AK056098', 'Var', (59, 67))	('H19', 'Gene', (108, 111))	('MUDENG', 'Gene', '55745', (160, 166))	('GUCY2GP', 'Gene', '390003', (99, 106))	('MUDENG', 'Gene', (160, 166))	('AK294004', 'Var', (79, 87))	('RP1', 'Gene', (182, 185))	('H19', 'Gene', '283120', (108, 111))	('GUCY2GP', 'Gene', (99, 106))	('H2BFXP', 'Gene', (113, 119))	('AF086415', 'Var', (49, 57))	('PVT1', 'Gene', (176, 180))	('FLJ36000', 'Var', (89, 97))	('MEG3', 'Gene', (154, 158))	('RP1', 'Gene', '6101', (182, 185))	('H2BFXP', 'Gene', '767811', (113, 119))	('LOC100506835', 'Var', (140, 152))
6822	30879091	The promoter of CDKN1A antisense DNA damage-activated RNA (PANDAR) is an lncRNA with 1506 nucleotides in length.	('antisense DNA', 'Var', (23, 36))	('CDKN1A', 'Gene', (16, 22))	('CDKN1A', 'Gene', '1026', (16, 22))	('PANDAR', 'Gene', '101154753', (59, 65))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('PANDAR', 'Gene', (59, 65))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))
6826	30879091	The proliferation of CRC DLD-1 cells was not affected by the knockdown of PANDAR.	('knockdown', 'Var', (61, 70))	('PANDAR', 'Gene', (74, 80))	('rat', 'Species', '10116', (11, 14))	('PANDAR', 'Gene', '101154753', (74, 80))
6829	30879091	The silencing of PANDAR enhanced apoptosis and attenuated senescence in curcumin-treated DLD-1 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('PANDAR', 'Gene', '101154753', (17, 23))	('apoptosis', 'CPA', (33, 42))	('PANDAR', 'Gene', (17, 23))	('senescence', 'MPA', (58, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('senescence', 'biological_process', 'GO:0010149', ('58', '68'))	('enhanced', 'PosReg', (24, 32))	('attenuated', 'NegReg', (47, 57))	('curcumin', 'Chemical', 'MESH:D003474', (72, 80))	('silencing', 'Var', (4, 13))
6831	30879091	Furthermore, PANDAR silencing can also switch cells from senescence to apoptosis partly by stimulating the expression of the p53-up-regulated modulator of apoptosis (PUMA).	('PUMA', 'Gene', (166, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('stimulating', 'Reg', (91, 102))	('PANDAR', 'Gene', (13, 19))	('expression', 'MPA', (107, 117))	('p53-up-regulated modulator of apoptosis', 'Gene', (125, 164))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('PUMA', 'Gene', '27113', (166, 170))	('p53-up-regulated modulator of apoptosis', 'Gene', '27113', (125, 164))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('silencing', 'Var', (20, 29))	('senescence', 'biological_process', 'GO:0010149', ('57', '67'))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('switch', 'Reg', (39, 45))	('PANDAR', 'Gene', '101154753', (13, 19))
6840	30879091	It was concluded that induction of DNA hypomethylation and MEG3 by DNC could be an effective choice for epigenetic therapy of HCC.	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('MEG3', 'Gene', (59, 63))	('HCC', 'Disease', (126, 129))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('35', '54'))	('hypomethylation', 'Var', (39, 54))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('DNC', 'Chemical', '-', (67, 70))	('MEG3', 'Gene', '55384', (59, 63))
6854	30879091	The EVs were found to induce drug resistance in ovarian cancer cells that were weakened by curcumin treatment.	('curcumin', 'Chemical', 'MESH:D003474', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('drug resistance', 'CPA', (29, 44))	('EVs', 'Var', (4, 7))	('drug resistance', 'biological_process', 'GO:0009315', ('29', '44'))	('drug resistance', 'biological_process', 'GO:0042493', ('29', '44'))	('induce', 'Reg', (22, 28))	('drug resistance', 'Phenotype', 'HP:0020174', (29, 44))	('ovarian cancer', 'Disease', (48, 62))
6859	30879091	Furthermore, curcumin significantly up-regulated the expression of lncRNAs such as GUCY2GP, H2BFXP, and LINC00623, while the expression of ZRANB2-AS2, LOC100506835, and FLJ36000 IncRNA was down-regulated.	('ZRANB2-AS2', 'Gene', '100852410;9406', (139, 149))	('down-regulated', 'NegReg', (189, 203))	('H2BFXP', 'Gene', (92, 98))	('RA', 'Phenotype', 'HP:0001370', (140, 142))	('curcumin', 'Chemical', 'MESH:D003474', (13, 21))	('LINC00623', 'Gene', '728855', (104, 113))	('up-regulated', 'PosReg', (36, 48))	('FLJ36000', 'Var', (169, 177))	('GUCY2GP', 'Gene', '390003', (83, 90))	('ZRANB2-AS2', 'Gene', (139, 149))	('H2BFXP', 'Gene', '767811', (92, 98))	('LINC00623', 'Gene', (104, 113))	('GUCY2GP', 'Gene', (83, 90))	('expression', 'MPA', (53, 63))	('LOC100506835', 'Var', (151, 163))
6860	30879091	In another study, curcumin-induced radiosensitization of nasopharyngeal carcinoma cells was mediated partly through modulation of lncRNAs such as AF086415, AK056098, AK095147, AK294004, MUDENG, and RP1-179N16.3.	('AK294004', 'Var', (176, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('AK095147', 'Var', (166, 174))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (57, 81))	('curcumin', 'Chemical', 'MESH:D003474', (18, 26))	('carcinoma', 'Disease', (72, 81))	('AK056098', 'Var', (156, 164))	('MUDENG', 'Gene', '55745', (186, 192))	('MUDENG', 'Gene', (186, 192))	('RP1', 'Gene', '6101', (198, 201))	('carcinoma', 'Disease', 'MESH:D009369', (72, 81))	('AF086415', 'Var', (146, 154))	('radiosensitization', 'CPA', (35, 53))	('RP1', 'Gene', (198, 201))
6881	30879091	Furthermore, the knockdown of AK001796 was associated with a significant reduction in the viability of lung cancer cells and reduced tumor growth.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('knockdown', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('reduced', 'NegReg', (125, 132))	('AK001796', 'Gene', '541471', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('viability', 'CPA', (90, 99))	('lung cancer', 'Disease', (103, 114))	('tumor', 'Disease', (133, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('AK001796', 'Gene', (30, 38))	('reduction', 'NegReg', (73, 82))
6900	30879091	Furthermore, H19 suppressed the promoter activity of BIK by recruiting EZH2 and by trimethylating the histone H3 at lysine 27.	('EZH2', 'Gene', (71, 75))	('trimethylating', 'Var', (83, 97))	('recruiting', 'PosReg', (60, 70))	('BIK', 'Gene', '638', (53, 56))	('promoter activity', 'MPA', (32, 49))	('lysine', 'Chemical', 'MESH:D008239', (116, 122))	('suppressed', 'NegReg', (17, 27))	('H19', 'Gene', '283120', (13, 16))	('BIK', 'Gene', (53, 56))	('EZH2', 'Gene', '2146', (71, 75))	('H19', 'Gene', (13, 16))
6910	30879091	The genetic polymorphisms of GAS5 can also predict the response of nasopharyngeal carcinoma patients to paclitaxel.	('carcinoma', 'Disease', 'MESH:D009369', (82, 91))	('response', 'MPA', (55, 63))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (67, 91))	('genetic polymorphisms', 'Var', (4, 25))	('GAS', 'molecular_function', 'GO:0034005', ('29', '32'))	('predict', 'Reg', (43, 50))	('carcinoma', 'Disease', (82, 91))	('GAS5', 'Gene', (29, 33))
6911	30879091	The inhibition of MA-linc1 enhances cell death in cancer cells induced by paclitaxel.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('MA-linc1', 'Gene', '100505636', (18, 26))	('cell death', 'biological_process', 'GO:0008219', ('36', '46'))	('inhibition', 'Var', (4, 14))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('paclitaxel', 'Chemical', 'MESH:D017239', (74, 84))	('enhances', 'PosReg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MA-linc1', 'Gene', (18, 26))
6921	30879091	The knockdown of ZFAS1 can suppress the growth, proliferation, cell-cycle progression, migration, and invasion.	('ZFAS1', 'Gene', (17, 22))	('migration', 'CPA', (87, 96))	('invasion', 'CPA', (102, 110))	('ZFAS1', 'Gene', '441951', (17, 22))	('cell-cycle', 'biological_process', 'GO:0007049', ('63', '73'))	('cell-cycle progression', 'CPA', (63, 85))	('growth', 'CPA', (40, 46))	('suppress', 'NegReg', (27, 35))	('knockdown', 'Var', (4, 13))	('rat', 'Species', '10116', (55, 58))	('rat', 'Species', '10116', (90, 93))
6929	30879091	Some other lncRNAs associated with paclitaxel resistance include H19 in breast cancer; SNHG12 in NSCLC; XR_938728, XR_947831, XR_938392, XR_948297, NR_036503, NR_073113, and NR_103801 in ovarian cancer; LINC00672 in endometrial cancer; n375709 in nasopharyngeal carcinoma ; HIF1AAS2 and AK124454 in triple-negative breast cancer; linc-ROR in breast cancer; KCNQ1OT1 and ANRIL in lung adenocarcinoma; and RP11-381N20.2 in cervical cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('breast cancer', 'Disease', (342, 355))	('endometrial cancer', 'Disease', (216, 234))	('SNHG12', 'Gene', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('H19', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (379, 398))	('endometrial cancer', 'Disease', 'MESH:D016889', (216, 234))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (379, 398))	('cancer', 'Disease', (430, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('LINC00672', 'Gene', (203, 212))	('HIF1AAS2', 'Gene', '100750247', (274, 282))	('ANRIL', 'Gene', '100048912', (370, 375))	('H19', 'Gene', '283120', (65, 68))	('paclitaxel', 'Chemical', 'MESH:D017239', (35, 45))	('ovarian cancer', 'Disease', (187, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (315, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (389, 398))	('carcinoma', 'Disease', (262, 271))	('cancer', 'Disease', (349, 355))	('SNHG12', 'Gene', '85028', (87, 93))	('carcinoma', 'Disease', (389, 398))	('HIF1AAS2', 'Gene', (274, 282))	('n375709', 'Var', (236, 243))	('RP11', 'Gene', '26121', (404, 408))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Disease', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (315, 328))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('breast cancer', 'Disease', (315, 328))	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (247, 271))	('cancer', 'Disease', (322, 328))	('cancer', 'Disease', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ANRIL', 'Gene', (370, 375))	('carcinoma', 'Disease', 'MESH:D009369', (262, 271))	('ROR', 'Gene', (335, 338))	('cancer', 'Disease', 'MESH:D009369', (430, 436))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('carcinoma', 'Disease', 'MESH:D009369', (389, 398))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('KCNQ1OT1', 'Gene', '10984', (357, 365))	('ROR', 'Gene', '100885779', (335, 338))	('LINC00672', 'Gene', '100505576', (203, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (342, 355))	('NSCLC', 'Disease', (97, 102))	('endometrial cancer', 'Phenotype', 'HP:0012114', (216, 234))	('lung adenocarcinoma', 'Disease', (379, 398))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('RP11', 'Gene', (404, 408))	('KCNQ1OT1', 'Gene', (357, 365))	('AK124454', 'Var', (287, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (342, 355))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
6934	30879091	EGCG can modulate multiple cell signaling pathways in tumor cells.	('modulate', 'Reg', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EGCG', 'Var', (0, 4))	('tumor', 'Disease', (54, 59))
6937	30879091	The identification of lncRNA AT102202 and its potential mRNA target, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was of particular importance.	('3-hydroxy-3-methylglutaryl coenzyme A reductase', 'Gene', (69, 116))	('AT102202', 'Var', (29, 37))	('HMGCR', 'Gene', (118, 123))	('3-hydroxy-3-methylglutaryl coenzyme A reductase', 'Gene', '3156', (69, 116))	('HMGCR', 'Gene', '3156', (118, 123))
6938	30879091	The quantitative PCR analyses revealed a down-regulation in the mRNA level of HMGCR and an up-regulation in AT102202.	('HMGCR', 'Gene', '3156', (78, 83))	('AT102202', 'Var', (108, 116))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('up-regulation', 'PosReg', (91, 104))	('down-regulation', 'NegReg', (41, 56))	('HMGCR', 'Gene', (78, 83))	('mRNA level', 'MPA', (64, 74))
6939	30879091	Furthermore, silencing of AT102202 was associated with an increased expression of HMGCR.	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('HMGCR', 'Gene', '3156', (82, 87))	('HMGCR', 'Gene', (82, 87))	('AT102202', 'Var', (26, 34))	('silencing', 'Var', (13, 22))
6940	30879091	The authors of this study concluded that AT102202 is involved in the improvement of cholesterol metabolism by EGCG.	('improvement', 'PosReg', (69, 80))	('EGCG', 'Gene', (110, 114))	('cholesterol', 'Chemical', 'MESH:D002784', (84, 95))	('EGCG', 'Chemical', 'MESH:C045651', (110, 114))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('84', '106'))	('AT102202', 'Var', (41, 49))	('cholesterol metabolism', 'MPA', (84, 106))
6946	30879091	EGCG can also enhance the sensitivity of ovarian cancer cells to cDDP.	('ovarian cancer', 'Disease', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('cDDP', 'Chemical', '-', (65, 69))	('enhance', 'PosReg', (14, 21))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('EGCG', 'Var', (0, 4))	('sensitivity', 'MPA', (26, 37))
6967	30879091	Furthermore, the gene silencing of HOTAIR was associated with a decrease in the proliferation, migration and invasion, while an induction in cell-cycle arrest and apoptosis was observed.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('invasion', 'CPA', (109, 117))	('HOTAIR', 'Gene', (35, 41))	('HOTAIR', 'Gene', '100124700', (35, 41))	('decrease', 'NegReg', (64, 72))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('gene silencing', 'Var', (17, 31))	('rat', 'Species', '10116', (98, 101))	('gene silencing', 'biological_process', 'GO:0016458', ('17', '31'))	('induction', 'Reg', (128, 137))	('arrest', 'Disease', (152, 158))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('141', '158'))	('rat', 'Species', '10116', (87, 90))
7008	30879091	Interestingly, GA-induced apoptosis in bladder cancer cells was suppressed by knockdown of GAS5.	('GAS', 'molecular_function', 'GO:0034005', ('91', '94'))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('apoptosis', 'CPA', (26, 35))	('GAS5', 'Gene', (91, 95))	('suppressed', 'NegReg', (64, 74))	('knockdown', 'Var', (78, 87))	('bladder cancer', 'Disease', (39, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('GA', 'Chemical', 'MESH:C052659', (91, 93))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GA', 'Chemical', 'MESH:C052659', (15, 17))
7047	30879091	The alkaloid also induced the expression of cancer susceptibility candidate 2 (CASC2) lncRNA, the silencing of which reversed the effects of sanguinarine.	('expression', 'MPA', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('silencing', 'Var', (98, 107))	('cancer susceptibility candidate 2', 'Gene', (44, 77))	('lncRNA', 'Protein', (86, 92))	('cancer susceptibility candidate 2', 'Gene', '255082', (44, 77))	('CASC2', 'Gene', '255082', (79, 84))	('CASC2', 'Gene', (79, 84))	('sanguinarine', 'Chemical', 'MESH:C005705', (141, 153))
7049	30879091	EIF4A3 could bind to CASC2; the knockdown of EIF4A3 reversed the effects of sanguinarine plus CASC2 silencing.	('CASC2', 'Gene', '255082', (21, 26))	('CASC2', 'Gene', (94, 99))	('sanguinarine', 'Chemical', 'MESH:C005705', (76, 88))	('EIF4', 'cellular_component', 'GO:0008304', ('45', '49'))	('CASC2', 'Gene', '255082', (94, 99))	('EIF4A3', 'Gene', (0, 6))	('EIF4A3', 'Gene', (45, 51))	('knockdown', 'Var', (32, 41))	('EIF4A3', 'Gene', '9775', (45, 51))	('EIF4A3', 'Gene', '9775', (0, 6))	('CASC2', 'Gene', (21, 26))	('EIF4', 'cellular_component', 'GO:0008304', ('0', '4'))
7061	30879091	The disruption of LINC01116 using CRISPR/CAS9 method suppressed the colony-forming ability of PC-3 cells by fourfold.	('PC-3', 'CellLine', 'CVCL:0035', (94, 98))	('LINC01116', 'Gene', (18, 27))	('colony-forming ability of PC-3 cells', 'CPA', (68, 104))	('LINC01116', 'Gene', '375295', (18, 27))	('disruption', 'Var', (4, 14))	('suppressed', 'NegReg', (53, 63))	('CAS', 'cellular_component', 'GO:0005650', ('41', '44'))
7063	30879091	Overall, these results suggest that the modulation of lncRNAs by SFN may contribute to its activities against prostate cancer.	('SFN', 'Chemical', 'MESH:C016766', (65, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('SFN', 'Gene', (65, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('activities', 'MPA', (91, 101))	('modulation', 'Var', (40, 50))	('prostate cancer', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
7082	30879091	Because most chronic diseases are caused by dysregulation of multiple genes, phytochemicals possess promise against these diseases.	('caused by', 'Reg', (34, 43))	('chronic diseases', 'Disease', 'MESH:D002908', (13, 29))	('chronic diseases', 'Disease', (13, 29))	('dysregulation', 'Var', (44, 57))
7093	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))
7120	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))
7201	32627065	reported significantly fewer patients with complication in the VATS group than in the thoracotomy group (27.3% vs 47.8%, P < 0.005).	('patients', 'Species', '9606', (29, 37))	('VATS', 'Var', (63, 67))	('fewer', 'NegReg', (23, 28))
7228	32987493	A computed tomography (CT) scan of the chest showed that the left main bronchus was thickened and occluded, and the left hilar was occupied by a tumor (28 mmx31 mm) associated with the left pulmonary artery and invasion of the left atrium (Fig 1A).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('pulmonary artery', 'Disease', (190, 206))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('pulmonary artery', 'Disease', 'MESH:D000071079', (190, 206))	('tumor', 'Disease', (145, 150))	('28 mmx31 mm', 'Var', (152, 163))
7238	32987493	Before initiating anlotinib, the patient's CT scan revealed a tumor in the central right upper lung (55 mmx65 mm) with an invasion of the right main bronchus and obstructive pneumonia in the right upper lung (Fig 2A).	('patient', 'Species', '9606', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('invasion', 'CPA', (122, 130))	('55 mmx65 mm', 'Var', (101, 112))	('pneumonia', 'Phenotype', 'HP:0002090', (174, 183))	('obstructive pneumonia', 'Disease', 'MESH:D011014', (162, 183))	('obstructive pneumonia', 'Disease', (162, 183))	('anlotinib', 'Chemical', 'MESH:C000625192', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
7273	32987493	The above is based on a randomized double-blind controlled phase III clinical trial called ALTER0303, whose results confirmed that anlotinib as a third-line treatment for NSCLC patients can significantly improve their overall survival rate with controllable side effects.	('anlotinib', 'Chemical', 'MESH:C000625192', (131, 140))	('SCLC', 'Phenotype', 'HP:0030357', (172, 176))	('patients', 'Species', '9606', (177, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('men', 'Species', '9606', (162, 165))	('anlotinib', 'Var', (131, 140))	('overall survival', 'MPA', (218, 234))	('NSCLC', 'Disease', (171, 176))	('improve', 'PosReg', (204, 211))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
7283	32987493	In the earliest clinical studies of bevacizumab, the first anti-angiogenic drug used in clinics, it was found that bevacizumab used in the treatment of lung cancer often caused BF, of which ETBF was the most common, BPF and BMF were also have been reported.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('men', 'Species', '9606', (144, 147))	('bevacizumab', 'Chemical', 'MESH:D000068258', (115, 126))	('ETBF', 'Disease', (190, 194))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('bevacizumab', 'Chemical', 'MESH:D000068258', (36, 47))	('bevacizumab', 'Var', (115, 126))	('caused', 'Reg', (170, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('lung cancer', 'Disease', (152, 163))
7337	32506804	Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T-cell infiltration (P = 0.003) in NE-low vs NE-high tumors.	('CD8', 'Gene', '925', (101, 104))	('CD45', 'Gene', '5788', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('NE-low', 'Var', (150, 156))	('tumor', 'Disease', (168, 173))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CD45', 'Gene', (13, 17))	('increased', 'PosReg', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('higher', 'PosReg', (51, 57))	('tumor', 'Disease', (61, 66))	('CD8', 'Gene', (101, 104))
7340	32506804	We also found significantly higher MHC II expression by malignant cells in NE-low (vs NE-high, P = 0.004) tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('expression', 'MPA', (42, 52))	('higher', 'PosReg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MHC II', 'Protein', (35, 41))	('NE-low', 'Var', (75, 81))
7341	32506804	TIM3 expression was significantly increased in NE-low (vs NE-high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05).	('metastases', 'Disease', (94, 104))	('tumors', 'Disease', (77, 83))	('primary tumors', 'Disease', (109, 123))	('expression', 'MPA', (5, 15))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('primary tumors', 'Disease', 'MESH:D001932', (109, 123))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('increased', 'PosReg', (34, 43))	('TIM3', 'Gene', (0, 4))	('TIM3', 'Gene', '84868', (0, 4))	('NE-low', 'Var', (47, 53))
7342	32506804	To our knowledge, this is the first human study that demonstrates in situ that NE-low SCLCs are associated with increased immune cell infiltration compared to NE-high tumors.	('SCLC', 'Gene', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('SCLC', 'Gene', '7864', (86, 90))	('NE-low', 'Var', (79, 85))	('immune cell infiltration', 'CPA', (122, 146))	('increased', 'PosReg', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('human', 'Species', '9606', (36, 41))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
7345	32506804	This study demonstrates that NE-low SCLCs are associated with increased immune-cell infiltration compared to NE-high tumours.	('increased', 'PosReg', (62, 71))	('tumours', 'Disease', (117, 124))	('SCLC', 'Gene', '7864', (36, 40))	('SCLC', 'Gene', (36, 40))	('immune-cell infiltration', 'CPA', (72, 96))	('NE-low', 'Var', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('tumours', 'Disease', 'MESH:D009369', (117, 124))
7354	32506804	In contrast, NE-low was associated with tumors with increased immunogenicity, in other words 'hot' or 'immune oasis' phenotype [5, 6, 7, 8].	('NE-low', 'Var', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('immunogenicity', 'MPA', (62, 76))	("'hot'", 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
7368	32506804	While antigen-presenting cells (APCs) constitutively express major histocompatibility complex (MHC) class II; many other cell types, including malignant cells, are also capable of expressing MHC II [26].	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('61', '93'))	('MHC II [', 'Var', (191, 199))	('APC', 'Disease', 'MESH:D011125', (32, 35))	('APC', 'Disease', (32, 35))
7383	32506804	Two 1-mm punches of tissue were taken from each donor tissue block for primary tumors, and one 1-mm punch from LN metastases blocks and seated into a recipient paraffin block in a positionally encoded array format (MP10 1.0 mm tissue punch on a manual TMA instrument; Beecher Instruments, Sun Prairie, WI, USA).	('MP10', 'Var', (215, 219))	('metastases', 'Disease', (114, 124))	('primary tumors', 'Disease', 'MESH:D001932', (71, 85))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('paraffin', 'Chemical', 'MESH:D010232', (160, 168))	('primary tumors', 'Disease', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
7386	32506804	Slides were stained on a Leica Bond RX autostainer using rabbit monoclonal antibody for IDO (#86630), CD45 (#13917), CD3 (#85061), CD8 (#8112), MHC II (#68258), PD-L1 (13684S), and PVR (#81254) from Cell Signaling (Danvers, MA, USA) and diluted 1 : 200 with Cell Signaling antibody diluent (#8112) prior to staining.	('#13917', 'Var', (108, 114))	('#8112', 'Var', (291, 296))	('Signaling', 'biological_process', 'GO:0023052', ('263', '272'))	('#81254', 'Var', (186, 192))	('antibody', 'molecular_function', 'GO:0003823', ('75', '83'))	('antibody', 'molecular_function', 'GO:0003823', ('273', '281'))	('#86630', 'Var', (93, 99))	('CD8', 'Gene', (131, 134))	('antibody', 'cellular_component', 'GO:0042571', ('75', '83'))	('antibody', 'cellular_component', 'GO:0042571', ('273', '281'))	('IDO', 'Gene', (88, 91))	('#68258', 'Var', (152, 158))	('PVR', 'Gene', '5817', (181, 184))	('antibody', 'cellular_component', 'GO:0019815', ('75', '83'))	('IDO', 'molecular_function', 'GO:0033754', ('88', '91'))	('antibody', 'cellular_component', 'GO:0019815', ('273', '281'))	('Signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('PVR', 'Gene', (181, 184))	('#8112', 'Var', (136, 141))	('CD45', 'Gene', (102, 106))	('CD8', 'Gene', '925', (131, 134))	('IDO', 'Gene', '3620', (88, 91))	('CD45', 'Gene', '5788', (102, 106))	('antibody', 'cellular_component', 'GO:0019814', ('75', '83'))	('antibody', 'cellular_component', 'GO:0019814', ('273', '281'))	('IDO', 'molecular_function', 'GO:0047719', ('88', '91'))	('PD-L1', 'Gene', (161, 166))	('PD-L1', 'Gene', '29126', (161, 166))	('#85061', 'Var', (122, 128))
7387	32506804	Antibodies TIM3 (PA0360), LAG3 (PA0300), and PD-1 (PA0216) were from Leica Biosystems (Wetzlar, Germany) diluted 1 : 200 with Leica antibody diluent.	('TIM3', 'Gene', (11, 15))	('antibody', 'cellular_component', 'GO:0042571', ('132', '140'))	('PD-1', 'Gene', (45, 49))	('PA0360', 'Var', (17, 23))	('LAG3', 'Gene', (26, 30))	('PD-1', 'Gene', '5133', (45, 49))	('TIM3', 'Gene', '84868', (11, 15))	('LAG3', 'Gene', '3902', (26, 30))	('antibody', 'cellular_component', 'GO:0019815', ('132', '140'))	('PA0300', 'Var', (32, 38))	('antibody', 'cellular_component', 'GO:0019814', ('132', '140'))	('antibody', 'molecular_function', 'GO:0003823', ('132', '140'))	('PA0216', 'Var', (51, 57))
7430	32506804	Next, we analyzed LN metastases in terms of NE subtypes and immune cell distribution, where we found a significantly increased density of CD45+, CD3+, and CD8+ cells in NE-low compared to NE-high LN metastases in tumor nests (Fig.	('CD45', 'Gene', (138, 142))	('CD3+', 'Var', (145, 149))	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('increased', 'PosReg', (117, 126))	('metastases', 'Disease', (21, 31))	('metastases in tumor', 'Disease', 'MESH:D009362', (199, 218))	('metastases in tumor', 'Disease', (199, 218))	('CD8', 'Gene', (155, 158))	('CD45', 'Gene', '5788', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('CD8', 'Gene', '925', (155, 158))	('NE-low', 'Var', (169, 175))	('metastases', 'Disease', (199, 209))	('metastases', 'Disease', 'MESH:D009362', (199, 209))
7431	32506804	Figure 3C,D,G,H show the relative immune cell distributions according to NE subtypes, where CD3/CD45 and CD8/CD3 ratios were significantly increased in NE-low (vs NE-high), tumors (P < 0.05) in tumor nests, but not in stroma.	('CD8', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('CD8', 'Gene', '925', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('increased', 'PosReg', (139, 148))	('CD45', 'Gene', '5788', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (194, 199))	('tumors', 'Disease', (173, 179))	('NE-low', 'Var', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('CD45', 'Gene', (96, 100))
7464	32506804	6H, tumor cells showed significantly higher MHC II expression in NE-low compared to NE-high primary tumors (P = 0.004; Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('primary tumors', 'Disease', 'MESH:D001932', (92, 106))	('higher', 'PosReg', (37, 43))	('tumor', 'Disease', (100, 105))	('MHC II', 'Gene', (44, 50))	('NE-low', 'Var', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('primary tumors', 'Disease', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
7529	32506804	In contrast, TIM3 was expressed by significantly more TILs in NE-low compared to NE-high tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('NE-low', 'Var', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('TIM3', 'Gene', (13, 17))	('more', 'PosReg', (49, 53))	('TIM3', 'Gene', '84868', (13, 17))
7531	32506804	In connection with the clinical relevance of TIM3, recently it was reported that inhibition of the TIM3-related molecular pathway promoted anticancer immunity and increased IFN-gamma production of T cells [60].	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('inhibition', 'Var', (81, 91))	('increased', 'PosReg', (163, 172))	('promoted', 'PosReg', (130, 138))	('IFN-gamma', 'Gene', (173, 182))	('IFN-gamma', 'Gene', '3458', (173, 182))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('TIM3', 'Gene', (99, 103))	('TIM3', 'Gene', '84868', (99, 103))	('TIM3', 'Gene', (45, 49))	('TIM3', 'Gene', '84868', (45, 49))
7698	32539833	The V-PLEX Proinflammatory Panel 1 includes 10 cytokines (IFNgamma, IL-10, IL-12p70, IL-1beta, IL-2, IL-4, IL-5, IL-6, TNFalpha and KC).	('IL-2', 'molecular_function', 'GO:0005134', ('95', '99'))	('IL-1beta', 'Gene', '16175', (85, 93))	('IL-12p70', 'Var', (75, 83))	('TNFalpha', 'Gene', (119, 127))	('IL-5', 'molecular_function', 'GO:0005137', ('107', '111'))	('IL-4', 'Gene', '16189', (101, 105))	('IL-10', 'Gene', '16153', (68, 73))	('IL-4', 'molecular_function', 'GO:0005136', ('101', '105'))	('P', 'Chemical', 'MESH:D010758', (11, 12))	('V', 'Chemical', 'MESH:D014639', (4, 5))	('IL-1beta', 'Gene', (85, 93))	('P', 'Chemical', 'MESH:D010758', (27, 28))	('IL-5', 'Gene', '16191', (107, 111))	('IFNgamma', 'Gene', '15978', (58, 66))	('IL-1', 'molecular_function', 'GO:0005149', ('85', '89'))	('IL-6', 'molecular_function', 'GO:0005138', ('113', '117'))	('IL-6', 'Gene', (113, 117))	('IL-5', 'Gene', (107, 111))	('IFNgamma', 'Gene', (58, 66))	('IL-2', 'Gene', '16183', (95, 99))	('IL-2', 'Gene', (95, 99))	('IL-12', 'molecular_function', 'GO:0005143', ('75', '80'))	('P', 'Chemical', 'MESH:D010758', (6, 7))	('IL-6', 'Gene', '16193', (113, 117))	('TNFalpha', 'Gene', '21926', (119, 127))	('IL-10', 'Gene', (68, 73))	('IL-10', 'molecular_function', 'GO:0005141', ('68', '73'))	('IL-4', 'Gene', (101, 105))
7752	32539833	Similarly, in the A549 exposures, deposited emissions barely increased cytotoxicity after exposure to both CCA samples compared to the clean air-exposed cells (Fig.	('cytotoxicity', 'Disease', (71, 83))	('CCA', 'Chemical', '-', (107, 110))	('A549', 'Var', (18, 22))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('S', 'Chemical', 'MESH:D013455', (0, 1))
7853	32539833	However, when inspecting the toxic equivalence (TEQ), the highest difference between wood types was seen for dibenzo [al] pyrene (27-fold), benzo [a] pyrene (6.6-fold) and dibenzo [ai] pyrene (3.6-fold), which was expected due to their higher TEF value.	('dibenzo', 'Var', (172, 179))	('benzo [a] pyrene', 'Chemical', 'MESH:D001564', (140, 156))	('dibenzo [ai] pyrene', 'Chemical', '-', (172, 191))	('dibenzo [al] pyrene', 'Chemical', '-', (109, 128))	('TEF', 'Gene', (243, 246))	('TEF', 'Gene', '21685', (243, 246))	('dibenzo [al] pyrene', 'MPA', (109, 128))	('toxic', 'MPA', (29, 34))	('benzo [a] pyrene', 'MPA', (140, 156))	('TEQ', 'Chemical', '-', (48, 51))
7855	32539833	Although 1H-phenalen-1-one (perinaphthenone) seems to be less mutagenic than benzo [a] pyrene, it was more than 40 times higher in concentration.	('perinaphthenone', 'Chemical', 'MESH:C038036', (28, 43))	('1H-phenalen-1-one', 'Var', (9, 26))	('Al', 'Chemical', 'MESH:D000535', (0, 2))	('benzo [a] pyrene', 'Chemical', 'MESH:D001564', (77, 93))	('higher', 'PosReg', (121, 127))	('1H-phenalen-1-one', 'Chemical', '-', (9, 26))
7863	32539833	It is known that gaseous PAHs, carbonyls, and other gaseous compounds such as NO2 can generate DNA damage in cells either directly or indirectly, for example, by oxidative stress.	('PAHs', 'Chemical', 'MESH:D011084', (25, 29))	('oxidative stress', 'MPA', (162, 178))	('carbon', 'Chemical', 'MESH:D002244', (31, 37))	('DNA damage', 'MPA', (95, 105))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('carbonyls', 'Var', (31, 40))	('oxidative stress', 'Phenotype', 'HP:0025464', (162, 178))	('NO2', 'Chemical', '-', (78, 81))
7890	32539833	In a study by Rice et al., doses of 0.1 and 1 mumol kg- 1 Cu were seen to cause large effects by inducing inflammatory response and cytotoxicity, whereas similar amounts of Zn resulted in a much lower level of association between composition and inflammatory response.	('inducing', 'PosReg', (97, 105))	('inflammatory response', 'biological_process', 'GO:0006954', ('246', '267'))	('0.1', 'Var', (36, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (132, 144))	('Zn', 'Chemical', 'MESH:D015032', (173, 175))	('inflammatory response', 'biological_process', 'GO:0006954', ('106', '127'))	('inflammatory response', 'CPA', (106, 127))	('Cu', 'Chemical', 'MESH:D003300', (58, 60))	('cytotoxicity', 'Disease', (132, 144))	('Rice', 'Species', '4530', (14, 18))
7941	32497150	Two rodent tumor models, B16-F10 and Py230, were determined to have upregulated anxA1 expression in the intratumoral vasculature.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('upregulated', 'PosReg', (68, 79))	('Py230', 'Var', (37, 42))	('tumor', 'Disease', (11, 16))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('anxA1', 'Gene', (80, 85))	('tumor', 'Disease', (109, 114))	('rat', 'Species', '10116', (107, 110))
8012	32497150	Upon orthotopic injection in C57BL/6 mice, Py230 cells form luminal mammary tumors and lung metastases.	('lung metastases', 'Disease', 'MESH:D009362', (87, 102))	('lung metastases', 'Disease', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Py230', 'Var', (43, 48))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('luminal', 'Chemical', 'MESH:D010634', (60, 67))	('mice', 'Species', '10090', (37, 41))
8038	32497150	Furthermore, besides characterization of anxA1 expression using IHC, we would also like to identify antibody capable of binding cell membrane-associated anxA127-346 for tumor uptake imaging study in tumor vasculature anxA1 positive rodent model.	('tumor', 'Disease', (199, 204))	('binding', 'molecular_function', 'GO:0005488', ('120', '127'))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('antibody', 'molecular_function', 'GO:0003823', ('100', '108'))	('antibody', 'cellular_component', 'GO:0019815', ('100', '108'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('uptake', 'biological_process', 'GO:0098657', ('175', '181'))	('uptake', 'biological_process', 'GO:0098739', ('175', '181'))	('tumor vasculature', 'Disease', (199, 216))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('antibody', 'cellular_component', 'GO:0042571', ('100', '108'))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('anxA127-346', 'Var', (153, 164))	('tumor vasculature', 'Disease', 'MESH:C565633', (199, 216))	('antibody', 'cellular_component', 'GO:0019814', ('100', '108'))	('cell membrane', 'cellular_component', 'GO:0005886', ('128', '141'))
8039	32497150	Although Clone 686122 (R&D Systems), Clone CL0199 (Sigma-Aldrich) and clone 29 (BD Biosciences) were able to bind cell membrane-associated anxA127-346 shown by flow cytometric assay (Fig 1A), they either have non-specific binding to anxA2 or have no species cross-reactivity with mouse.	('membrane-associated', 'Var', (119, 138))	('binding', 'molecular_function', 'GO:0005488', ('222', '229'))	('CL0199', 'Chemical', '-', (43, 49))	('non-specific', 'Interaction', (209, 221))	('mouse', 'Species', '10090', (280, 285))	('cell membrane', 'cellular_component', 'GO:0005886', ('114', '127'))
8074	32497150	To characterize anxA1 expression in tumor vasculature, we assessed the binding characteristics of a large panel of antibodies to identify those that bind N-terminal-cleaved anxA1.	('tumor vasculature', 'Disease', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('N-terminal-cleaved', 'Var', (154, 172))	('tumor vasculature', 'Disease', 'MESH:C565633', (36, 53))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('anxA1', 'Gene', (173, 178))
8091	32497150	On the basis of these data, it appears that tumor uptake of anti-anxA1 antibodies may be dependent on the tumor model or involves the engagement of specific epitopes that are not addressed by these antibodies.	('antibodies', 'Var', (71, 81))	('anti-anxA1 antibodies', 'Var', (60, 81))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('anti-anxA1', 'Gene', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('uptake', 'biological_process', 'GO:0098657', ('50', '56'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('uptake', 'biological_process', 'GO:0098739', ('50', '56'))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (106, 111))
8096	32497150	In conclusion, we used phage panning techniques to isolate anti-anxA1 antibodies with binding profiles designed to target anxA127-346, a truncated form of anxA1 that had previously been identified on the luminal surface of tumor endothelium.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('luminal', 'Chemical', 'MESH:D010634', (204, 211))	('anxA127-346', 'Var', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))
8158	32425696	Recently, HOXD-AS1 has been identified as an oncogene and enhances the epithelial-mesenchymal transition (EMT) process of breast carcinoma cell through serving as a competing endogenous RNA (ceRNA) for miR-421.	('epithelial-mesenchymal transition', 'CPA', (71, 104))	('breast carcinoma', 'Disease', 'MESH:D001943', (122, 138))	('breast carcinoma', 'Disease', (122, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('EMT', 'biological_process', 'GO:0001837', ('106', '109'))	('RNA', 'cellular_component', 'GO:0005562', ('186', '189'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('71', '104'))	('miR-421', 'Gene', (202, 209))	('breast carcinoma', 'Phenotype', 'HP:0003002', (122, 138))	('HOXD-AS1', 'Var', (10, 18))	('miR-421', 'Gene', '693122', (202, 209))	('enhances', 'PosReg', (58, 66))
8159	32425696	In ovarian carcinoma, HOXD-AS1 promotes the proliferation and invasion of cancer cell through modulating miR-133a-3p level and Wnt signaling axis.	('ovarian carcinoma', 'Disease', (3, 20))	('Wnt signaling axis', 'Pathway', (127, 145))	('promotes', 'PosReg', (31, 39))	('HOXD-AS1', 'Var', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('modulating', 'Reg', (94, 104))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (3, 20))	('miR-133a-3p level', 'MPA', (105, 122))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (3, 20))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('proliferation', 'CPA', (44, 57))
8160	32425696	In human gastric cancer (GC), HOXD-AS1 silencing inhibits cancer cell growth through inactivating janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('human', 'Species', '9606', (3, 8))	('gastric cancer', 'Disease', 'MESH:D013274', (9, 23))	('GC', 'Phenotype', 'HP:0012126', (25, 27))	('cancer', 'Disease', (17, 23))	('silencing', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('janus kinase 2', 'Gene', '3717', (98, 112))	('JAK2', 'Gene', '3717', (165, 169))	('janus kinase 2', 'Gene', (98, 112))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (9, 23))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('STAT3', 'Gene', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('inactivating', 'NegReg', (85, 97))	('JAK2', 'Gene', (165, 169))	('gastric cancer', 'Disease', (9, 23))	('STAT3', 'Gene', '6774', (170, 175))	('JAK', 'molecular_function', 'GO:0004713', ('165', '168'))	('inhibits', 'NegReg', (49, 57))	('signal transducer and activator of transcription 3', 'Gene', '6774', (113, 163))	('cancer', 'Disease', (58, 64))	('transcription', 'biological_process', 'GO:0006351', ('148', '161'))
8164	32425696	Previous investigations also suggest that the dysregulation of miR-326 contributes to multiple tumor types, such as cholangiocarcinoma, pancreatic ductal adenocarcinoma and medulloblastoma.	('miR-326', 'Gene', (63, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('medulloblastoma', 'Disease', (173, 188))	('multiple tumor', 'Disease', (86, 100))	('multiple tumor', 'Disease', 'MESH:D009369', (86, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('miR-326', 'Gene', '442900', (63, 70))	('pancreatic ductal adenocarcinoma', 'Disease', (136, 168))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (136, 168))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (136, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('medulloblastoma', 'Disease', 'MESH:D008527', (173, 188))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('dysregulation', 'Var', (46, 59))	('medulloblastoma', 'Phenotype', 'HP:0002885', (173, 188))	('cholangiocarcinoma', 'Disease', (116, 134))	('contributes', 'Reg', (71, 82))
8165	32425696	In osteosarcoma, small nucleolar RNA host gene 1 (SNHG1) regulates the level of NIN1 binding protein 1 homolog (NOB1) by sponging miR-326 and promotes the tumorigenesis of osteosarcoma cell.	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('17', '36'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('tumor', 'Disease', (155, 160))	('NOB1', 'Gene', '28987', (112, 116))	('SNHG1', 'Gene', (50, 55))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('osteosarcoma', 'Disease', (172, 184))	('osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('osteosarcoma', 'Disease', (3, 15))	('sponging', 'Var', (121, 129))	('miR-326', 'Gene', (130, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('SNHG1', 'Gene', '23642', (50, 55))	('miR-326', 'Gene', '442900', (130, 137))	('NOB1', 'Gene', (112, 116))	('level', 'MPA', (71, 76))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('17', '36'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('small nucleolar RNA host gene 1', 'Gene', '23642', (17, 48))	('small nucleolar RNA host gene 1', 'Gene', (17, 48))	('promotes', 'PosReg', (142, 150))
8188	32425696	HEK-293T cell was cotransfected with miR-326 and luciferase reporter vector that containing wild type (wt) SLC27A4 3'-UTR or mutant type (mut) SLC27A4 3'-UTR by using Lipofectamine  3000.	('miR-326', 'Gene', '442900', (37, 44))	('Lipofectamine', 'Chemical', 'MESH:C086724', (167, 180))	('SLC27A4', 'Gene', '10999', (143, 150))	('SLC27A4', 'Gene', (143, 150))	('miR-326', 'Gene', (37, 44))	('HEK-293T', 'CellLine', 'CVCL:0063', (0, 8))	('SLC27A4', 'Gene', '10999', (107, 114))	('mutant type', 'Var', (125, 136))	('SLC27A4', 'Gene', (107, 114))
8189	32425696	To explore HOXD-AS1's influence on miR-326, HEK-293T cell was cotransfected with miR-326 and luciferase reporter vector that containing wt HOXD-AS1 sequence or mut HOXD-AS1 sequence.	('miR-326', 'Gene', (35, 42))	('mut', 'Var', (160, 163))	('HEK-293T', 'CellLine', 'CVCL:0063', (44, 52))	('miR-326', 'Gene', '442900', (35, 42))	('miR-326', 'Gene', (81, 88))	('miR-326', 'Gene', '442900', (81, 88))
8221	32425696	Finally, the qPCR assay implied that HOXD-AS1 levels were suppressed in tumors that were formed by sh-HOXD-AS1 transfected HepG2 cells (Additional file 1: Figure S2b).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('sh-HOXD-AS1', 'Gene', (99, 110))	('suppressed', 'NegReg', (58, 68))	('tumors', 'Disease', (72, 78))	('HOXD-AS1 levels', 'MPA', (37, 52))	('transfected', 'Var', (111, 122))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('sh-HOXD-AS1', 'Gene', '401022', (99, 110))	('HepG2', 'CellLine', 'CVCL:0027', (123, 128))
8240	32425696	The wild type (wt) sequence of HOXD-AS1 containing the binding sites of miR-326 (wt-HOXD-AS1) or mutant type (mut) fragment (mut-HOXD-AS1) of HOXD-AS1 was inserted into luciferase reporter plasmid.	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('miR-326', 'Gene', '442900', (72, 79))	('miR-326', 'Gene', (72, 79))	('mutant', 'Var', (97, 103))
8241	32425696	HEK-293T cells were cotransfected with the plasmid combination with miR-NC or miR-326.	('miR-NC', 'Var', (68, 74))	('miR-326', 'Gene', (78, 85))	('miR-326', 'Gene', '442900', (78, 85))	('HEK-293T', 'CellLine', 'CVCL:0063', (0, 8))
8253	32425696	The proliferation test suggested that miR-326 overexpression restrained the proliferation while silencing of miR-326 enhanced HepG2 and SMMC-7721 cells proliferation (Fig.	('SMMC-7721', 'CellLine', 'CVCL:0534', (136, 145))	('miR-326', 'Gene', (38, 45))	('silencing', 'Var', (96, 105))	('miR-326', 'Gene', '442900', (38, 45))	('proliferation', 'CPA', (76, 89))	('HepG2', 'CellLine', 'CVCL:0027', (126, 131))	('miR-326', 'Gene', (109, 116))	('enhanced', 'PosReg', (117, 125))	('miR-326', 'Gene', '442900', (109, 116))
8254	32425696	Furthermore, miR-326 transfection inhibited the colony formation as well as invasive abilities of and SMMC-7721 and HepG2 cells while silencing of miR-326 caused opposites results (Fig.	('colony formation', 'CPA', (48, 64))	('invasive abilities of', 'CPA', (76, 97))	('SMMC-7721', 'CellLine', 'CVCL:0534', (102, 111))	('miR-326', 'Gene', '442900', (13, 20))	('miR-326', 'Gene', '442900', (147, 154))	('inhibited', 'NegReg', (34, 43))	('transfection', 'Var', (21, 33))	('HepG2', 'CellLine', 'CVCL:0027', (116, 121))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('silencing', 'Var', (134, 143))	('miR-326', 'Gene', (147, 154))	('miR-326', 'Gene', (13, 20))
8256	32425696	We observed that the inhibitory effects of HOXD-AS1 knockdown on the invasion and colony formation of HepG2 cells were rescued by the miR-326 inhibitor cotransfection (Fig.	('colony formation', 'CPA', (82, 98))	('miR-326', 'Gene', (134, 141))	('HepG2', 'CellLine', 'CVCL:0027', (102, 107))	('invasion', 'CPA', (69, 77))	('miR-326', 'Gene', '442900', (134, 141))	('knockdown', 'Var', (52, 61))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
8272	32425696	To future investigate the function of SLC27A4 in HCC cells, SMMC-7721 and HepG2 cells were transfected siSLC27A4 to decrease the level of SLC27A4.	('SLC27A4', 'Gene', '10999', (105, 112))	('HepG2', 'CellLine', 'CVCL:0027', (74, 79))	('SLC27A4', 'Gene', (105, 112))	('SMMC-7721', 'CellLine', 'CVCL:0534', (60, 69))	('decrease', 'NegReg', (116, 124))	('HCC', 'Gene', (49, 52))	('SLC27A4', 'Gene', '10999', (38, 45))	('HCC', 'Phenotype', 'HP:0001402', (49, 52))	('SLC27A4', 'Gene', (38, 45))	('SLC27A4', 'Gene', '10999', (138, 145))	('level', 'MPA', (129, 134))	('SLC27A4', 'Gene', (138, 145))	('transfected', 'Var', (91, 102))	('HCC', 'Gene', '619501', (49, 52))
8278	32425696	Previous investigations have verified that HOXD-AS1 promotes the development of multiple tumor types, including colorectal cancer, melanoma and ovarian cancer.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('multiple tumor', 'Disease', (80, 94))	('multiple tumor', 'Disease', 'MESH:D009369', (80, 94))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('HOXD-AS1', 'Var', (43, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('promotes', 'PosReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('development of', 'CPA', (65, 79))	('melanoma and ovarian cancer', 'Disease', 'MESH:D008545', (131, 158))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
8286	32425696	Previous study proves that miRNA-326 restrains the growth and aggressiveness of cervical carcinoma cell by mediating ETS Transcription Factor ELK1 (ELK1).	('ELK1', 'Gene', (142, 146))	('ELK1', 'Gene', (148, 152))	('miRNA-326', 'Var', (27, 36))	('ELK1', 'Gene', '2002', (148, 152))	('ELK1', 'Gene', '2002', (142, 146))	('growth', 'CPA', (51, 57))	('aggressiveness of cervical carcinoma', 'Disease', (62, 98))	('restrains', 'NegReg', (37, 46))	('aggressiveness', 'Phenotype', 'HP:0000718', (62, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('mediating', 'Reg', (107, 116))	('aggressiveness of cervical carcinoma', 'Disease', 'MESH:D002583', (62, 98))
8297	32425696	In the current study, we proved that HOXD-AS1 silencing increased the protein expressions and mRNA levels of epithelial marker, E-cadherin and suppressed the expression of mesenchymal marker, N-cadherin in HCC cell.	('E-cadherin', 'Gene', (128, 138))	('E-cadherin', 'Gene', '999', (128, 138))	('HCC', 'Phenotype', 'HP:0001402', (206, 209))	('N-cadherin', 'Gene', (192, 202))	('mRNA levels', 'MPA', (94, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('130', '138'))	('increased', 'PosReg', (56, 65))	('expression', 'MPA', (158, 168))	('silencing', 'Var', (46, 55))	('suppressed', 'NegReg', (143, 153))	('protein expressions', 'MPA', (70, 89))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('HCC', 'Gene', (206, 209))	('N-cadherin', 'Gene', '1000', (192, 202))	('HCC', 'Gene', '619501', (206, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('194', '202'))
8308	32373211	Results: We show that marizomib inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy.	('marizomib', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('proteasome', 'molecular_function', 'GO:0004299', ('50', '60'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('better', 'PosReg', (96, 102))	('tumor', 'Disease', (108, 113))	('marizomib', 'Chemical', 'MESH:C475865', (22, 31))	('proteasome', 'cellular_component', 'GO:0000502', ('50', '60'))	('inhibits', 'NegReg', (32, 40))	('patient', 'Species', '9606', (146, 153))	('BC', 'Phenotype', 'HP:0003002', (128, 130))
8311	32373211	We demonstrate that marizomib-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and combined inhibition of glycolysis with marizomib leads to a synergistic anti-cancer activity.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('inhibition', 'Var', (136, 146))	('upregulates', 'PosReg', (56, 67))	('marizomib', 'Chemical', 'MESH:C475865', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('OXPHOS inhibition', 'MPA', (38, 55))	('glycolysis', 'MPA', (68, 78))	('glycolysis', 'biological_process', 'GO:0006096', ('68', '78'))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('136', '160'))	('OXPHOS', 'biological_process', 'GO:0002082', ('38', '44'))	('marizomib', 'Chemical', 'MESH:C475865', (20, 29))	('BC', 'Phenotype', 'HP:0003002', (114, 116))
8322	32373211	While Btz, Cfz, and Ixz selectively inhibit the chymotrypsin-like proteasome activity (CT-L), they fail to inhibit the trypsin-like (T-L) and caspase-like (CP-L) proteasome activity, which are known to degrade proteins.	('Btz', 'Chemical', 'MESH:D000069286', (6, 9))	('proteasome', 'cellular_component', 'GO:0000502', ('162', '172'))	('chymotrypsin-like proteasome activity', 'MPA', (48, 85))	('proteasome', 'molecular_function', 'GO:0004299', ('162', '172'))	('inhibit', 'NegReg', (36, 43))	('trypsin-like', 'MPA', (119, 131))	('Btz', 'Var', (6, 9))	('proteasome', 'cellular_component', 'GO:0000502', ('66', '76'))	('Cfz', 'Chemical', 'MESH:C524865', (11, 14))	('proteasome', 'molecular_function', 'GO:0004299', ('66', '76'))	('Ixz', 'Chemical', 'MESH:C548400', (20, 23))
8331	32373211	Based on this information, we hypothesized that Mzb can simultaneously inhibit multiple proteasome catalytic sites, which may enhance its anti-tumor activity in TNBCs compared to the previous generation compounds.	('enhance', 'PosReg', (126, 133))	('tumor', 'Disease', (143, 148))	('Mzb', 'Var', (48, 51))	('inhibit', 'NegReg', (71, 78))	('BC', 'Phenotype', 'HP:0003002', (163, 165))	('proteasome', 'molecular_function', 'GO:0004299', ('88', '98'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Mzb', 'Chemical', 'MESH:C475865', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('proteasome', 'cellular_component', 'GO:0000502', ('88', '98'))
8333	32373211	We show that Mzb strongly inhibits proteasome functions by blocking CT-L, T-L, and CP-L proteasome activity, induces caspase-3 dependent apoptosis, and inhibits tumor cell proliferation in vitro in 2D and 3D cultures.	('inhibits', 'NegReg', (26, 34))	('tumor', 'Disease', (161, 166))	('CT-L', 'MPA', (68, 72))	('induces', 'Reg', (109, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('caspase-3', 'Gene', '836', (117, 126))	('activity', 'MPA', (99, 107))	('proteasome functions', 'MPA', (35, 55))	('CP-L', 'Var', (83, 87))	('caspase-3', 'Gene', (117, 126))	('proteasome', 'molecular_function', 'GO:0004299', ('88', '98'))	('proteasome', 'molecular_function', 'GO:0004299', ('35', '45'))	('T-L', 'MPA', (74, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('167', '185'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('proteasome', 'cellular_component', 'GO:0000502', ('35', '45'))	('proteasome', 'cellular_component', 'GO:0000502', ('88', '98'))	('inhibits', 'NegReg', (152, 160))	('Mzb', 'Chemical', 'MESH:C475865', (13, 16))	('Mzb', 'Var', (13, 16))	('blocking', 'NegReg', (59, 67))
8334	32373211	Here, we describe an additional, novel mechanism for the anti-cancer activity of Mzb and demonstrate that Mzb inhibits complex II-dependent mitochondrial respiration leading to a reduced oxidative phosphorylation (OXPHOS).	('oxidative phosphorylation', 'MPA', (187, 212))	('complex II-dependent mitochondrial respiration', 'MPA', (119, 165))	('Mzb', 'Chemical', 'MESH:C475865', (81, 84))	('inhibits', 'NegReg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('respiration', 'biological_process', 'GO:0007585', ('154', '165'))	('complex II', 'molecular_function', 'GO:0008177', ('119', '129'))	('Mzb', 'Chemical', 'MESH:C475865', (106, 109))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('OXPHOS', 'biological_process', 'GO:0002082', ('214', '220'))	('respiration', 'biological_process', 'GO:0045333', ('154', '165'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('187', '212'))	('reduced', 'NegReg', (179, 186))	('Mzb', 'Var', (106, 109))
8335	32373211	We further show that Mzb significantly reduces primary tumor growth and induces apoptosis in human TNBC cell line xenografts, a murine syngeneic TNBC model, and patient-derived tumor xenograft (PDX) models in vivo.	('murine', 'Species', '10090', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TNBC', 'Gene', (99, 103))	('patient', 'Species', '9606', (161, 168))	('BC', 'Phenotype', 'HP:0003002', (147, 149))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('tumor', 'Disease', (177, 182))	('human', 'Species', '9606', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('reduces', 'NegReg', (39, 46))	('induces', 'Reg', (72, 79))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Mzb', 'Chemical', 'MESH:C475865', (21, 24))	('Mzb', 'Var', (21, 24))	('apoptosis', 'CPA', (80, 89))	('BC', 'Phenotype', 'HP:0003002', (101, 103))
8337	32373211	Our results document that Mzb inhibits TNBC metastasis by inhibiting OXPHOS and reducing the number of circulating tumor cells (CTCs) in vivo.	('OXPHOS', 'biological_process', 'GO:0002082', ('69', '75'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Mzb', 'Chemical', 'MESH:C475865', (26, 29))	('OXPHOS', 'MPA', (69, 75))	('tumor', 'Disease', (115, 120))	('inhibiting', 'NegReg', (58, 68))	('Mzb', 'Var', (26, 29))	('BC', 'Phenotype', 'HP:0003002', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('reducing', 'NegReg', (80, 88))	('inhibits', 'NegReg', (30, 38))	('TNBC', 'Gene', (39, 43))
8338	32373211	Finally, we show that Mzb significantly reduces lung and brain metastatic burden in vivo after resecting the primary TNBC tumors.	('Mzb', 'Chemical', 'MESH:C475865', (22, 25))	('TNBC tumors', 'Disease', (117, 128))	('BC', 'Phenotype', 'HP:0003002', (119, 121))	('Mzb', 'Var', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('reduces', 'NegReg', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('TNBC tumors', 'Disease', 'MESH:D009369', (117, 128))
8345	32373211	SUM159PT or MDA-MB-231 were grown to 50-70% confluence, treated with either Mzb or Btz (100 nM) for 9 h and 24 h, respectively.	('Mzb', 'Chemical', 'MESH:C475865', (76, 79))	('Btz', 'Chemical', 'MESH:D000069286', (83, 86))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (12, 22))	('SUM159PT', 'Var', (0, 8))	('MDA-MB-231', 'Gene', (12, 22))	('SUM159PT', 'Chemical', '-', (0, 8))
8348	32373211	SUM159PT or MDA-MB-231 were grown to 50-70% confluence, treated with Mzb (100 nM) for 9 h and 24 h, respectively.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (12, 22))	('Mzb', 'Chemical', 'MESH:C475865', (69, 72))	('SUM159PT', 'Var', (0, 8))	('MDA-MB-231', 'Gene', (12, 22))	('SUM159PT', 'Chemical', '-', (0, 8))
8376	32373211	Additionally, Mzb also increased the expression of p27, a known proteasome substrate, in SUM159PT and MDA-MB-231 cells, indicating proteasome activity inhibition (Figure S1C).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (102, 112))	('Mzb', 'Var', (14, 17))	('proteasome', 'cellular_component', 'GO:0000502', ('64', '74'))	('p27', 'Gene', '10671', (51, 54))	('Mzb', 'Chemical', 'MESH:C475865', (14, 17))	('proteasome', 'cellular_component', 'GO:0000502', ('131', '141'))	('proteasome', 'molecular_function', 'GO:0004299', ('131', '141'))	('p27', 'Gene', (51, 54))	('increased', 'PosReg', (23, 32))	('proteasome', 'MPA', (131, 141))	('expression', 'MPA', (37, 47))	('SUM159PT', 'Var', (89, 97))	('proteasome', 'molecular_function', 'GO:0004299', ('64', '74'))	('SUM159PT', 'Chemical', '-', (89, 97))
8377	32373211	Thus, Mzb inhibits all three proteasome active sites in TNBC cells, exerting an overall stronger proteasome inhibitory effect in TNBCs.	('inhibits', 'NegReg', (10, 18))	('proteasome inhibitory effect', 'MPA', (97, 125))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('BC', 'Phenotype', 'HP:0003002', (58, 60))	('Mzb', 'Chemical', 'MESH:C475865', (6, 9))	('proteasome', 'molecular_function', 'GO:0004299', ('29', '39'))	('proteasome', 'cellular_component', 'GO:0000502', ('29', '39'))	('Mzb', 'Var', (6, 9))	('proteasome', 'molecular_function', 'GO:0004299', ('97', '107'))	('proteasome', 'cellular_component', 'GO:0000502', ('97', '107'))	('stronger', 'PosReg', (88, 96))
8383	32373211	Mzb significantly reduced the number of colonies for TNBC lines (SUM159PT and MDA-MB-231) but not for non-TNBC lines (MCF7 and ZR-75-1) (Figure 1C, D), suggesting that Mzb selectively inhibits TNBC cell growth.	('SUM159PT', 'Chemical', '-', (65, 73))	('TNBC cell growth', 'CPA', (193, 209))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (78, 88))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('cell growth', 'biological_process', 'GO:0016049', ('198', '209'))	('reduced', 'NegReg', (18, 25))	('Mzb', 'Chemical', 'MESH:C475865', (168, 171))	('MCF7', 'CellLine', 'CVCL:0031', (118, 122))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('inhibits', 'NegReg', (184, 192))	('BC', 'Phenotype', 'HP:0003002', (108, 110))	('Mzb', 'Var', (168, 171))	('BC', 'Phenotype', 'HP:0003002', (55, 57))
8384	32373211	We next examined whether Mzb can inhibit tumor growth in a 3D culture setting, which simulates the in vivo physiological environment of tumor cells and is used for enriching tumor-initiating cells.	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('inhibit', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Mzb', 'Chemical', 'MESH:C475865', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (136, 141))	('Mzb', 'Var', (25, 28))
8387	32373211	Interestingly, Mzb completely eliminated SUM159PT spheroid formation (Figure 1E).	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('eliminated', 'NegReg', (30, 40))	('Mzb', 'Chemical', 'MESH:C475865', (15, 18))	('SUM159PT', 'Var', (41, 49))	('SUM159PT', 'Chemical', '-', (41, 49))
8388	32373211	Thus, Mzb effectively reduces tumor cell growth in both 2D and 3D cultures.	('cell growth', 'biological_process', 'GO:0016049', ('36', '47'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Mzb', 'Chemical', 'MESH:C475865', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduces', 'NegReg', (22, 29))	('tumor', 'Disease', (30, 35))	('Mzb', 'Var', (6, 9))
8390	32373211	We therefore examined whether Mzb induces caspase-dependent apoptosis in TNBC cells.	('BC', 'Phenotype', 'HP:0003002', (75, 77))	('Mzb', 'Chemical', 'MESH:C475865', (30, 33))	('induces', 'Reg', (34, 41))	('caspase-dependent', 'CPA', (42, 59))	('Mzb', 'Var', (30, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))
8391	32373211	Mzb increased caspase-3 activity, as measured by the cleavage of caspase-3-specific substrate Ac-DEVD-AMC in TNBC cells but not in non-malignant breast cells (Figure S2A).	('activity', 'MPA', (24, 32))	('caspase-3', 'Gene', '836', (14, 23))	('caspase-3', 'Gene', '836', (65, 74))	('BC', 'Phenotype', 'HP:0003002', (111, 113))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('14', '32'))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('caspase-3', 'Gene', (14, 23))	('caspase-3', 'Gene', (65, 74))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('14', '32'))	('Ac-DEVD-AMC', 'Chemical', 'MESH:C112287', (94, 105))	('increased', 'PosReg', (4, 13))	('Mzb', 'Var', (0, 3))
8393	32373211	Furthermore, Mzb treatment resulted in a considerable cleavage of PARP1, a classical marker of apoptosis, in TNBCs cells (SUM159PT, MDA-MB-231, and BT-549) (Figure S2C).	('PARP1', 'Gene', '142', (66, 71))	('PARP1', 'Gene', (66, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('BT-549', 'CellLine', 'CVCL:1092', (148, 154))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('Mzb', 'Chemical', 'MESH:C475865', (13, 16))	('SUM159PT', 'Chemical', '-', (122, 130))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (132, 142))	('SUM159PT', 'Var', (122, 130))	('BC', 'Phenotype', 'HP:0003002', (111, 113))	('cleavage', 'MPA', (54, 62))
8395	32373211	Our results showed that Mzb reduced the expression of anti-apoptotic proteins Mcl-1 and Bcl-2, and of the survival protein survivin.	('expression', 'MPA', (40, 50))	('Mcl-1', 'Gene', (78, 83))	('Mzb', 'Var', (24, 27))	('reduced', 'NegReg', (28, 35))	('anti-apoptotic', 'CPA', (54, 68))	('Bcl-2', 'molecular_function', 'GO:0015283', ('88', '93'))	('Bcl-2', 'Gene', (88, 93))	('Bcl-2', 'Gene', '596', (88, 93))	('survivin', 'Protein', (123, 131))	('Mcl-1', 'Gene', '4170', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('Mzb', 'Chemical', 'MESH:C475865', (24, 27))
8397	32373211	Hence, our data reveal that Mzb induces caspase-3-dependent apoptosis in TNBC cells.	('BC', 'Phenotype', 'HP:0003002', (75, 77))	('Mzb', 'Var', (28, 31))	('caspase-3', 'Gene', (40, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('Mzb', 'Chemical', 'MESH:C475865', (28, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('caspase-3', 'Gene', '836', (40, 49))
8410	32373211	We found that Mzb significantly reduced routine respiration of the cells by ~50% after 9- and 24- h treatments, however the maximum respiratory capacity of the cells was unaffected (Figure 2E).	('respiration', 'biological_process', 'GO:0045333', ('48', '59'))	('Mzb', 'Var', (14, 17))	('reduced', 'NegReg', (32, 39))	('routine respiration', 'MPA', (40, 59))	('respiration', 'biological_process', 'GO:0007585', ('48', '59'))	('Mzb', 'Chemical', 'MESH:C475865', (14, 17))
8411	32373211	In order to better understand the respiration inhibition capability of Mzb, we next examined if Mzb inhibits complex I-dependent or complex II-dependent respiration in SUM159PT cells.	('SUM159PT', 'Chemical', '-', (168, 176))	('Mzb', 'Var', (96, 99))	('respiration', 'biological_process', 'GO:0045333', ('153', '164'))	('inhibits', 'NegReg', (100, 108))	('complex II-dependent respiration', 'MPA', (132, 164))	('complex II', 'molecular_function', 'GO:0008177', ('132', '142'))	('Mzb', 'Chemical', 'MESH:C475865', (71, 74))	('complex I', 'cellular_component', 'GO:0030964', ('109', '118'))	('respiration', 'biological_process', 'GO:0045333', ('34', '45'))	('complex I-dependent', 'MPA', (109, 128))	('Mzb', 'Chemical', 'MESH:C475865', (96, 99))	('respiration', 'biological_process', 'GO:0007585', ('153', '164'))	('respiration', 'biological_process', 'GO:0007585', ('34', '45'))
8414	32373211	Furthermore, Mzb reduced ATP generation (Figure 2G) and increased reactive oxygen species (ROS) formation (Figure 2H) in SUM159PT cells in a dose-dependent manner.	('ATP generation', 'MPA', (25, 39))	('ROS) formation', 'biological_process', 'GO:1903409', ('91', '105'))	('SUM159PT', 'Chemical', '-', (121, 129))	('increased', 'PosReg', (56, 65))	('ATP', 'Chemical', 'MESH:D000255', (25, 28))	('Mzb', 'Chemical', 'MESH:C475865', (13, 16))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (56, 89))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (66, 89))	('ROS', 'Chemical', 'MESH:D017382', (91, 94))	('Mzb', 'Var', (13, 16))	('reduced', 'NegReg', (17, 24))
8415	32373211	Similar to the effects on SUM159PT cells, Mzb reduced routine and complex II-dependent respiration (Figure S3A, B), decreased ATP generation (Figure S3C), and increased ROS levels (Figure S3D) in MDA-MB-231 cells.	('increased ROS levels', 'Phenotype', 'HP:0025464', (159, 179))	('Mzb', 'Var', (42, 45))	('respiration', 'biological_process', 'GO:0007585', ('87', '98'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (196, 206))	('complex II', 'molecular_function', 'GO:0008177', ('66', '76'))	('increased', 'PosReg', (159, 168))	('ROS levels', 'MPA', (169, 179))	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('ROS', 'Chemical', 'MESH:D017382', (169, 172))	('reduced', 'NegReg', (46, 53))	('respiration', 'biological_process', 'GO:0045333', ('87', '98'))	('ATP generation', 'MPA', (126, 140))	('Mzb', 'Chemical', 'MESH:C475865', (42, 45))	('SUM159PT', 'Chemical', '-', (26, 34))	('decreased', 'NegReg', (116, 125))
8416	32373211	Hence, Mzb inhibits mitochondrial respiration in TNBC cells in addition to the proteasome complex inhibition.	('Mzb', 'Var', (7, 10))	('mitochondrial respiration', 'MPA', (20, 45))	('proteasome', 'molecular_function', 'GO:0004299', ('79', '89'))	('inhibits', 'NegReg', (11, 19))	('respiration', 'biological_process', 'GO:0045333', ('34', '45'))	('BC', 'Phenotype', 'HP:0003002', (51, 53))	('Mzb', 'Chemical', 'MESH:C475865', (7, 10))	('proteasome complex', 'cellular_component', 'GO:0000502', ('79', '97'))	('respiration', 'biological_process', 'GO:0007585', ('34', '45'))
8420	32373211	We next delineated the mechanism by which Mzb inhibits OXPHOS in TNBC cells.	('BC', 'Phenotype', 'HP:0003002', (67, 69))	('Mzb', 'Var', (42, 45))	('OXPHOS', 'biological_process', 'GO:0002082', ('55', '61'))	('OXPHOS', 'MPA', (55, 61))	('inhibits', 'NegReg', (46, 54))	('Mzb', 'Chemical', 'MESH:C475865', (42, 45))
8428	32373211	Interestingly, PGC-1alpha overexpression partially rescued SUM159PT cells from undergoing Mzb-induced cell death (Figure S4E) and it also rescued Mzb-induced OXPHOS gene downregulation (Figure S4F).	('OXPHOS', 'biological_process', 'GO:0002082', ('158', '164'))	('Mzb', 'Chemical', 'MESH:C475865', (146, 149))	('cell death', 'biological_process', 'GO:0008219', ('102', '112'))	('downregulation', 'NegReg', (170, 184))	('SUM159PT', 'Var', (59, 67))	('Mzb', 'Chemical', 'MESH:C475865', (90, 93))	('PGC-1alpha', 'Gene', (15, 25))	('SUM159PT', 'Chemical', '-', (59, 67))
8438	32373211	Mzb treatment significantly reduced the percentage of ALDH1+ BCSCs from approximately 23% in control tumors to 4-5% (Figure 3E), suggesting that Mzb does not only impact the bulk-tumor population but also impacts BCSCs, and therefore regressed patient-derived tumors in vivo.	('tumor', 'Disease', (260, 265))	('BCSCs', 'CPA', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('Mzb', 'Chemical', 'MESH:C475865', (145, 148))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('Mzb', 'Var', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ALDH', 'molecular_function', 'GO:0004030', ('54', '58'))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('ALDH1', 'Gene', '216', (54, 59))	('tumors', 'Disease', (260, 266))	('BC', 'Phenotype', 'HP:0003002', (213, 215))	('patient', 'Species', '9606', (244, 251))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('tumors', 'Disease', (101, 107))	('impacts', 'Reg', (205, 212))	('BC', 'Phenotype', 'HP:0003002', (61, 63))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumor', 'Disease', (101, 106))	('ALDH1', 'Gene', (54, 59))	('impact', 'Reg', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (179, 184))
8441	32373211	Our results show that Mzb significantly reduced 4T1.2 tumor growth (Figure 4A) and tumor weight (Figure 4B) compared to the vehicle-treated group.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Mzb', 'Chemical', 'MESH:C475865', (22, 25))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Mzb', 'Var', (22, 25))	('reduced', 'NegReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('4T1.2', 'Gene', (48, 53))
8446	32373211	Mzb treatment (100 nM) reduced mRNA levels of multiple EMT markers including ZEB1, Vimentin, and Slug in 4T1.2, SUM159PT, and MDA-MB-231 cells (Figure S5A-C).	('mRNA levels of multiple', 'MPA', (31, 54))	('Vimentin', 'cellular_component', 'GO:0045099', ('83', '91'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (126, 136))	('Slug', 'MPA', (97, 101))	('Vimentin', 'Protein', (83, 91))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('SUM159PT', 'Chemical', '-', (112, 120))	('SUM159PT', 'Var', (112, 120))	('Vimentin', 'cellular_component', 'GO:0045098', ('83', '91'))	('reduced', 'NegReg', (23, 30))	('EMT', 'biological_process', 'GO:0001837', ('55', '58'))
8447	32373211	Mzb also reduced SUM159PT and MDA-MB-231 cell migration in vitro (Figure S5D).	('MDA-MB-231 cell migration', 'CPA', (30, 55))	('cell migration', 'biological_process', 'GO:0016477', ('41', '55'))	('reduced', 'NegReg', (9, 16))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('SUM159PT', 'Chemical', '-', (17, 25))	('SUM159PT', 'Var', (17, 25))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (30, 40))
8448	32373211	Thus, our data indicate that Mzb reduces TNBC tumor growth and inhibits metastases.	('BC', 'Phenotype', 'HP:0003002', (43, 45))	('metastases', 'Disease', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('Mzb', 'Chemical', 'MESH:C475865', (29, 32))	('TNBC tumor', 'Disease', 'MESH:D009369', (41, 51))	('inhibits', 'NegReg', (63, 71))	('Mzb', 'Var', (29, 32))	('TNBC tumor', 'Disease', (41, 51))	('reduces', 'NegReg', (33, 40))
8450	32373211	Mice were treated with half-maximum tolerated dose (MTD) of Mzb (0.075 mg/kg) or doxorubicin (5 mg/kg) alone or in combination.	('Mzb', 'Chemical', 'MESH:C475865', (60, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('0.075', 'Var', (65, 70))	('Mzb', 'Gene', (60, 63))	('Mice', 'Species', '10090', (0, 4))
8459	32373211	Our data revealed that Mzb dramatically reduced the number of micro and macro lung metastatic nodules in 4T1BR4 tumor model (Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('macro lung', 'Phenotype', 'HP:0002088', (72, 82))	('Mzb', 'Chemical', 'MESH:C475865', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('reduced', 'NegReg', (40, 47))	('Mzb', 'Var', (23, 26))	('tumor', 'Disease', (112, 117))
8460	32373211	Similarly, Mzb reduced the number of micro brain metastatic nodules (Figure 5B).	('reduced', 'NegReg', (15, 22))	('Mzb', 'Chemical', 'MESH:C475865', (11, 14))	('Mzb', 'Var', (11, 14))	('micro brain metastatic nodules', 'CPA', (37, 67))
8462	32373211	Our data convincingly show that Mzb exerts potent cytotoxicity on metastatic TNBCs by reducing the overall lung metastasis burden and micro metastasis in the brain.	('Mzb', 'Chemical', 'MESH:C475865', (32, 35))	('cytotoxicity', 'Disease', 'MESH:D064420', (50, 62))	('Mzb', 'Var', (32, 35))	('micro metastasis in the brain', 'CPA', (134, 163))	('lung metastasis burden', 'CPA', (107, 129))	('reducing', 'NegReg', (86, 94))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('cytotoxicity', 'Disease', (50, 62))
8464	32373211	In our study we also found that Mzb-induced a significant downregulation of the key regulator of cell metabolism PGC-1alpha, which has been shown to be upregulated in metastatic breast cancer cells and to promote breast cancer metastasis by stimulating OXPHOS, increasing cell motility and invasive properties without impacting the expression of EMT-related genes, suggesting that Mzb catalyzed suppression of PGC-1alpha levels is not mutually exclusive to suppression of EMT markers.	('OXPHOS', 'biological_process', 'GO:0002082', ('253', '259'))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('PGC-1alpha', 'Gene', (113, 123))	('increasing', 'PosReg', (261, 271))	('EMT', 'biological_process', 'GO:0001837', ('346', '349'))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', (213, 226))	('promote', 'PosReg', (205, 212))	('metabolism', 'biological_process', 'GO:0008152', ('102', '112'))	('cell motility', 'biological_process', 'GO:0048870', ('272', '285'))	('Mzb', 'Chemical', 'MESH:C475865', (32, 35))	('invasive properties', 'CPA', (290, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('downregulation', 'NegReg', (58, 72))	('cell motility', 'CPA', (272, 285))	('EMT', 'biological_process', 'GO:0001837', ('472', '475'))	('Mzb', 'Chemical', 'MESH:C475865', (381, 384))	('Mzb-induced', 'Var', (32, 43))	('upregulated', 'PosReg', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))	('OXPHOS', 'MPA', (253, 259))
8466	32373211	Notably, Mzb significantly reduced the mRNA levels of PGC-1alpha and EMT genes including ZEB1, vimentin, and slug (Figure 5D) in primary tumors.	('reduced', 'NegReg', (27, 34))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('vimentin', 'cellular_component', 'GO:0045099', ('95', '103'))	('Mzb', 'Chemical', 'MESH:C475865', (9, 12))	('slug', 'Gene', (109, 113))	('vimentin', 'cellular_component', 'GO:0045098', ('95', '103'))	('primary tumors', 'Disease', 'MESH:D001932', (129, 143))	('PGC-1alpha', 'Protein', (54, 64))	('vimentin', 'Gene', '7431', (95, 103))	('slug', 'Gene', '6591', (109, 113))	('mRNA levels', 'MPA', (39, 50))	('Mzb', 'Var', (9, 12))	('vimentin', 'Gene', (95, 103))	('EMT genes', 'Gene', (69, 78))	('ZEB1', 'Gene', (89, 93))	('primary tumors', 'Disease', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
8470	32373211	Interestingly, Mzb dramatically reduced CTCs in the 4T1BR model in vivo (Figure 5E).	('Mzb', 'Chemical', 'MESH:C475865', (15, 18))	('CTCs', 'MPA', (40, 44))	('reduced', 'NegReg', (32, 39))	('Mzb', 'Var', (15, 18))
8471	32373211	Hence, our data suggested that Mzb may inhibit TNBC lung metastasis via repressing PGC-1alpha and consequent OXPHOS inhibition in addition to suppressing expression of EMT markers.	('repressing', 'NegReg', (72, 82))	('TNBC lung metastasis', 'Disease', 'MESH:D009362', (47, 67))	('TNBC lung metastasis', 'Disease', (47, 67))	('Mzb', 'Var', (31, 34))	('inhibit', 'NegReg', (39, 46))	('OXPHOS', 'biological_process', 'GO:0002082', ('109', '115'))	('Mzb', 'Chemical', 'MESH:C475865', (31, 34))	('EMT markers', 'CPA', (168, 179))	('suppressing', 'NegReg', (142, 153))	('EMT', 'biological_process', 'GO:0001837', ('168', '171'))	('PGC-1alpha', 'Gene', (83, 93))	('BC', 'Phenotype', 'HP:0003002', (49, 51))	('OXPHOS inhibition', 'MPA', (109, 126))	('expression', 'MPA', (154, 164))
8477	32373211	We therefore examined if Mzb upregulates glycolysis in TNBC cells when OXPHOS is inhibited.	('BC', 'Phenotype', 'HP:0003002', (57, 59))	('OXPHOS', 'biological_process', 'GO:0002082', ('71', '77'))	('upregulates', 'PosReg', (29, 40))	('glycolysis', 'biological_process', 'GO:0006096', ('41', '51'))	('Mzb', 'Chemical', 'MESH:C475865', (25, 28))	('glycolysis', 'MPA', (41, 51))	('Mzb', 'Var', (25, 28))
8492	32373211	In this study, we show for the first time that Mzb strongly inhibits TNBC primary tumor growth and inhibits its metastasis to the lungs and micro-metastasis to the brain in vivo.	('BC', 'Phenotype', 'HP:0003002', (71, 73))	('inhibits', 'NegReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('TNBC', 'Gene', (69, 73))	('micro-metastasis to the brain', 'CPA', (140, 169))	('Mzb', 'Chemical', 'MESH:C475865', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibits', 'NegReg', (60, 68))	('tumor', 'Disease', (82, 87))	('Mzb', 'Var', (47, 50))
8500	32373211	In line with these studies, we show that while Btz only inhibited the CT-L1 activity in TNBC cells, Mzb at much lower concentration inhibited all three proteasome activities and exerted a greater apoptosis in TNBC cells.	('inhibited', 'NegReg', (132, 141))	('BC', 'Phenotype', 'HP:0003002', (211, 213))	('Mzb', 'Var', (100, 103))	('proteasome', 'molecular_function', 'GO:0004299', ('152', '162'))	('CT-L1 activity', 'MPA', (70, 84))	('proteasome', 'cellular_component', 'GO:0000502', ('152', '162'))	('apoptosis', 'CPA', (196, 205))	('Mzb', 'Chemical', 'MESH:C475865', (100, 103))	('inhibited', 'NegReg', (56, 65))	('BC', 'Phenotype', 'HP:0003002', (90, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('Btz', 'Chemical', 'MESH:D000069286', (47, 50))
8503	32373211	In line with this notion, our data indicates that Mzb, by simultaneously inhibiting proteasome activity and OXPHOS, may provide an effective therapy option for TNBC patients.	('Mzb', 'Chemical', 'MESH:C475865', (50, 53))	('proteasome activity', 'MPA', (84, 103))	('OXPHOS', 'MPA', (108, 114))	('OXPHOS', 'biological_process', 'GO:0002082', ('108', '114'))	('TNBC', 'Disease', (160, 164))	('Mzb', 'Var', (50, 53))	('patients', 'Species', '9606', (165, 173))	('proteasome', 'molecular_function', 'GO:0004299', ('84', '94'))	('inhibiting', 'NegReg', (73, 83))	('proteasome', 'cellular_component', 'GO:0000502', ('84', '94'))	('BC', 'Phenotype', 'HP:0003002', (162, 164))
8506	32373211	Mzb also inhibited in vivo tumor growth in pancreatic cancer models.	('inhibited', 'NegReg', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Mzb', 'Var', (0, 3))
8508	32373211	In line with these studies, our results showed that Mzb significantly reduced the tumor growth and induced apoptosis in multiple TNBC xenograft models.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('reduced', 'NegReg', (70, 77))	('induced', 'Reg', (99, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('Mzb', 'Var', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('apoptosis', 'CPA', (107, 116))	('tumor', 'Disease', (82, 87))	('Mzb', 'Chemical', 'MESH:C475865', (52, 55))
8511	32373211	Thus, our data convincingly demonstrates that Mzb exerts a superior anti-cancer activity in TNBC preclinical models both as monotherapy and in combination with chemotherapy.	('cancer', 'Disease', (73, 79))	('Mzb', 'Chemical', 'MESH:C475865', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Mzb', 'Var', (46, 49))	('BC', 'Phenotype', 'HP:0003002', (94, 96))	('TNBC', 'Gene', (92, 96))
8523	32373211	These data also imply that similar to glioblastoma, Mzb can cross the blood-brain barrier, reach brain metastatic TNBC, and exert cytotoxic effect.	('cytotoxic effect', 'CPA', (130, 146))	('brain metastatic TNBC', 'CPA', (97, 118))	('BC', 'Phenotype', 'HP:0003002', (116, 118))	('Mzb', 'Var', (52, 55))	('glioblastoma', 'Disease', (38, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (38, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('reach', 'PosReg', (91, 96))	('Mzb', 'Chemical', 'MESH:C475865', (52, 55))
8524	32373211	Our findings also show that Mzb significantly reduces lung metastasis in the aggressive and highly metastatic 4T1BR4 syngeneic TNBC model in vivo (Figure 5).	('BC', 'Phenotype', 'HP:0003002', (129, 131))	('Mzb', 'Var', (28, 31))	('Mzb', 'Chemical', 'MESH:C475865', (28, 31))	('lung metastasis', 'CPA', (54, 69))	('reduces', 'NegReg', (46, 53))
8531	32373211	Moreover, our data show that Mzb also reduced mRNA levels of various EMT markers including ZEB1, Vimentin, and Slug, suggesting that Mzb may inhibit TNBC lung metastasis via multiple mechanisms.	('Vimentin', 'cellular_component', 'GO:0045098', ('97', '105'))	('Slug', 'MPA', (111, 115))	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('reduced', 'NegReg', (38, 45))	('Mzb', 'Chemical', 'MESH:C475865', (29, 32))	('Mzb', 'Chemical', 'MESH:C475865', (133, 136))	('Vimentin', 'cellular_component', 'GO:0045099', ('97', '105'))	('mRNA levels', 'MPA', (46, 57))	('TNBC lung metastasis', 'Disease', 'MESH:D009362', (149, 169))	('BC', 'Phenotype', 'HP:0003002', (151, 153))	('Mzb', 'Var', (133, 136))	('inhibit', 'NegReg', (141, 148))	('TNBC lung metastasis', 'Disease', (149, 169))	('Vimentin', 'MPA', (97, 105))
8533	32373211	Notably, our data also show that Mzb has potential to reduce lung and brain metastatic burden in TNBC patients and hence can be translated into a clinical trial for TNBC patients in metastatic settings.	('patients', 'Species', '9606', (170, 178))	('BC', 'Phenotype', 'HP:0003002', (167, 169))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('reduce', 'NegReg', (54, 60))	('patients', 'Species', '9606', (102, 110))	('Mzb', 'Chemical', 'MESH:C475865', (33, 36))	('TNBC', 'Disease', (97, 101))	('Mzb', 'Var', (33, 36))
8560	32308722	To elucidate the mechanisms of FLP inhibiting vasculogenesis and to address the role circulating and carcinomatous tissue exosomes play, the values of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and PDGFR which were closely related to angiogenesis, were estimated in serum and carcinomatous tissue exosomes.	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('194', '224'))	('vasculogenesis', 'biological_process', 'GO:0001570', ('46', '60'))	('carcinomatous', 'Disease', (101, 114))	('carcinomatous', 'Disease', 'MESH:D055756', (315, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('vasculogenesis', 'CPA', (46, 60))	('FLP', 'Var', (31, 34))	('vascular endothelial growth factor', 'Gene', (151, 185))	('carcinomatous', 'Disease', (315, 328))	('vascular endothelial growth factor', 'Gene', '22339', (151, 185))	('PDGFR', 'Gene', '18596', (237, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('inhibiting', 'NegReg', (35, 45))	('angiogenesis', 'biological_process', 'GO:0001525', ('273', '285'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('151', '185'))	('carcinomatous', 'Disease', 'MESH:D055756', (101, 114))	('PDGFR', 'Gene', (237, 242))	('PDGF', 'molecular_function', 'GO:0005161', ('226', '230'))
8622	32308722	The average tumour weight of MO mice was 1.00 +- 0.15 g. Compared to that of MO mice, the average tumour weight was significantly lower in FLP-treated and CTX-treated mice (P < 0.05, P < 0.01; Figure 4(a)).	('tumour weight', 'Disease', (98, 111))	('lower', 'NegReg', (130, 135))	('FLP-treated', 'Var', (139, 150))	('tumour weight', 'Disease', 'MESH:D009369', (12, 25))	('CTX', 'Gene', '57276', (155, 158))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour weight', 'Disease', 'MESH:D009369', (98, 111))	('CTX', 'Gene', (155, 158))	('mice', 'Species', '10090', (32, 36))	('mice', 'Species', '10090', (80, 84))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour weight', 'Disease', (12, 25))	('mice', 'Species', '10090', (167, 171))
8623	32308722	The average spleen weight of MO mice was 0.24 +- 0.01 g. Compared to that of MO mice, the average spleen weight was significantly lower in FLP-treated mice (P < 0.05; Figure 4(a)).	('lower', 'NegReg', (130, 135))	('FLP-treated', 'Var', (139, 150))	('mice', 'Species', '10090', (151, 155))	('mice', 'Species', '10090', (32, 36))	('mice', 'Species', '10090', (80, 84))	('spleen weight', 'CPA', (98, 111))
8647	32308722	Additionally, VEGF and PDGF protein levels were significantly decreased in FLP-treated MO mice compared to those of MO mice (P < 0.05).	('mice', 'Species', '10090', (119, 123))	('decreased', 'NegReg', (62, 71))	('FLP-treated', 'Var', (75, 86))	('mice', 'Species', '10090', (90, 94))	('PDGF', 'molecular_function', 'GO:0005161', ('23', '27'))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
8659	32308722	TNF-alpha levels did not exhibit obvious differences in the tumours of MO mice compared to those of CTX-treated mice; however, TNF-alpha levels were obviously decreased in FLP-treated MO mice compared to those of CTX-treated mice (P < 0.05).	('TNF-alpha levels', 'MPA', (127, 143))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('CTX', 'Gene', (213, 216))	('FLP-treated', 'Var', (172, 183))	('CTX', 'Gene', '57276', (213, 216))	('mice', 'Species', '10090', (187, 191))	('decreased', 'NegReg', (159, 168))	('CTX', 'Gene', (100, 103))	('CTX', 'Gene', '57276', (100, 103))	('mice', 'Species', '10090', (225, 229))	('mice', 'Species', '10090', (74, 78))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('mice', 'Species', '10090', (112, 116))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
8701	32308722	This study examined cytokine levels and found that the levels of inflammation-related cytokines, such as IL-6, IL-1beta, and TNF-alpha, were decreased in FLP-treated MO mice in the tumour tissues compared to those of MO mice.	('inflammation', 'Disease', (65, 77))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('mice', 'Species', '10090', (220, 224))	('FLP-treated', 'Var', (154, 165))	('IL-1', 'molecular_function', 'GO:0005149', ('111', '115'))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('decreased', 'NegReg', (141, 150))	('tumour', 'Disease', (181, 187))	('mice', 'Species', '10090', (169, 173))	('inflammation', 'biological_process', 'GO:0006954', ('65', '77'))	('TNF-alpha', 'MPA', (125, 134))	('inflammation', 'Disease', 'MESH:D007249', (65, 77))	('levels of', 'MPA', (55, 64))	('IL-6', 'molecular_function', 'GO:0005138', ('105', '109'))
8707	32308722	Inhibitors and activators of NF-kappaB could decrease and increase VEGF levels in carcinoma, respectively.	('NF-kappaB', 'Gene', (29, 38))	('carcinoma', 'Disease', 'MESH:D009369', (82, 91))	('increase', 'PosReg', (58, 66))	('VEGF levels', 'MPA', (67, 78))	('Inhibitors', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('NF-kappaB', 'Gene', '18033', (29, 38))	('carcinoma', 'Disease', (82, 91))
8709	32308722	In this study, inflammatory cytokines that could enhance the tumourigenic process such as IL-6, IL-1beta, and TNF-alpha were decreased in FLP-treated MO mice in the tumour tissues and serum compared to those of MO mice, which is in accordance with previous studies.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('inflammatory cytokines', 'MPA', (15, 37))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('IL-1', 'molecular_function', 'GO:0005149', ('96', '100'))	('decreased', 'NegReg', (125, 134))	('enhance', 'PosReg', (49, 56))	('tumour', 'Disease', (61, 67))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('TNF-alpha', 'Gene', (110, 119))	('tumour', 'Disease', (165, 171))	('mice', 'Species', '10090', (153, 157))	('FLP-treated', 'Var', (138, 149))	('IL-6', 'molecular_function', 'GO:0005138', ('90', '94'))	('mice', 'Species', '10090', (214, 218))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
8724	32226297	PHGDH is highly expressed in tumors as a result of amplification, transcription, or its degradation and stability alteration, which dysregulates the serine biosynthesis pathway via metabolic enzyme activity to nourish tumors.	('dysregulates', 'Reg', (132, 144))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('serine biosynthesis pathway', 'Pathway', (149, 176))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('enzyme activity', 'molecular_function', 'GO:0003824', ('191', '206'))	('metabolic enzyme activity', 'MPA', (181, 206))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (29, 35))	('amplification', 'Var', (51, 64))	('biosynthesis', 'biological_process', 'GO:0009058', ('156', '168'))	('alteration', 'Reg', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('degradation', 'biological_process', 'GO:0009056', ('88', '99'))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (218, 224))	('PHGDH', 'Gene', (0, 5))	('degradation', 'MPA', (88, 99))	('serine', 'Chemical', 'MESH:D012694', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
8748	32226297	also found that the expression of PHGDH beta variants could be caused by malignancy or deterioration of a malignant phenotype, but their relationship is unclear.	('rat', 'Species', '10116', (94, 97))	('expression', 'MPA', (20, 30))	('variants', 'Var', (45, 53))	('PHGDH beta', 'Gene', (34, 44))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('malignancy', 'Disease', (73, 83))	('caused by', 'Reg', (63, 72))
8769	32226297	It is lined by several loop regions of the first monomers Arg54-Val59, Ala76-Val83, Asn97-Gly101, Gly152- Leu153, Asp175-Ile178, His206-Leu216, Cys234- Val240, Asp260-Asp269, and Cys281-Ser287 and one loop of the second monomer Trp133-Lys136.	('Lys136', 'Chemical', '-', (235, 241))	('Asp175-Ile178', 'Var', (114, 127))	('His206-Leu216', 'Var', (129, 142))	('Gly152', 'Chemical', '-', (98, 104))	('Asp260-Asp269', 'Var', (160, 173))	('Asp269', 'Chemical', '-', (167, 173))	('His206', 'Chemical', '-', (129, 135))	('Ser', 'cellular_component', 'GO:0005790', ('186', '189'))	('Ile178', 'Chemical', '-', (121, 127))	('Cys281-Ser287', 'Var', (179, 192))	('Cys234- Val240', 'Var', (144, 158))	('Val240', 'Chemical', '-', (152, 158))	('Leu153', 'Chemical', '-', (106, 112))	('Arg54', 'Chemical', '-', (58, 63))	('Arg54-Val59', 'Var', (58, 69))	('Cys234', 'Chemical', '-', (144, 150))	('Asp260', 'Chemical', '-', (160, 166))	('Asn97-Gly101', 'Var', (84, 96))	('Leu216', 'Chemical', '-', (136, 142))	('Ala76', 'Chemical', '-', (71, 76))	('Ala76-Val83', 'Var', (71, 82))	('Ser287', 'Chemical', '-', (186, 192))	('Val83', 'Chemical', '-', (77, 82))	('Trp133', 'Chemical', '-', (228, 234))	('Asn97', 'Chemical', '-', (84, 89))	('Gly101', 'Chemical', '-', (90, 96))	('Gly152- Leu153', 'Var', (98, 112))	('Asp175', 'Chemical', '-', (114, 120))	('Val59', 'Chemical', '-', (64, 69))	('Cys281', 'Chemical', '-', (179, 185))
8774	32226297	In metastatic variants of estrogen receptor-negative breast cancer cells, PHGDH and PSAT protein are highly expressed and related to poor prognosis, decreased overall survival, higher tumor grade, and high expression of the proliferative markers proliferating cell nuclear antigen and Ki-67.	('rat', 'Species', '10116', (231, 234))	('estrogen receptor', 'Gene', '2099', (26, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('PSAT', 'Gene', (84, 88))	('PSAT', 'Gene', '29968', (84, 88))	('rat', 'Species', '10116', (253, 256))	('tumor', 'Disease', (184, 189))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('breast cancer', 'Disease', (53, 66))	('PHGDH', 'Gene', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('expression', 'MPA', (206, 216))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('246', '280'))	('decreased', 'NegReg', (149, 158))	('estrogen receptor', 'Gene', (26, 43))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('higher', 'PosReg', (177, 183))	('overall survival', 'CPA', (159, 175))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('variants', 'Var', (14, 22))	('poor', 'NegReg', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
8776	32226297	Certain breast cancers depend on genomically amplified PHGDH, which diverts glucose carbons away from glycolysis into oxidative stress and biosynthetic pathways.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('glycolysis', 'biological_process', 'GO:0006096', ('102', '112'))	('glucose carbons', 'MPA', (76, 91))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('breast cancers depend', 'Disease', 'MESH:D001943', (8, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (8, 22))	('genomically amplified', 'Var', (33, 54))	('glycolysis', 'MPA', (102, 112))	('carbons', 'Chemical', 'MESH:D002244', (84, 91))	('PHGDH', 'Gene', (55, 60))	('oxidative stress', 'Phenotype', 'HP:0025464', (118, 134))	('diverts', 'Reg', (68, 75))	('breast cancers depend', 'Disease', (8, 29))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
8778	32226297	In the human pancreatic cancer cell lines BxPC-3 and SW1990, knockdown of PHGDH inhibits the cell proliferation, migration, and invasion abilities by downregulating the expression of cyclin B1, cyclin D1, MMP-2, and MMP-9.	('cyclin', 'molecular_function', 'GO:0016538', ('194', '200'))	('cyclin D1', 'Gene', '595', (194, 203))	('MMP-2', 'Gene', '4313', (205, 210))	('knockdown', 'Var', (61, 70))	('inhibits', 'NegReg', (80, 88))	('expression', 'MPA', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (13, 30))	('invasion abilities', 'CPA', (128, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('cyclin', 'molecular_function', 'GO:0016538', ('183', '189'))	('MMP-2', 'Gene', (205, 210))	('MMP-9', 'Gene', '4318', (216, 221))	('pancreatic cancer', 'Disease', (13, 30))	('MMP-9', 'Gene', (216, 221))	('PHGDH', 'Gene', (74, 79))	('MMP-9', 'molecular_function', 'GO:0004229', ('216', '221'))	('human', 'Species', '9606', (7, 12))	('cell proliferation', 'CPA', (93, 111))	('SW1990', 'CellLine', 'CVCL:1723;-0.034985155985866545', (53, 59))	('rat', 'Species', '10116', (116, 119))	('MMP-2', 'molecular_function', 'GO:0004228', ('205', '210'))	('rat', 'Species', '10116', (105, 108))	('cyclin B1', 'Gene', '891', (183, 192))	('cyclin D1', 'Gene', (194, 203))	('cyclin B1', 'Gene', (183, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('migration', 'CPA', (113, 122))	('BxPC-3', 'CellLine', 'CVCL:0186;0.014967983430495092', (42, 48))	('downregulating', 'NegReg', (150, 164))
8785	32226297	In most cases, tumor cell proliferation is promoted by increased level of PHGDH and supressed when PHGDH is knocked out or mutated in specific site..	('cell proliferation', 'biological_process', 'GO:0008283', ('21', '39'))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('promoted', 'PosReg', (43, 51))	('increased', 'PosReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Disease', (15, 20))	('mutated', 'Var', (123, 130))
8787	32226297	For example, adding excess serine to the growth medium of PHGDH knockdown PANC-1 cells was unable to rescue cell proliferation.	('serine', 'Chemical', 'MESH:D012694', (27, 33))	('knockdown', 'Var', (64, 73))	('PHGDH', 'Gene', (58, 63))	('rat', 'Species', '10116', (120, 123))	('cell proliferation', 'CPA', (108, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))
8791	32226297	In the translation initiation process, eIF4E recognizes m7 GTP on mRNA and eIF4A unwinds the 5'mRNA structure to compose pre-initiation complexes.	('eIF4', 'cellular_component', 'GO:0008304', ('75', '79'))	('eIF4E', 'Gene', '1977', (39, 44))	('eIF4', 'cellular_component', 'GO:0008304', ('39', '43'))	('m7 GTP', 'Var', (56, 62))	('unwinds', 'NegReg', (81, 88))	('eIF4E', 'Gene', (39, 44))	("5'mRNA structure", 'MPA', (93, 109))	('translation initiation', 'biological_process', 'GO:0006413', ('7', '29'))	('eIF4A', 'Gene', (75, 80))	('eIF4A', 'Gene', '1973', (75, 80))	('mRNA', 'MPA', (66, 70))	('pre', 'molecular_function', 'GO:0003904', ('121', '124'))
8799	32226297	Large amounts of D-2HG produced by IDH active site mutants in glioma and acute myeloid leukemia (AML) promotes the formation and malignant progression of gliomas and the transformation of leukemic cells.	('acute myeloid leukemia', 'Disease', (73, 95))	('promotes', 'PosReg', (102, 110))	('malignant progression', 'CPA', (129, 150))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH', 'Gene', '3417', (35, 38))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('glioma', 'Disease', (154, 160))	('gliomas', 'Disease', (154, 161))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (79, 95))	('leukemic', 'Disease', 'MESH:D007938', (188, 196))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('mutants', 'Var', (51, 58))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('D-2', 'Gene', (17, 20))	('leukemic', 'Disease', (188, 196))	('AML', 'Disease', (97, 100))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (73, 95))	('formation', 'biological_process', 'GO:0009058', ('115', '124'))	('formation', 'CPA', (115, 124))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (73, 95))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('transformation', 'CPA', (170, 184))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('D-2', 'Gene', '1734', (17, 20))	('glioma', 'Disease', (62, 68))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('IDH', 'Gene', (35, 38))
8800	32226297	The mechanisms of PHGDH amplification promoting tumor growth include supplying serine for protein synthesis and one-carbon metabolism, promoting the TCA cycle, and non-enzymatic functions including FOXM1 binding.	('promoting', 'PosReg', (38, 47))	('binding', 'molecular_function', 'GO:0005488', ('204', '211'))	('one-carbon metabolism', 'biological_process', 'GO:0006730', ('112', '133'))	('TCA cycle', 'MPA', (149, 158))	('carbon', 'Chemical', 'MESH:D002244', (116, 122))	('protein synthesis', 'biological_process', 'GO:0006412', ('90', '107'))	('one-carbon metabolism', 'MPA', (112, 133))	('FOXM1', 'Gene', '2305', (198, 203))	('TCA cycle', 'biological_process', 'GO:0006099', ('149', '158'))	('tumor', 'Disease', (48, 53))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('TCA', 'Chemical', 'MESH:D014233', (149, 152))	('amplification', 'Var', (24, 37))	('PHGDH', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('FOXM1', 'Gene', (198, 203))	('supplying serine for protein synthesis', 'MPA', (69, 107))	('promoting', 'PosReg', (135, 144))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
8804	32226297	PHGDH gene copy number gain is observed at a higher frequency in melanoma than other cancers and PHGDH expression can accelerate melanoma progression in mice.	('rat', 'Species', '10116', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('PHGDH', 'Gene', (0, 5))	('melanoma than other cancers', 'Disease', (65, 92))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('copy number', 'Var', (11, 22))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('accelerate', 'PosReg', (118, 128))	('mice', 'Species', '10090', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('gain', 'PosReg', (23, 27))	('melanoma', 'Disease', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('melanoma than other cancers', 'Disease', 'MESH:C563985', (65, 92))	('PHGDH', 'Gene', (97, 102))
8805	32226297	In addition to amplification, PHGDH expression can be upregulated transcriptionally by Sp1/NF-Y, activating transcription factor 4 (ATF4), protooncogene c-Myc, and TGF-beta and epigenetically by lysine methyltransferase G9A.	('Sp1', 'Species', '1274414', (87, 90))	('transcription factor', 'molecular_function', 'GO:0000981', ('108', '128'))	('upregulated', 'PosReg', (54, 65))	('ATF4', 'Gene', '468', (132, 136))	('TGF-', 'Gene', '7040', (164, 168))	('PHGDH', 'Gene', (30, 35))	('TGF-', 'Gene', (164, 168))	('Sp1/NF-Y', 'Gene', (87, 95))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))	('G9A', 'Mutation', 'rs1284786337', (220, 223))	('expression', 'MPA', (36, 46))	('epigenetically', 'Var', (177, 191))	('ATF4', 'Gene', (132, 136))
8806	32226297	It has been clarified that Sp1 binds to the proximal GC-motif (-194 to -185) and NF-Y binds to the CCAAT-motif (165 to -154), dramatically regulating the promoter activity of the human PHGDH gene in HeLa cells by a ChIP assay.	('human', 'Species', '9606', (179, 184))	('PHGDH gene', 'Gene', (185, 195))	('promoter activity', 'MPA', (154, 171))	('Sp1', 'Species', '1274414', (27, 30))	('-194', 'Var', (63, 67))	('regulating', 'Reg', (139, 149))
8809	32226297	Human non-small cell lung cancer with high NRF2 protein expression displayed significantly higher expression of ATF4, PHGDH, PSAT1, and SHMT2, which was significantly related to poorer prognosis and higher tumor grade.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (6, 32))	('Human', 'Species', '9606', (0, 5))	('NRF2', 'Gene', '4780', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (10, 32))	('PSAT1', 'Gene', '29968', (125, 130))	('SHMT2', 'Gene', (136, 141))	('PSAT1', 'Gene', (125, 130))	('PHGDH', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('protein', 'Protein', (48, 55))	('high', 'Var', (38, 42))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (6, 32))	('NRF2', 'Gene', (43, 47))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('higher', 'PosReg', (91, 97))	('ATF4', 'Gene', (112, 116))	('non-small cell lung cancer', 'Disease', (6, 32))	('ATF4', 'Gene', '468', (112, 116))	('SHMT2', 'Gene', '6472', (136, 141))	('tumor', 'Disease', (206, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('related', 'Reg', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('expression', 'MPA', (98, 108))
8814	32226297	G9A, an H3K9 methyltransferase, has a central role in catalyzing transcriptional activation of the serine-glycine biosynthetic pathway by upregulating the expression of PHGDH, PSAT1, PSPH, and SHMT with H3K9me1, an epigenetic marker associated with active chromatin.	('G9A', 'Mutation', 'rs1284786337', (0, 3))	('PSAT1', 'Gene', '29968', (176, 181))	('serine', 'Chemical', 'MESH:D012694', (99, 105))	('chromatin', 'cellular_component', 'GO:0000785', ('256', '265'))	('serine-glycine biosynthetic', 'Pathway', (99, 126))	('PSPH', 'Gene', (183, 187))	('upregulating', 'PosReg', (138, 150))	('H3K9me1', 'Var', (203, 210))	('SHMT', 'Gene', '6470', (193, 197))	('PSAT1', 'Gene', (176, 181))	('PSPH', 'Gene', '5723', (183, 187))	('PHGDH', 'Gene', (169, 174))	('glycine', 'Chemical', 'MESH:D005998', (106, 113))	('SHMT', 'Gene', (193, 197))
8828	32226297	found that disulfiram (DSF) (Figure 8B), an anti-alcohol drug, also inhibited PHGDH activity via converting PHGDH tetramer into either an inactive dimer covalently linked by a disulfide bridge involving Cys116 on adjacent monomers or, to a lesser extent, an inactive intermediate.	('disulfide', 'Chemical', 'MESH:D004220', (176, 185))	('PHGDH', 'Gene', (78, 83))	('Cys116', 'Chemical', '-', (203, 209))	('inhibited', 'NegReg', (68, 77))	('activity', 'MPA', (84, 92))	('disulfiram', 'Chemical', 'MESH:D004221', (11, 21))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('DSF', 'Chemical', 'MESH:D004221', (23, 26))	('Cys116', 'Var', (203, 209))	('PHGDH', 'Gene', (108, 113))	('converting', 'Reg', (97, 107))
8830	32226297	NCT-503, also a non-competitive inhibitor in regards to substrates and cofactors, closely binds to the active site as a mutation of C234 in the protein's active site to reduce the inhibitory effect of PHGDH.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('inhibitory effect', 'MPA', (180, 197))	('PHGDH', 'Gene', (201, 206))	('C234 in', 'Var', (132, 139))	('rat', 'Species', '10116', (61, 64))	('reduce', 'NegReg', (169, 175))
8837	32226297	PKUMDL-WQ-2101 and PKUMDL-WQ-2201 inhibited PHGDH activity mainly by forming hydrogen-bond networks with R134, K57, and T59 of site I and T59, T56, and K57 of site II, respectively, which limits the movement of the rigid domains and prevents the active sites from closing, thus stabilizing PHGDH in the inactive conformation.	('K57', 'Var', (152, 155))	('PHGDH', 'Enzyme', (44, 49))	('rigid domains', 'MPA', (215, 228))	('PKUMDL-WQ-2101', 'Var', (0, 14))	('hydrogen', 'Chemical', 'MESH:D006859', (77, 85))	('inhibited', 'NegReg', (34, 43))	('hydrogen-bond', 'Interaction', (77, 90))	('K57', 'Var', (111, 114))	('limits', 'NegReg', (188, 194))	('T59', 'Var', (138, 141))	('T56', 'Var', (143, 146))	('active sites', 'MPA', (246, 258))	('prevents', 'NegReg', (233, 241))	('R134', 'Var', (105, 109))	('movement', 'MPA', (199, 207))	('T56', 'CellLine', 'CVCL:J280;-0.033863253815608736', (143, 146))	('T59', 'Var', (120, 123))	('activity', 'MPA', (50, 58))	('PKUMDL-WQ-2201', 'Var', (19, 33))
8841	32226297	PKUMDL-WQ-2101 and PKUMDL-WQ-2201 also suppressed tumor growth in mice.	('PKUMDL-WQ-2101', 'Var', (0, 14))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PKUMDL-WQ-2201', 'Var', (19, 33))	('suppressed', 'NegReg', (39, 49))	('tumor', 'Disease', (50, 55))
8845	32226297	A ligand-binding pocket with two protruding arginines and dramatically hydrophilic hydrogen bindings of Arg118 with two phenol groups and Arg113 with lactam carbonyl was predicted.	('carbon', 'Chemical', 'MESH:D002244', (157, 163))	('Arg113', 'Chemical', '-', (138, 144))	('arginines', 'Chemical', 'MESH:D001120', (44, 53))	('Arg113', 'Var', (138, 144))	('hydrogen', 'Chemical', 'MESH:D006859', (83, 91))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('Arg118', 'Var', (104, 110))	('phenol', 'Chemical', 'MESH:D019800', (120, 126))	('Arg118', 'Chemical', '-', (104, 110))	('ligand', 'molecular_function', 'GO:0005488', ('2', '8'))
8850	32226297	The ligand-binding pocket was dramatically hydrophobic, and hydrophobic interactions between Val301 and ring A, Pro331 and ring D, and Ile333 and ring B were predicted.	('Pro331', 'Chemical', '-', (112, 118))	('ligand', 'molecular_function', 'GO:0005488', ('4', '10'))	('Pro331', 'Var', (112, 118))	('Val301', 'Chemical', '-', (93, 99))	('Val301', 'Var', (93, 99))	('binding', 'molecular_function', 'GO:0005488', ('11', '18'))	('Ile333', 'Var', (135, 141))	('Ile333', 'Chemical', '-', (135, 141))
8851	32226297	Several hydrogen bonds were predicted between Gln302 with the carbonyl group of ring A, Asp305 and Thr313 with the 3-hydroxyl group, and Pro327 with the 22-hydroxyl group.	('predicted', 'Reg', (28, 37))	('Asp305', 'Chemical', '-', (88, 94))	('Pro327', 'Chemical', '-', (137, 143))	('hydrogen', 'Interaction', (8, 16))	('carbon', 'Chemical', 'MESH:D002244', (62, 68))	('Thr313', 'Chemical', '-', (99, 105))	('Gln302', 'Var', (46, 52))	('Pro327', 'Var', (137, 143))	('hydrogen', 'Chemical', 'MESH:D006859', (8, 16))	('Asp305', 'Var', (88, 94))	('Gln302', 'Chemical', '-', (46, 52))	('Thr313', 'Var', (99, 105))
8859	32226297	Consequently, inhibition of PHGDH via shRNA caused doxorubicin-induced oxidative stress and increased doxorubicin sensitivity.	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('PHGDH', 'Protein', (28, 33))	('doxorubicin', 'Chemical', 'MESH:D004317', (102, 113))	('increased', 'PosReg', (92, 101))	('doxorubicin', 'Chemical', 'MESH:D004317', (51, 62))	('doxorubicin-induced oxidative stress', 'MPA', (51, 87))	('caused', 'Reg', (44, 50))	('inhibition', 'Var', (14, 24))	('doxorubicin sensitivity', 'MPA', (102, 125))
8866	32226297	Knockdown of PHGDH or using methotrexate to inhibit nucleotide metabolism by impeding the folate cycle downstream of serine biosynthesis can sensitize SK-MEL-28VR1 cells to vemurafenib.	('methotrexate', 'Chemical', 'MESH:D008727', (28, 40))	('biosynthesis', 'biological_process', 'GO:0009058', ('124', '136'))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('52', '73'))	('folate cycle downstream of serine biosynthesis', 'MPA', (90, 136))	('Knockdown', 'Var', (0, 9))	('SK-MEL-28VR1', 'CellLine', 'CVCL:AP99;-0.013326361128860532', (151, 163))	('inhibit', 'NegReg', (44, 51))	('folate', 'Chemical', 'MESH:D005492', (90, 96))	('serine', 'Chemical', 'MESH:D012694', (117, 123))	('PHGDH', 'Gene', (13, 18))	('vemurafenib', 'Chemical', 'MESH:D000077484', (173, 184))	('nucleotide metabolism', 'MPA', (52, 73))	('impeding', 'NegReg', (77, 85))	('sensitize', 'Reg', (141, 150))
8867	32226297	The PHGDH level was also significantly increased in EGFR inhibitor erlotinib-resistant lung adenocarcinoma PC9ER4 and HCC827ER9 cells, which regulate the transcriptions of genes associated with DNA damage repair and nucleotide metabolism.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('EGFR', 'Gene', '1956', (52, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('EGFR', 'Gene', (52, 56))	('PHGDH level', 'MPA', (4, 15))	('erlotinib', 'Chemical', 'MESH:D000069347', (67, 76))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('PC9ER4', 'CellLine', 'CVCL:S750;0.017082116639350484', (107, 113))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('216', '237'))	('HCC827ER9', 'CellLine', 'CVCL:V408;0.021460471017522006', (118, 127))	('increased', 'PosReg', (39, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('inhibitor', 'Var', (57, 66))
8870	32226297	PHGDH knocked down with RNAi and knocked out by CRISPR/Cas9 or inactivated by inhibitor can overcome tyrosine kinase inhibitor (TKI) drug resistance, including sorafenib, regorafenib, or lenvatinib, in hepatocellular carcinoma (HCC).	('lenvatinib', 'Chemical', 'MESH:C531958', (187, 197))	('regorafenib', 'Chemical', 'MESH:C559147', (171, 182))	('drug resistance', 'biological_process', 'GO:0009315', ('133', '148'))	('drug resistance', 'biological_process', 'GO:0042493', ('133', '148'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (202, 226))	('HCC', 'Gene', '619501', (228, 231))	('HCC', 'Phenotype', 'HP:0001402', (228, 231))	('drug resistance', 'Phenotype', 'HP:0020174', (133, 148))	('HCC', 'Gene', (228, 231))	('overcome', 'PosReg', (92, 100))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (202, 226))	('sorafenib', 'Chemical', 'MESH:D000077157', (160, 169))	('Cas', 'cellular_component', 'GO:0005650', ('55', '58'))	('hepatocellular carcinoma', 'Disease', (202, 226))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('110', '126'))	('RNAi', 'biological_process', 'GO:0016246', ('24', '28'))	('PHGDH', 'Gene', (0, 5))	('knocked down', 'Var', (6, 18))	('knocked out', 'Var', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
8956	30967648	New results from the Cancer Genome Atlas Research Project have identified genetic mutations that are common among 12 different types of cancer, including carcinomas, adenocarcinomas and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (186, 195))	('Cancer', 'Disease', (21, 27))	('cancer', 'Disease', (136, 142))	('melanomas', 'Disease', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('carcinomas', 'Disease', (171, 181))	('common', 'Reg', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('carcinomas', 'Disease', (154, 164))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Disease', 'MESH:D009369', (171, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('mutations', 'Var', (82, 91))	('adenocarcinomas', 'Disease', 'MESH:D000230', (166, 181))	('carcinomas', 'Disease', 'MESH:D009369', (154, 164))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('adenocarcinomas', 'Disease', (166, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
8977	30967648	Usually this occurs by mutations in the CDKN2A gen.	('mutations', 'Var', (23, 32))	('occurs by', 'Reg', (13, 22))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))
9001	30867736	Predictive and prognostic value of phosphorylated c-KIT and PDGFRA in advanced non-small cell lung cancer harboring ALK fusion Secondary KIT gene amplification leads to tyrosine kinase inhibitor resistance in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (209, 228))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (295, 300))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('leads to', 'Reg', (160, 168))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (267, 293))	('ALK', 'Gene', '238', (116, 119))	('amplification', 'Var', (146, 159))	('anaplastic lymphoma kinase', 'Gene', '238', (209, 235))	('tyrosine kinase inhibitor resistance', 'MPA', (169, 205))	('anaplastic lymphoma kinase', 'Gene', (209, 235))	('ALK', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('non-small cell lung cancer', 'Disease', (79, 105))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('178', '194'))	('PDGFRA', 'Gene', '5156', (60, 66))	('PDGFRA', 'Gene', (60, 66))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (271, 293))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (267, 293))	('SCLC', 'Phenotype', 'HP:0030357', (296, 300))	('lymphoma', 'Phenotype', 'HP:0002665', (220, 228))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('c-KIT', 'Gene', (50, 55))	('KIT', 'molecular_function', 'GO:0005020', ('137', '140'))	('ALK', 'Gene', '238', (237, 240))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('NSCLC', 'Disease', 'MESH:D002289', (295, 300))	('c-KIT', 'Gene', '3815', (50, 55))	('ALK', 'Gene', (237, 240))	('non-small cell lung cancer', 'Disease', (267, 293))	('NSCLC', 'Disease', (295, 300))
9002	30867736	The presence of the 4q12 amplicon causes the activation of downstream mast/stem cell growth factor receptor Kit (c-Kit) or platelet-derived growth factor receptor alpha (PDGFRA) signaling pathways.	('platelet-derived growth factor receptor alpha', 'Gene', (123, 168))	('4q12', 'Var', (20, 24))	('c-Kit', 'Gene', (113, 118))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('c-Kit', 'Gene', '3815', (113, 118))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('123', '153'))	('PDGFRA', 'Gene', (170, 176))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (123, 168))	('PDGFRA', 'Gene', '5156', (170, 176))	('presence', 'Var', (4, 12))	('activation', 'PosReg', (45, 55))
9008	30867736	In addition, the patients with high levels of p-c-Kit exhibited lower overall survival times than those with low levels.	('high levels', 'Var', (31, 42))	('overall survival times', 'CPA', (70, 92))	('lower', 'NegReg', (64, 69))	('c-Kit', 'Gene', (48, 53))	('patients', 'Species', '9606', (17, 25))	('c-Kit', 'Gene', '3815', (48, 53))
9013	30867736	Anaplastic lymphoma kinase (ALK)-fusion genes, including encoding echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant, represent a small but important fraction of oncogenic driver mutations in non-small cell lung cancer (NSCLC), accounting for approximately 3-7% in all cases worldwide.	('NSCLC', 'Disease', 'MESH:D002289', (244, 249))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (66, 114))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (216, 242))	('microtubule', 'cellular_component', 'GO:0005874', ('77', '88'))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('NSCLC', 'Disease', (244, 249))	('ALK', 'Gene', '238', (28, 31))	('EML4', 'Gene', (116, 120))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('EML4', 'Gene', '27436', (116, 120))	('echinoderm microtubule-associated protein-like 4', 'Gene', (66, 114))	('ALK', 'Gene', (28, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (244, 249))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('ALK', 'Gene', '238', (122, 125))	('non-small cell lung cancer', 'Disease', (216, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('ALK', 'Gene', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('mutations', 'Var', (203, 212))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (216, 242))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('SCLC', 'Phenotype', 'HP:0030357', (245, 249))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (220, 242))
9015	30867736	Resistance to first-generation TKI crizotinib within the first 2 years following treatment is mediated by a variety of mechanisms, including secondary mutations within the ALK tyrosine kinase domain and activation of alternative signaling pathways, including those involving the ALK fusion gene or secondary KIT gene amplification.	('ALK', 'Gene', '238', (279, 282))	('ALK', 'Gene', (172, 175))	('ALK', 'Gene', (279, 282))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('KIT', 'molecular_function', 'GO:0005020', ('308', '311'))	('crizotinib', 'Chemical', 'MESH:D000077547', (35, 45))	('activation', 'PosReg', (203, 213))	('alternative signaling pathways', 'Pathway', (217, 247))	('mutations', 'Var', (151, 160))	('ALK', 'Gene', '238', (172, 175))
9016	30867736	Single nucleotide polymorphism (SNP) array data on NSCLC tissues and cell lines were evaluated for copy number aberrations, and amplification of chromosomal segment 4q12 overlapping the locus of proto-oncogenes PDGFRA and KIT was observed in 4.2% NSCLC samples.	('NSCLC', 'Disease', (247, 252))	('amplification', 'Var', (128, 141))	('NSCLC', 'Disease', 'MESH:D002289', (247, 252))	('SCLC', 'Phenotype', 'HP:0030357', (52, 56))	('SCLC', 'Phenotype', 'HP:0030357', (248, 252))	('NSCLC', 'Disease', (51, 56))	('KIT', 'molecular_function', 'GO:0005020', ('222', '225'))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('KIT', 'Gene', (222, 225))	('NSCLC', 'Phenotype', 'HP:0030358', (247, 252))	('PDGFRA', 'Gene', (211, 217))	('PDGFRA', 'Gene', '5156', (211, 217))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
9032	30867736	Following incubation at 4 C overnight with anti-c-Kit (phosphor Y703) (dilution, 1:50; ab62154) or anti-PDGFRA (phosphor Y754) (dilution, 1:100; ab5460) antibody obtained from Abcam.	('PDGFRA', 'Gene', (104, 110))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('PDGFRA', 'Gene', '5156', (104, 110))	('c-Kit', 'Gene', (48, 53))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('c-Kit', 'Gene', '3815', (48, 53))	('phosphor', 'Var', (112, 120))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))
9054	30867736	The one- and three-year OS rates in the patients with high p-c-Kit levels were 60 and 25%, respectively, and in those with low levels they were 86 and 69% respectively (Table I).	('high', 'Var', (54, 58))	('c-Kit', 'Gene', '3815', (61, 66))	('patients', 'Species', '9606', (40, 48))	('c-Kit', 'Gene', (61, 66))
9066	30867736	It is therefore hypothesized that the PDGFRA pathway is associated with a subset of brain metastases occurring in patients with ALK fusion NSCLC, as in the case of the aforementioned patient with PDGFRA amplification in the metastatic brain tumor.	('brain tumor', 'Disease', (235, 246))	('PDGFRA', 'Gene', (38, 44))	('brain tumor', 'Disease', 'MESH:D001932', (235, 246))	('PDGFRA', 'Gene', '5156', (38, 44))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('associated', 'Reg', (56, 66))	('patient', 'Species', '9606', (183, 190))	('amplification', 'Var', (203, 216))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))	('PDGFRA', 'Gene', (196, 202))	('metastases', 'Disease', (90, 100))	('PDGFRA', 'Gene', '5156', (196, 202))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('patients', 'Species', '9606', (114, 122))	('brain', 'Disease', (84, 89))	('ALK', 'Gene', '238', (128, 131))	('NSCLC', 'Disease', (139, 144))	('ALK', 'Gene', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('brain tumor', 'Phenotype', 'HP:0030692', (235, 246))	('patient', 'Species', '9606', (114, 121))
9071	30867736	To date, only BIM deletion polymorphism and EML4-ALK variants 3a/b have been found to be associated with poor clinical response of patients with ALK fusion NSCLC to crizotinib.	('patients', 'Species', '9606', (131, 139))	('BIM', 'Gene', (14, 17))	('EML4', 'Gene', (44, 48))	('associated', 'Reg', (89, 99))	('EML4', 'Gene', '27436', (44, 48))	('ALK', 'Gene', '238', (49, 52))	('ALK', 'Gene', '238', (145, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('NSCLC', 'Disease', (156, 161))	('ALK', 'Gene', (49, 52))	('SCLC', 'Phenotype', 'HP:0030357', (157, 161))	('ALK', 'Gene', (145, 148))	('deletion polymorphism', 'Var', (18, 39))	('crizotinib', 'Chemical', 'MESH:D000077547', (165, 175))	('variants', 'Var', (53, 61))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))
9074	30867736	Additionally, high levels of p-c-Kit was the only independent prognostic factor for poor PFS time following crizotinib treatment (HR=2.7, P<0.05).	('crizotinib', 'Chemical', 'MESH:D000077547', (108, 118))	('poor', 'NegReg', (84, 88))	('high', 'Var', (14, 18))	('poor PFS time', 'Phenotype', 'HP:0005165', (84, 97))	('c-Kit', 'Gene', (31, 36))	('PFS', 'Disease', (89, 92))	('c-Kit', 'Gene', '3815', (31, 36))
9075	30867736	Although the study has some limitations due to small sample numbers and uncertainty of interpretation of the immunochemical staining results, patients with low levels of p-c-Kit responded significantly better to crizotinib treatment compared with the patients treated by crizotinib reported in the previous clinical trials in which the median PFS was 11 months.	('better', 'PosReg', (202, 208))	('c-Kit', 'Gene', (172, 177))	('patients', 'Species', '9606', (251, 259))	('c-Kit', 'Gene', '3815', (172, 177))	('crizotinib', 'Chemical', 'MESH:D000077547', (212, 222))	('crizotinib', 'Chemical', 'MESH:D000077547', (271, 281))	('patients', 'Species', '9606', (142, 150))	('responded', 'MPA', (178, 187))	('low levels', 'Var', (156, 166))
9083	30867736	KIT gene functional mutations may be driver mutations in certain malignant tumors, including gastrointestinal stromal tumors, leukemia, lymphoma and mast cell tumors.	('gastrointestinal stromal tumors', 'Disease', (93, 124))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mast cell tumors', 'Disease', 'MESH:D008415', (149, 165))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('functional mutations', 'Var', (9, 29))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('malignant tumors', 'Disease', 'MESH:D018198', (65, 81))	('leukemia', 'Disease', (126, 134))	('leukemia', 'Disease', 'MESH:D007938', (126, 134))	('malignant tumors', 'Disease', (65, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mast cell tumors', 'Disease', (149, 165))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (93, 124))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (93, 124))	('mast cell tumors', 'Phenotype', 'HP:0100495', (149, 165))	('lymphoma', 'Disease', (136, 144))	('lymphoma', 'Disease', 'MESH:D008223', (136, 144))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('KIT gene', 'Gene', (0, 8))
9086	30867736	Studies on c-Kit in NSCLC have focused more on the early stages of the cancer, and the expression of c-Kit in NSCLC tumors has been associated with an increased mortality rate.	('expression', 'Var', (87, 97))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('c-Kit', 'Gene', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('cancer', 'Disease', (71, 77))	('NSCLC', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('c-Kit', 'Gene', '3815', (11, 16))	('NSCLC', 'Disease', (20, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('NSCLC tumors', 'Disease', (110, 122))	('c-Kit', 'Gene', '3815', (101, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('c-Kit', 'Gene', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('associated with', 'Reg', (132, 147))	('NSCLC tumors', 'Disease', 'MESH:D009369', (110, 122))	('SCLC', 'Phenotype', 'HP:0030357', (21, 25))
9090	30867736	The results demonstrated that patients with high levels of p-c-Kit exhibited significantly lower survival times than those with low levels (P<0.05).	('lower', 'NegReg', (91, 96))	('c-Kit', 'Gene', (61, 66))	('c-Kit', 'Gene', '3815', (61, 66))	('patients', 'Species', '9606', (30, 38))	('survival times', 'CPA', (97, 111))	('high levels', 'Var', (44, 55))
9091	30867736	Furthermore, high levels of p-c-Kit was the only significant indicator of poor survival in patients with ALK fusion NSCLC (HR=5.3, P<0.05).	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('ALK', 'Gene', (105, 108))	('patients', 'Species', '9606', (91, 99))	('c-Kit', 'Gene', (30, 35))	('high', 'Var', (13, 17))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('poor', 'NegReg', (74, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('c-Kit', 'Gene', '3815', (30, 35))	('ALK', 'Gene', '238', (105, 108))	('NSCLC', 'Disease', (116, 121))
9199	30518125	CGH2XX associated with Lobophytum crissum, is cytotoxic to human acute lymphoblastic leukemia (MOLT-4) cells, and shows anti-inflammatory activity by inhibiting the release of elastase by human neutrophils.	('inhibiting', 'NegReg', (150, 160))	('human', 'Species', '9606', (59, 64))	('human', 'Species', '9606', (188, 193))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (65, 93))	('acute lymphoblastic leukemia', 'Disease', (65, 93))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (71, 93))	('release of elastase by human neutrophils', 'MPA', (165, 205))	('anti-inflammatory activity', 'MPA', (120, 146))	('CGH2XX', 'Var', (0, 6))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (65, 93))
9290	30341336	H5N1 virus infection stimulated significantly higher CEACAM1 protein expression when compared to influenza A PR8 (H1N1) virus, suggesting a key role for CEACAM1 in influenza virus pathogenicity.	('H1N1', 'Species', '114727', (114, 118))	('H5N1', 'Var', (0, 4))	('higher', 'PosReg', (46, 52))	('CEACAM1 protein', 'Protein', (53, 68))	('influenza', 'Species', '11320', (164, 173))	('H5N1', 'Species', '102793', (0, 4))	('virus infection', 'Disease', (5, 20))	('influenza', 'Species', '11320', (97, 106))	('influenza virus', 'Species', '11309', (164, 179))	('virus infection', 'Disease', 'MESH:D015658', (5, 20))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
9291	30341336	Furthermore, silencing of endogenous CEACAM1 resulted in reduced levels of proinflammatory cytokine/chemokine production, as well as reduced levels of virus replication following H5N1 infection.	('levels of virus replication', 'MPA', (141, 168))	('chemokine production', 'biological_process', 'GO:0032602', ('100', '120'))	('H5N1', 'Species', '102793', (179, 183))	('infection', 'Disease', (184, 193))	('reduced levels of proinflammatory cytokine', 'Phenotype', 'HP:0012648', (57, 99))	('CEACAM1', 'Gene', (37, 44))	('infection', 'Disease', 'MESH:D007239', (184, 193))	('reduced', 'NegReg', (57, 64))	('reduced', 'NegReg', (133, 140))	('silencing', 'Var', (13, 22))
9332	30341336	ATII cells isolated from human patients were infected with H5N1 on the apical side at a multiplicity of infection (MOI) of 2 for 24 hours and RNA extracted.	('human', 'Species', '9606', (25, 30))	('H5N1', 'Species', '102793', (59, 63))	('infection', 'Disease', (104, 113))	('patients', 'Species', '9606', (31, 39))	('RNA', 'cellular_component', 'GO:0005562', ('142', '145'))	('infection', 'Disease', 'MESH:D007239', (104, 113))	('H5N1', 'Var', (59, 63))
9336	30341336	In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway mapping showed that many of the upregulated genes in the HD group were mapped to TNF signaling (hsa04668), Toll-like receptor signaling (hsa04620), cytokine-cytokine receptor interaction (hsa04060) and RIG-I-like receptor signaling (hsa04622) (Table 2, Table S3).	('hsa04060', 'Var', (256, 264))	('HD', 'Disease', 'MESH:D006816', (125, 127))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('hsa04620', 'Var', (205, 213))	('TNF', 'Gene', (149, 152))	('signaling', 'biological_process', 'GO:0023052', ('290', '299'))	('signaling', 'biological_process', 'GO:0023052', ('194', '203'))	('RIG-I', 'Gene', '23586', (270, 275))	('TNF', 'Gene', '7124', (149, 152))	('RIG-I', 'Gene', (270, 275))	('upregulated', 'PosReg', (100, 111))
9341	30341336	Gene Ontology (GO) enrichment analysis of genes upregulated by apocynin showed the involvement of the type I interferon signaling pathway (GO:0060337), the defense response to virus (GO:0009615), negative regulation of viral processes (GO:48525) and the response to stress (GO:0006950) (Table S2, "ND vs. HA Up").	('apocynin', 'Chemical', 'MESH:C056165', (63, 71))	('type I interferon signaling pathway', 'Pathway', (102, 137))	('defense response', 'CPA', (156, 172))	('defense response to virus', 'biological_process', 'GO:0051607', ('156', '181'))	('response to stress', 'biological_process', 'GO:0006950', ('254', '272'))	('regulation', 'biological_process', 'GO:0065007', ('205', '215'))	('GO:0006950', 'Var', (274, 284))	('viral', 'CPA', (219, 224))	('upregulated', 'PosReg', (48, 59))	('apocynin', 'Gene', (63, 71))	('Gene Ontology', 'biological_process', 'GO:0003673', ('0', '13'))	('type I interferon signaling pathway', 'biological_process', 'GO:0060337', ('102', '137'))
9347	30341336	The 55 genes include those involved in influenza A immunity (hsa05164; DDX58, IFIH1, IFNB1, MYD88, PML, STAT2), Jak-STAT signaling (hsa04630; IFNB1, IL15RA, IL22RA1, STAT2), RIG-I-like receptor signaling (hsa04622; DDX58, IFIH1, IFNB1) and Antigen processing and presentation (hsa04612; TAP2, TAP1, HLA-DOB) (Tables S3 and S4).	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('hsa04612;', 'Var', (277, 286))	('IFNB1', 'Gene', (142, 147))	('IFNB1', 'Gene', (229, 234))	('RIG-I', 'Gene', (174, 179))	('DDX58', 'Gene', (71, 76))	('Antigen processing and presentation', 'biological_process', 'GO:0019882', ('240', '275'))	('DDX58', 'Gene', (215, 220))	('Jak', 'molecular_function', 'GO:0004713', ('112', '115'))	('influenza', 'Species', '11320', (39, 48))	('IFNB1', 'Gene', '3456', (142, 147))	('IFNB1', 'Gene', (85, 90))	('Jak-STAT signaling', 'MPA', (112, 130))	('DDX58', 'Gene', '23586', (71, 76))	('IFNB1', 'Gene', '3456', (229, 234))	('DDX58', 'Gene', '23586', (215, 220))	('signaling', 'biological_process', 'GO:0023052', ('194', '203'))	('IFIH1', 'Gene', '64135', (222, 227))	('IFIH1', 'Gene', (222, 227))	('IFIH1', 'Gene', '64135', (78, 83))	('IFIH1', 'Gene', (78, 83))	('IL22', 'molecular_function', 'GO:0045518', ('157', '161'))	('RIG-I', 'Gene', '23586', (174, 179))	('IFNB1', 'Gene', '3456', (85, 90))	('IL15', 'molecular_function', 'GO:0016170', ('149', '153'))
9375	30341336	In addition, many of the H5N1-upregulated genes mapped to metabolic pathways (hsa01100), cytokine-cytokine receptor interaction (hsa04060), Influenza A (hsa05164), TNF signaling (hsa04668) or Jak-STAT signaling (hsa04630) (Table S3).	('metabolic pathways', 'Pathway', (58, 76))	('Influenza', 'Species', '11320', (140, 149))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('cytokine-cytokine receptor interaction', 'MPA', (89, 127))	('H5N1-upregulated', 'Gene', (25, 41))	('hsa04668', 'Var', (179, 187))	('TNF', 'Gene', '7124', (164, 167))	('hsa05164', 'Var', (153, 161))	('H5N1', 'Species', '102793', (25, 29))	('hsa04630', 'Var', (212, 220))	('Jak', 'molecular_function', 'GO:0004713', ('192', '195'))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('hsa04060', 'Var', (129, 137))	('TNF', 'Gene', (164, 167))
9387	30341336	Lower MOIs of 0.5, 1 and 2 of HPAI H5N1 were tested due to the strong cytopathogenic effect H5N1 causes at higher MOIs.	('HPAI', 'molecular_function', 'GO:0043863', ('30', '34'))	('H5N1', 'Species', '102793', (92, 96))	('cytopathogenic effect', 'MPA', (70, 91))	('H5N1', 'Var', (92, 96))	('H5N1', 'Species', '102793', (35, 39))
9389	30341336	CEACAM1 protein expression in ATII cells infected with H5N1 at MOIs of 0.5 were higher at 48 hpi than those observed at 24 hpi (Fig.	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('hpi', 'molecular_function', 'GO:0009978', ('93', '96'))	('hpi', 'molecular_function', 'GO:0009978', ('123', '126'))	('H5N1', 'Var', (55, 59))	('protein', 'Protein', (8, 15))	('hpi', 'molecular_function', 'GO:0047987', ('93', '96'))	('H5N1', 'Species', '102793', (55, 59))	('CEACAM1', 'Gene', (0, 7))	('higher', 'PosReg', (80, 86))	('hpi', 'molecular_function', 'GO:0047987', ('123', '126'))
9391	30341336	In order to understand the role of CEACAM1 in influenza pathogenesis, A549 and ATII cells were transfected with siCEACAM1 to knockdown endogenous CEACAM1 protein expression.	('knockdown', 'Var', (125, 134))	('CEACAM1', 'Gene', (146, 153))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))	('influenza', 'Species', '11320', (46, 55))	('protein', 'Protein', (154, 161))
9395	30341336	CEACAM1 protein expression was reduced by approximately 50% in both ATII and A549 cells following siCEACAM1 transfection when compared with siNeg-transfected cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('reduced', 'NegReg', (31, 38))	('protein', 'Protein', (8, 15))	('CEACAM1', 'Gene', (0, 7))	('siCEACAM1 transfection', 'Var', (98, 120))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
9398	30341336	The functional consequences of CEACAM1 knockdown were then examined in ATII and A549 cells following H5N1 infection.	('infection', 'Disease', 'MESH:D007239', (106, 115))	('knockdown', 'Var', (39, 48))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('H5N1', 'Species', '102793', (101, 105))	('infection', 'Disease', (106, 115))	('CEACAM1', 'Gene', (31, 38))
9408	30341336	Examples include modulation of ROS to reduce inflammation and inhibition of NFkappaB and mitogenic Raf/MEK/ERK kinase cascade activation to suppress viral replication.	('MEK', 'Gene', (103, 106))	('reduce', 'NegReg', (38, 44))	('ROS', 'Protein', (31, 34))	('inhibition', 'NegReg', (62, 72))	('Raf', 'Gene', '22882', (99, 102))	('NFkappaB', 'Gene', '4790', (76, 84))	('ERK', 'Gene', (107, 110))	('inflammation', 'Disease', (45, 57))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('inflammation', 'biological_process', 'GO:0006954', ('45', '57'))	('viral replication', 'biological_process', 'GO:0008166', ('149', '166'))	('NFkappaB', 'Gene', (76, 84))	('ERK', 'Gene', '2048', (107, 110))	('viral replication', 'biological_process', 'GO:0019079', ('149', '166'))	('modulation', 'Var', (17, 27))	('viral replication', 'biological_process', 'GO:0019058', ('149', '166'))	('viral replication', 'CPA', (149, 166))	('Raf', 'Gene', (99, 102))	('MEK', 'Gene', '5609', (103, 106))	('ERK', 'molecular_function', 'GO:0004707', ('107', '110'))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('suppress', 'NegReg', (140, 148))
9431	30341336	Influenza viruses, however, employ several strategies to escape NK effector functions, including modification of influenza hemagglutinin (HA) glycosylation to avoid NK activating receptor binding.	('binding', 'Interaction', (188, 195))	('influenza', 'Species', '11320', (113, 122))	('receptor binding', 'molecular_function', 'GO:0005102', ('179', '195'))	('glycosylation', 'biological_process', 'GO:0070085', ('142', '155'))	('modification', 'Var', (97, 109))	('Influenza', 'Species', '11320', (0, 9))
9432	30341336	Homo- or heterophilic CEACAM1 interactions have been shown to inhibit NK-killing, and are thought to contribute to tumor cell immune evasion.	('contribute', 'Reg', (101, 111))	('NK-killing', 'CPA', (70, 80))	('immune evasion', 'biological_process', 'GO:0042783', ('126', '140'))	('interactions', 'Interaction', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('immune evasion', 'biological_process', 'GO:0051842', ('126', '140'))	('CEACAM1', 'Gene', (22, 29))	('tumor', 'Disease', (115, 120))	('heterophilic', 'Var', (9, 21))	('inhibit', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
9436	30341336	demonstrated that CEACAM1 was upregulated following recognition of viral RNA by RIG-I, and that this upregulation was interferon regulatory factor 3 (IRF3)-dependent.	('IRF3', 'Gene', (150, 154))	('CEACAM1', 'Gene', (18, 25))	('IRF3', 'Gene', '3661', (150, 154))	('interferon regulatory factor 3', 'Gene', '3661', (118, 148))	('RIG-I', 'Gene', (80, 85))	('upregulated', 'PosReg', (30, 41))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('viral', 'Var', (67, 72))	('interferon regulatory factor 3', 'Gene', (118, 148))	('RIG-I', 'Gene', '23586', (80, 85))
9437	30341336	In addition, phosphorylation of CEACAM1 by SHP2 inhibited viral replication by reducing phosphorylation of mammalian target of rapamycin (mTOR) to suppress global cellular protein production.	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('mTOR', 'Gene', (138, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('viral replication', 'CPA', (58, 75))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('SHP2', 'Gene', (43, 47))	('phosphorylation', 'MPA', (88, 103))	('mTOR', 'Gene', '2475', (138, 142))	('global cellular protein production', 'MPA', (156, 190))	('reducing', 'NegReg', (79, 87))	('mammalian target of rapamycin', 'Gene', '2475', (107, 136))	('inhibited', 'NegReg', (48, 57))	('mammalian target of rapamycin', 'Gene', (107, 136))	('viral replication', 'biological_process', 'GO:0008166', ('58', '75'))	('phosphorylation', 'Var', (13, 28))	('SHP2', 'Gene', '5781', (43, 47))	('viral replication', 'biological_process', 'GO:0019079', ('58', '75'))	('suppress', 'NegReg', (147, 155))	('viral replication', 'biological_process', 'GO:0019058', ('58', '75'))
9440	30341336	However, in contrast to the inhibitory effects of CEACAM1 on influenza virus replication observed by Vitenshtein et al., knockdown of endogenous CEACAM1 protein expression reduced HPAI H5N1 titers by 4.8-fold in ATII cells.	('knockdown', 'Var', (121, 130))	('reduced', 'NegReg', (172, 179))	('influenza virus', 'Species', '11309', (61, 76))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('HPAI', 'molecular_function', 'GO:0043863', ('180', '184'))	('protein', 'Protein', (153, 160))	('H5N1', 'Species', '102793', (185, 189))	('HPAI', 'MPA', (180, 184))	('titers', 'MPA', (190, 196))	('CEACAM1', 'Gene', (145, 152))
9446	30341336	Importantly, knockdown of CEACAM1 expression resulted in a reduction in influenza virus replication and suggests targeting of this molecule may assist in improving disease outcomes.	('influenza virus', 'Protein', (72, 87))	('replication', 'MPA', (88, 99))	('CEACAM1', 'Gene', (26, 33))	('reduction', 'NegReg', (59, 68))	('knockdown', 'Var', (13, 22))	('influenza virus', 'Species', '11309', (72, 87))
9520	29725260	Thus, only patients with EGFR activation mutations can benefit from this mechanism.	('mutations', 'Var', (41, 50))	('EGFR', 'Gene', (25, 29))	('activation', 'PosReg', (30, 40))	('patients', 'Species', '9606', (11, 19))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
9536	29725260	Also, knockdown of cyclin J (CCNJ) can increase the sensitivity of DDP-based chemotherapy and the effect can be achieved by miRNA-146a.	('cyclin J', 'Gene', (19, 27))	('increase', 'PosReg', (39, 47))	('sensitivity', 'MPA', (52, 63))	('cyclin J', 'Gene', '54619', (19, 27))	('knockdown', 'Var', (6, 15))	('CCNJ', 'Gene', (29, 33))	('CCNJ', 'Gene', '54619', (29, 33))	('DDP-based chemotherapy', 'MPA', (67, 89))	('miR', 'Gene', (124, 127))	('miR', 'Gene', '220972', (124, 127))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))
9547	29725260	In addition, miRNA-138 promotes radiosensitivity and leads to apoptosis by targeting Sentrin/SUMO-specific protease 1 (SENP1), which is a marker of radioresistance in NSCLC.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('Sentrin/SUMO-specific protease 1', 'Gene', '29843;7341', (85, 117))	('Sentrin/SUMO-specific protease 1', 'Gene', (85, 117))	('promotes', 'PosReg', (23, 31))	('SENP1', 'Gene', (119, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('targeting', 'Reg', (75, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('apoptosis', 'CPA', (62, 71))	('radiosensitivity', 'CPA', (32, 48))	('SENP1', 'Gene', '29843', (119, 124))	('miRNA-138', 'Var', (13, 22))	('leads to', 'Reg', (53, 61))	('NSCLC', 'Disease', (167, 172))	('miRNA-138', 'Chemical', '-', (13, 22))
9555	29725260	These mutations influence the adenosine triphosphate (ATP)-binding region of EGFR, which is the same region where TKIs bind.	('ATP', 'Chemical', 'MESH:D000255', (54, 57))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (30, 52))	('influence', 'Reg', (16, 25))	('EGFR', 'Gene', '1956', (77, 81))	('ATP)-binding', 'molecular_function', 'GO:0005524', ('54', '66'))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))	('mutations', 'Var', (6, 15))
9572	29725260	showed that inhibition of miR-196a could reverse cisplatin resistance of A549/DDP cell lines.	('inhibition', 'Var', (12, 22))	('miR', 'Gene', '220972', (26, 29))	('reverse', 'NegReg', (41, 48))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('miR', 'Gene', (26, 29))	('cisplatin resistance', 'MPA', (49, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))
9584	29725260	MiRNA-138 can deter chemo-resistance by inhibiting ZEB-induced EMT in patients with NSCLC.	('patients', 'Species', '9606', (70, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('chemo-resistance', 'MPA', (20, 36))	('MiRNA-138', 'Var', (0, 9))	('ZEB', 'Chemical', '-', (51, 54))	('ZEB-induced EMT', 'CPA', (51, 66))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('deter', 'NegReg', (14, 19))	('MiRNA-138', 'Chemical', '-', (0, 9))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))	('inhibiting', 'NegReg', (40, 50))
9586	29725260	MiRNA-338-3p can inhibit the growth, migration and invasion of NSCLC by controlling Sox4-induced EMT.	('Sox4', 'Gene', (84, 88))	('NSCLC', 'Disease', (63, 68))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('rat', 'Species', '10116', (40, 43))	('migration', 'CPA', (37, 46))	('growth', 'CPA', (29, 35))	('inhibit', 'NegReg', (17, 24))	('Sox4', 'Gene', '6659', (84, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('invasion', 'CPA', (51, 59))	('MiRNA-338-3p', 'Var', (0, 12))
9612	29725260	With high sensitivity and accuracy, dysregulated expression levels of miRNA in vivo may indicate the occurrence of NSCLC earlier than the appearance of symptoms and abnormal CT images.	('expression levels', 'MPA', (49, 66))	('indicate', 'Reg', (88, 96))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('dysregulated', 'Var', (36, 48))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
9615	29725260	The most promising example is that NSCLC cell lines with EGFR mutation are more sensitive to EGFR-TKIs than those wild types, and mutation events might relate with expression level of these miRNAs.	('relate', 'Reg', (152, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('NSCLC', 'Disease', (35, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (57, 61))	('mutation', 'Var', (62, 70))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('EGFR', 'Gene', (57, 61))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))	('sensitive', 'MPA', (80, 89))
9620	29725260	More research data show that abnormal expression of miRNAs play important roles in the progression and drug-resistance of NSCLC by modulating oncogenic or tumor-suppressing genes and can act as biomarkers for therapy in NSCLC.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('NSCLC', 'Disease', (220, 225))	('drug-resistance', 'biological_process', 'GO:0009315', ('103', '118'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('drug-resistance', 'CPA', (103, 118))	('miR', 'Gene', (52, 55))	('tumor', 'Disease', (155, 160))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('drug-resistance', 'Phenotype', 'HP:0020174', (103, 118))	('abnormal', 'Var', (29, 37))	('modulating', 'Reg', (131, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('miR', 'Gene', '220972', (52, 55))	('NSCLC', 'Disease', (122, 127))	('drug-resistance', 'biological_process', 'GO:0042493', ('103', '118'))	('oncogenic', 'Gene', (142, 151))
9635	29697362	We calculate the somatic single nucleotide variants (SNVs), insertions and deletions (INDELs), and copy number variations (CNVs) using Mutect, Strelka, and EXCAVATOR, respectively.	('insertions', 'Var', (60, 70))	('single nucleotide variants', 'Var', (25, 51))	('deletions', 'Var', (75, 84))	('INDEL', 'Chemical', '-', (86, 91))	('copy number variations', 'Var', (99, 121))
9637	29697362	Genomic alterations were curated at both the gene and variant levels to identify function-affecting variants in cancer genes of the COSMIC database.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('variants', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (112, 118))
9641	29697362	BioDataBank is our knowledgebase encompassing gene, protein, gene variants in cancer, population (cohort) data, and drugs for clinical therapy.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('variants', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
9652	29697362	For example, EGFR chr7:55259515 T > G mutation can be annotated as p.L858R only through proper choice of transcript among many different EGFR transcripts.	('EGFR', 'Gene', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('p.L858R', 'Mutation', 'rs121434568', (67, 74))	('EGFR', 'Gene', '1956', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('55259515 T > G', 'Mutation', 'rs121434568', (23, 37))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('p.L858R', 'Var', (67, 74))
9653	29697362	We further added transcripts concordant with all clinically actionable variants in MyCancerGenome.	('variants', 'Var', (71, 79))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Cancer', 'Disease', (85, 91))
9657	29697362	We further provide filtering utility to select genes of known importance in cancer as well as variants based on patient frequency and functional impact (Fig.	('patient', 'Species', '9606', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('variants', 'Var', (94, 102))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
9668	29697362	In tumor, not one but several alternative driver alterations in different genes can lead to similar downstream events.	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('alterations', 'Var', (49, 60))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (3, 8))
9686	29697362	BAM Binary Alignment Map CNA Copy Number Aberration CNV Copy Number Variation INDEL Insertion or Deletion LUAD Lung Adenocarcinoma NGS Next Generation Sequencing SNV Sing Nucleotide Variant, TCGA The Cancer Genome Atlas, VCF Variant Call Format WES Whole Exome Sequencing WTS Whole Transcriptome Sequencing YJ have developed and tested the system with TC, JK, and JP.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('VCF', 'Gene', (221, 224))	('TC', 'Chemical', 'MESH:D013667', (352, 354))	('Deletion', 'Var', (97, 105))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('VCF', 'Gene', '1714', (221, 224))	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('INDEL', 'Chemical', '-', (78, 83))	('BAM', 'Gene', (0, 3))	('Cancer', 'Disease', (200, 206))	('BAM', 'Gene', '9126', (0, 3))	('Cancer', 'Disease', 'MESH:D009369', (200, 206))	('Variation', 'Var', (68, 77))	('TC', 'Chemical', 'MESH:D013667', (191, 193))	('Adenocarcinoma', 'Disease', (116, 130))
9780	29172277	Yang et al., (2006) also reported a significant association MCM2 expression with poor prognosis in patients with NSCLC, which suggests that identifying higher tumor proliferation may have an important role in predicting prognosis of NSCLC.	('NSCLC', 'Disease', (233, 238))	('NSCLC', 'Disease', 'MESH:D002289', (233, 238))	('MCM2', 'Gene', '4171', (60, 64))	('MCM2', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('association', 'Interaction', (48, 59))	('patients', 'Species', '9606', (99, 107))	('tumor', 'Disease', (159, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (233, 238))	('NSCLC', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('expression', 'Var', (65, 75))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
9783	29075129	Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially.	('NSCLC', 'Disease', (255, 260))	('EGFR', 'Gene', '1956', (214, 218))	('-mutant', 'Var', (219, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('214', '218'))	('EGFR', 'Gene', '1956', (277, 281))	('non-small cell lung cancer', 'Disease', (44, 70))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (227, 253))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('180', '203'))	('epidermal growth factor receptor', 'Gene', (180, 212))	('epidermal growth factor receptor', 'Gene', '1956', (180, 212))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (44, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (48, 70))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (231, 253))	('cell lung cancer', 'Disease', 'MESH:D008175', (237, 253))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (227, 253))	('icotinib', 'Chemical', 'MESH:C531470', (14, 22))	('EGFR', 'Gene', (214, 218))	('EGFR', 'Gene', (277, 281))	('cell lung cancer', 'Disease', 'MESH:D008175', (54, 70))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (44, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('277', '281'))	('icotinib', 'Chemical', 'MESH:C531470', (77, 85))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('patients', 'Species', '9606', (166, 174))	('non-small cell lung cancer', 'Disease', (227, 253))
9799	29075129	According to previous statistics, epidermal growth factor receptor (EGFR) gene mutations are present in approximately 17% of patients with advanced NSCLC, and EGFR-targeted therapy has achieved measurable effects in these patients.	('epidermal growth factor receptor', 'Gene', (34, 66))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('34', '57'))	('EGFR', 'Gene', '1956', (159, 163))	('NSCLC', 'Disease', (148, 153))	('patients', 'Species', '9606', (222, 230))	('EGFR', 'molecular_function', 'GO:0005006', ('159', '163'))	('epidermal growth factor receptor', 'Gene', '1956', (34, 66))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('EGFR', 'Gene', (159, 163))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (79, 88))	('patients', 'Species', '9606', (125, 133))
9801	29075129	The superior efficacy of EGFR-TKIs for patients harboring EGFR-sensitive mutations compared with standard chemotherapy has been demonstrated in several prospective clinical trials.	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('EGFR', 'Gene', '1956', (25, 29))	('mutations', 'Var', (73, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
9808	29075129	Among the secondary mutations, a threonine-to-methionine substitution at amino acid position 790 in exon 20 (T790M) accounts for nearly 50% of resistant tumors.	('threonine-to-methionine substitution at amino acid position 790', 'Mutation', 'rs121434569', (33, 96))	('T790M', 'Mutation', 'rs121434569', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('T790M', 'Var', (109, 114))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
9809	29075129	Moreover, 10%-20% of acquired resistance is due to amplification of the c-Met oncogene.	('due', 'Reg', (44, 47))	('c-Met', 'Gene', (72, 77))	('c-Met', 'Gene', '4233', (72, 77))	('acquired resistance', 'Disease', (21, 40))	('amplification', 'Var', (51, 64))
9849	29075129	Of 27 patients, 23 were found with EGFR-sensitive mutation, while in the remaining four patients EGFR mutation was not detected.	('EGFR', 'Gene', '1956', (97, 101))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (6, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('found', 'Reg', (24, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('mutation', 'Var', (50, 58))
9870	29075129	Although the PFS was higher in patients who underwent icotinib failure within 6 months than those with icotinib failure after more than 6 months, there was no significant difference between them.	('icotinib', 'Chemical', 'MESH:C531470', (54, 62))	('icotinib failure', 'Var', (54, 70))	('PFS', 'MPA', (13, 16))	('patients', 'Species', '9606', (31, 39))	('higher', 'PosReg', (21, 27))	('icotinib', 'Chemical', 'MESH:C531470', (103, 111))
9897	28881820	Brain metastases in patients with non-small cell lung cancer: the role of mutated-EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear.	('L858R', 'Mutation', 'rs121434568', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('NSCLC', 'Disease', (308, 313))	('non-small cell lung cancer', 'Disease', (34, 60))	('metastases', 'Disease', 'MESH:D009362', (232, 242))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (166, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (308, 313))	('metastases', 'Disease', (232, 242))	('L858R point mutation', 'Var', (116, 136))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('patients', 'Species', '9606', (20, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('Non-small cell lung cancer', 'Disease', (166, 192))	('patients', 'Species', '9606', (201, 209))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (34, 60))	('NSCLC', 'Disease', (194, 199))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (54, 60))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('brain metastases', 'Disease', 'MESH:D009362', (226, 242))	('cancer', 'Disease', (186, 192))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('brain metastases', 'Disease', (226, 242))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (34, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('develop', 'PosReg', (218, 225))	('NSCLC', 'Disease', 'MESH:D002289', (308, 313))	('metastases', 'Disease', (6, 16))
9898	28881820	We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('L858R', 'Mutation', 'rs121434568', (109, 114))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('44', '67'))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('deletion', 'Var', (97, 105))	('L858R', 'Var', (109, 114))
9902	28881820	Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770).	('EGFR', 'Gene', '1956', (14, 18))	('overall survival', 'MPA', (70, 86))	('EGFR', 'Gene', (14, 18))	('SBM', 'Disease', (167, 170))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('deletion', 'Var', (27, 35))	('L858R', 'Mutation', 'rs121434568', (138, 143))	('longer', 'PosReg', (63, 69))
9909	28881820	Epidermal growth factor receptor (EGFR) is one of the most common oncogenes, activating mutations of which drive tumor growth in NSCLC.	('tumor', 'Disease', (113, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('mutations', 'Var', (88, 97))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('NSCLC', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('drive', 'PosReg', (107, 112))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('EGFR', 'Gene', '1956', (34, 38))
9910	28881820	The association between the EGFR mutation status and BM in patients with NSCLC has been noted in the past.	('EGFR', 'Gene', '1956', (28, 32))	('mutation', 'Var', (33, 41))	('association', 'Interaction', (4, 15))	('EGFR', 'Gene', (28, 32))	('NSCLC', 'Disease', (73, 78))	('patients', 'Species', '9606', (59, 67))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
9912	28881820	In addition, evidence suggests that EGFR exon 19 deletion-positive NSCLC is distinct from EGFR exon 21 (L858R) point mutation-positive NSCLC with regard to the tumor response to treatment and patient survival.	('patient', 'Species', '9606', (192, 199))	('L858R', 'Mutation', 'rs121434568', (104, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (90, 94))	('NSCLC', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('EGFR', 'Gene', '1956', (36, 40))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', (90, 94))	('NSCLC', 'Disease', (67, 72))	('deletion-positive', 'Var', (49, 66))	('EGFR', 'Gene', (36, 40))	('tumor', 'Disease', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
9913	28881820	Nonetheless, the question regarding whether these two common subtypes of EGFR mutations have different impacts on the occurrence of BM in NSCLC has not been well addressed.	('EGFR', 'Gene', '1956', (73, 77))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('impacts', 'Reg', (103, 110))
9917	28881820	The participation of activating EGFR mutations in lung cancer cell mobility is unknown.	('lung cancer', 'Disease', (50, 61))	('activating', 'PosReg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('EGFR', 'Gene', '1956', (32, 36))	('mutations', 'Var', (37, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
9918	28881820	Therefore, in this study, we determined whether EGFR mutations, including the exon 19 deletion and L858R point mutation subtypes, predict the occurrence of the SBM in NSCLC patients, and characterized the role of activating EGFR mutations in lung cancer cell dissemination.	('SBM', 'Disease', (160, 163))	('EGFR', 'Gene', '1956', (48, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('EGFR', 'molecular_function', 'GO:0005006', ('224', '228'))	('predict', 'Reg', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('activating', 'PosReg', (213, 223))	('EGFR', 'Gene', (224, 228))	('patients', 'Species', '9606', (173, 181))	('mutations', 'Var', (229, 238))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('L858R', 'Mutation', 'rs121434568', (99, 104))	('lung cancer', 'Disease', (242, 253))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('EGFR', 'Gene', '1956', (224, 228))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('NSCLC', 'Disease', (167, 172))
9919	28881820	Of 596 NSCLC patients, 384 had a determined EGFR mutation status and were eligible for further analysis (Figure 1).	('NSCLC', 'Disease', (7, 12))	('patients', 'Species', '9606', (13, 21))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('mutation', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (7, 12))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
9920	28881820	Mutated-EGFRs were found in 186 (48.4%) of the 384 eligible patients (Figure 1), including an in-frame deletion in exon 19 (n = 79), a point mutation (L858R) in exon 21 (n = 97), and uncommon mutations (n = 10, 3 with an exon 18 point mutation, 6 with an exon 20 mutation, and 1 with an exon 18 and 20 mutation).	('exon', 'Var', (255, 259))	('patients', 'Species', '9606', (60, 68))	('L858R', 'Var', (151, 156))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (8, 12))	('L858R', 'Mutation', 'rs121434568', (151, 156))
9928	28881820	In details, 53.1% of the exon 19 deletion-positive patients and 49.5% of the L858R point mutation-positive patients experienced BM during their entire disease course.	('deletion-positive', 'Var', (33, 50))	('L858R', 'Mutation', 'rs121434568', (77, 82))	('exon', 'Var', (25, 29))	('patients', 'Species', '9606', (51, 59))	('experienced', 'Reg', (116, 127))	('patients', 'Species', '9606', (107, 115))
9929	28881820	The multivariable logistic regression analysis, as shown in Table 2, revealed that the presence of mutated-EGFR was significantly associated with a higher overall cumulative incidence of BM, as compared to that of WT-EGFR (odds ratio (OR) = 2.24, 95% confidence interval (CI), 1.37-3.64, P = 0.001) after adjusting for gender (not significant), age (OR = 2.44, 95% CI, 1.52-4.00, P < 0.001), smoking history (not significant), and stage at lung cancer diagnosis (OR = 4.02, 95% CI, 1.94-8.32, P < 0.001).	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'Gene', (217, 221))	('EGFR', 'Gene', '1956', (107, 111))	('presence', 'Var', (87, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('lung cancer', 'Disease', (440, 451))	('EGFR', 'Gene', (107, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (440, 451))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('lung cancer', 'Disease', 'MESH:D008175', (440, 451))
9930	28881820	In terms of the specific subtype of mutated-EGFRs, both the presence of exon 19 deletion and the presence of L858R point mutation were significantly associated with BM compared to the presence of WT-EGFR (OR = 2.18, 95% CI, 1.19-4.00, P = 0.012, and OR = 2.13, 95% CI, 1.23-3.75, P = 0.009, respectively); however, the difference between the exon 19 deletion-positive and the L858R point mutation-positive groups was not statistically significant (OR = 1.03, 95% CI, 0.54-1.94, P = 0.939).	('deletion', 'Var', (80, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('EGFR', 'Gene', (199, 203))	('L858R', 'Mutation', 'rs121434568', (109, 114))	('EGFR', 'Gene', '1956', (199, 203))	('presence', 'Var', (60, 68))	('associated', 'Reg', (149, 159))	('EGFR', 'Gene', '1956', (44, 48))	('L858R', 'Mutation', 'rs121434568', (376, 381))	('EGFR', 'Gene', (44, 48))	('L858R', 'Var', (109, 114))
9936	28881820	As to the stage I-IIIA patients primarily treated with surgery, the cumulative incidence of SBM between the mutated- and the WT-EGFR groups were not statistically different (25.0% (6/24) and 18.7% (3/16), respectively, P = 0.88, data not shown).	('mutated-', 'Var', (108, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('SBM', 'Disease', (92, 95))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))
9937	28881820	As to the comparison between the exon 19 deletion-positive and the L858R mutation-positive groups from stage IIIB-IV patients, there was a slightly longer median OS (20.6 vs.14.2 months, P of log-rank test = 0.368) in the former (Figure 2D), but no difference in the cumulative incidence of SBM (39.5% vs. 34.5%, HR= 1.12, 95% CI = 0.60-2.09, P = 0.720, Figure 2E) was observed between the two groups.	('L858R', 'Mutation', 'rs121434568', (67, 72))	('OS', 'Chemical', '-', (162, 164))	('deletion-positive', 'Var', (41, 58))	('exon', 'Var', (33, 37))	('longer', 'PosReg', (148, 154))	('patients', 'Species', '9606', (117, 125))	('L858R', 'Var', (67, 72))
9938	28881820	To confirm whether the presence of mutated-EGFR was independently associated with SBM, multivariable analysis was performed.	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('SBM', 'Disease', (82, 85))	('associated', 'Reg', (66, 76))	('EGFR', 'Gene', '1956', (43, 47))	('presence', 'Var', (23, 31))	('EGFR', 'Gene', (43, 47))
9939	28881820	For stage IIIB-IV NSCLC patients, the presence of mutated-EGFR was significantly associated with the occurrence of SBM as compared to that of WT-EGFR (HR = 2.98, 95% CI, 1.50-5.93, P = 0.002) after adjusting age (HR = 2.00, 95% CI =1.16-3.45, P = 0.012) and other common demographic covariates (Table 3).	('SBM', 'Disease', (115, 118))	('presence', 'Var', (38, 46))	('EGFR', 'Gene', '1956', (58, 62))	('NSCLC', 'Disease', (18, 23))	('EGFR', 'Gene', '1956', (145, 149))	('EGFR', 'Gene', (58, 62))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('EGFR', 'Gene', (145, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('patients', 'Species', '9606', (24, 32))	('associated', 'Reg', (81, 91))
9940	28881820	Similar results were observed for both the exon 19 deletion-positive and the L858R point mutation-positive groups when compared to the WT-EGFR group (HR = 2.79, 95% CI, 0.36-1.25, adjusted P = 0.012 and HR = 3.08, 95% CI, 0.33-1.49, P = 0.002, respectively).	('EGFR', 'Gene', '1956', (138, 142))	('L858R', 'Mutation', 'rs121434568', (77, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('EGFR', 'Gene', (138, 142))	('exon 19 deletion-positive', 'Var', (43, 68))	('deletion-positive', 'Var', (51, 68))	('L858R', 'Var', (77, 82))
9941	28881820	Further analysis revealed that there was no difference for SBM occurrence between the exon 19 deletion and L858R point mutation groups (HR = 0.91, 95% CI, 0.47-1.74, P = 0.770).	('exon 19 deletion', 'Var', (86, 102))	('SBM', 'Disease', (59, 62))	('L858R', 'Mutation', 'rs121434568', (107, 112))	('L858R', 'Var', (107, 112))
9942	28881820	To study the potential effect of the mutated-EGFRs on lung cancer progression, mutated EGFR [L858R (a point mutation in exon 21) or Del 3 (an in-frame deletion in exon 19)] or the wild-type (WT) one was introduced into H1437 (non-mutated) lung adenocarcinoma cells via lentiviral infection (Figure 3A).	('lung cancer', 'Disease', (54, 65))	('EGFR', 'Gene', '1956', (87, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('EGFR', 'Gene', (45, 49))	('mutated', 'Var', (79, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (239, 258))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('lung adenocarcinoma cells via lentiviral infection', 'Disease', (239, 289))	('EGFR', 'Gene', (87, 91))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('L858R', 'Mutation', 'rs121434568', (93, 98))	('lung adenocarcinoma cells via lentiviral infection', 'Disease', 'MESH:D000077192', (239, 289))	('EGFR', 'Gene', '1956', (45, 49))	('H1437', 'CellLine', 'CVCL:1472', (219, 224))
9943	28881820	The ectopic expression of mutated- but not WT-EGFRs induced a morphological change from an epithelial phenotype to a spindle-like morphology (Figure 3B and Supplementary Figure 1A).	('EGFR', 'Gene', '1956', (46, 50))	('spindle-like morphology', 'CPA', (117, 140))	('mutated-', 'Var', (26, 34))	('EGFR', 'Gene', (46, 50))	('spindle', 'cellular_component', 'GO:0005819', ('117', '124'))	('morphological change', 'CPA', (62, 82))
9956	28881820	As to stage IIIB-IV diseases with mutated-EGFRs, the L858R mutation-positive tumors had a slightly shorter MTSBM compared to the exon 19 deletion-positive ones (22.9 vs. 26.4 months, P = 0.743), but the difference was not statistically different.	('shorter', 'NegReg', (99, 106))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('EGFR', 'Gene', '1956', (42, 46))	('L858R', 'Mutation', 'rs121434568', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('EGFR', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MTSBM', 'MPA', (107, 112))	('L858R', 'Var', (53, 58))
9960	28881820	The present study showed that the presence of mutated-EGFRs not only was associated with overall BM but also predicted SBM in stage IIIB-IV NSCLC, irrespective of the length of patient OS.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('SBM', 'Disease', (119, 122))	('patient', 'Species', '9606', (177, 184))	('NSCLC', 'Disease', (140, 145))	('associated', 'Reg', (73, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))	('predicted', 'Reg', (109, 118))	('presence', 'Var', (34, 42))	('OS', 'Chemical', '-', (185, 187))
9962	28881820	As to the subtype of mutated-EGFRs, the exon 19 deletion-positive and the L858R point mutation-positive patient groups shared a similar cumulative incidence of SBM.	('L858R', 'Mutation', 'rs121434568', (74, 79))	('SBM', 'Disease', (160, 163))	('exon 19 deletion-positive', 'Var', (40, 65))	('EGFR', 'Gene', '1956', (29, 33))	('patient', 'Species', '9606', (104, 111))	('EGFR', 'Gene', (29, 33))	('L858R', 'Var', (74, 79))	('deletion-positive', 'Var', (48, 65))
9968	28881820	We found that, independent of the survival factor, the presence of mutated-EGFRs was significantly associated with an increased risk of SBM in NSCLC as compared to those with WT-EGFR (HR = 2.98, P = 0.002).	('presence', 'Var', (55, 63))	('EGFR', 'Gene', '1956', (178, 182))	('NSCLC', 'Disease', (143, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('178', '182'))	('EGFR', 'Gene', (178, 182))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('SBM', 'Disease', (136, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))
9971	28881820	Prior in vitro experiments showed that the activation of EGFR upon ligand stimulation or by the mutation of EGFRvIII rather than EGFR overexpression correlates with cell migration and invasion in epithelial cancer cell lines, such as breast, oral squamous and glioblastoma cancers, and in NIH3T3 fibroblasts.	('cell migration', 'CPA', (165, 179))	('activation', 'PosReg', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('NIH3T3', 'CellLine', 'CVCL:0594', (289, 295))	('EGFR', 'Gene', (129, 133))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('epithelial cancer', 'Disease', (196, 213))	('EGFR', 'Gene', '1956', (108, 112))	('mutation', 'Var', (96, 104))	('squamous and glioblastoma cancers', 'Disease', 'MESH:D005909', (247, 280))	('glioblastoma', 'Phenotype', 'HP:0012174', (260, 272))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('ligand', 'molecular_function', 'GO:0005488', ('67', '73'))	('EGFR', 'Gene', (57, 61))	('invasion', 'CPA', (184, 192))	('breast', 'Disease', (234, 240))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', (108, 112))	('cell migration', 'biological_process', 'GO:0016477', ('165', '179'))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('epithelial cancer', 'Phenotype', 'HP:0031492', (196, 213))	('EGFR', 'Gene', '1956', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('epithelial cancer', 'Disease', 'MESH:D000077216', (196, 213))
9979	28881820	Patients with an exon 19 deletion have longer survival compared to those with an L858R mutation, theoretically implying that more BM would be observed throughout the disease course of the former.	('survival', 'MPA', (46, 54))	('L858R', 'Mutation', 'rs121434568', (81, 86))	('Patients', 'Species', '9606', (0, 8))	('deletion', 'Var', (25, 33))	('longer', 'PosReg', (39, 45))
9981	28881820	Our analysis further showed that the cumulative incidence of SBM in stage IIIB-IV NSCLC was similar between the EGFR exon 19 deletion-positive and the L858R mutation-positive groups (39.5%, vs. 34.5%), although the former exhibited a slightly longer OS (20.6 vs. 14.2 months).	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('SBM', 'Disease', (61, 64))	('L858R', 'Var', (151, 156))	('OS', 'Chemical', '-', (250, 252))	('EGFR', 'Gene', '1956', (112, 116))	('L858R', 'Mutation', 'rs121434568', (151, 156))	('NSCLC', 'Disease', (82, 87))	('deletion-positive', 'Var', (125, 142))
9982	28881820	This finding may be partially explained by the observations that the L858R mutation-positive tumors had an inferior disease control rate to EGFR-TKIs as first-line treatment (63.6% vs. 100%, P of chi-square test = 0.017, table not shown).	('inferior disease', 'Disease', (107, 123))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('EGFR', 'Gene', (140, 144))	('L858R', 'Var', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('inferior disease', 'Disease', 'MESH:D056989', (107, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('140', '144'))	('L858R', 'Mutation', 'rs121434568', (69, 74))	('tumors', 'Disease', (93, 99))	('EGFR', 'Gene', '1956', (140, 144))
9989	28881820	The possibility of EGFR mutation discordance between the primary and metastatic sites may influence our results and represents another limitation.	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))	('influence', 'Reg', (90, 99))	('mutation discordance', 'Var', (24, 44))
9990	28881820	Based on the report indicating that the heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma, we used the EGFR mutation status determined from primary or metastatic lung cancer specimens as a surrogate of the entire eligible population.	('lung cancer', 'Disease', (198, 209))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('EGFR', 'Gene', '1956', (70, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('EGFR', 'Gene', (139, 143))	('lung adenocarcinoma', 'Disease', (106, 125))
9997	28881820	In addition, the presence of mutated-EGFRs predicted an increased risk for SBM independent of age and other common covariates, and was associated with a shorter MTSBM in stage IIIB-IV NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('SBM', 'Disease', (75, 78))	('patients', 'Species', '9606', (190, 198))	('shorter', 'NegReg', (153, 160))	('NSCLC', 'Disease', (184, 189))	('EGFR', 'Gene', '1956', (37, 41))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('presence', 'Var', (17, 25))	('EGFR', 'Gene', (37, 41))
9998	28881820	Furthermore, the presence of an EGFR exon19 deletion and the presence of an L858R point mutation are comparable to predict subsequent BM.	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('L858R', 'Var', (76, 81))	('EGFR', 'Gene', (32, 36))	('L858R', 'Mutation', 'rs121434568', (76, 81))
10005	28881820	EGFR exon 18-21 mutations were determined using direct DNA sequencing, as previously described (Supplementary Materials and Methods).	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (16, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('EGFR', 'Gene', '1956', (0, 4))
10006	28881820	Patients with any or a combination of detectable EGFR exon 18-21 mutations, including common (exon 19 deletion and L858R point mutation), uncommon mutations (eg., exon 20 insertion, exon 18 mutation) and compound mutation (eg., exon 18/20), were placed into the mutated-EGFR group, and patients with no detectable mutated-EGFRs were put into the WT-EGFR group.	('L858R', 'Mutation', 'rs121434568', (115, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('270', '274'))	('exon 18-21', 'Gene', (54, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (65, 74))	('Patients', 'Species', '9606', (0, 8))	('exon', 'Var', (94, 98))	('EGFR', 'Gene', '1956', (322, 326))	('EGFR', 'Gene', (270, 274))	('EGFR', 'Gene', (349, 353))	('EGFR', 'molecular_function', 'GO:0005006', ('349', '353'))	('compound mutation', 'Var', (204, 221))	('L858R point mutation', 'Var', (115, 135))	('exon 18 mutation', 'Var', (182, 198))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', '1956', (270, 274))	('EGFR', 'Gene', '1956', (349, 353))	('EGFR', 'Gene', (322, 326))	('patients', 'Species', '9606', (286, 294))
10011	28881820	The association between EGFR mutations (mutated vs. WT) and overall BM (BM at the diagnosis of lung cancer and SBM) was determined using a multivariable logistic regression analysis.	('EGFR', 'Gene', '1956', (24, 28))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('EGFR', 'Gene', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))
10012	28881820	For those NSCLC patients without BM at the diagnosis of lung cancer, we tested the association between the presence of mutated-EGFR and SBM using a time-to-event analysis considering death as a competing risk (Fine and Gray's sub-distribution hazard model).	('NSCLC', 'Disease', (10, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('presence', 'Var', (107, 115))	('NSCLC', 'Disease', 'MESH:D002289', (10, 15))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', '1956', (127, 131))	('SBM', 'Disease', (136, 139))	('association', 'Interaction', (83, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tested', 'Reg', (72, 78))	('lung cancer', 'Disease', (56, 67))	('EGFR', 'Gene', (127, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
10013	28881820	To compare the exon 19, L858R and WT groups, we conducted a separate model (both logistic and time-to-event models) incorporating the details of EGFRs.	('L858R', 'Var', (24, 29))	('EGFR', 'Gene', (145, 149))	('EGFR', 'Gene', '1956', (145, 149))	('L858R', 'Mutation', 'rs121434568', (24, 29))
10016	28881820	In addition, we depicted OS using the Kaplan-Meier method and compared group differences (i.e., EGFR mutations) using log-rank tests.	('OS', 'Chemical', '-', (25, 27))	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', (96, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('EGFR', 'Gene', '1956', (96, 100))
10018	28881820	BM brain metastases EGFR epidermal growth factor receptor CI confidence interval ECIS electric cell-substrate impedance sensing HR hazard ratio HUVEC human umbilical vascular endothelial cells MTSBM median time interval between the diagnosis of lung cancer and the detection of SBM NR not reached NSCLC non-small cell lung cancer OR odds ratio OS overall survival SBM subsequent BM TKD tyrosine kinase domain TKI tyrosine kinase inhibitors WT wild-type	('EGFR', 'Gene', (20, 24))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (307, 329))	('OS', 'Chemical', '-', (344, 346))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('25', '48'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (303, 329))	('lung cancer', 'Disease', (245, 256))	('lung cancer', 'Disease', 'MESH:D008175', (318, 329))	('NSCLC', 'Disease', 'MESH:D002289', (297, 302))	('EGFR', 'Gene', '1956', (20, 24))	('human', 'Species', '9606', (150, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (318, 329))	('non-small cell lung cancer', 'Disease', (303, 329))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('NSCLC', 'Disease', (297, 302))	('brain metastases', 'Disease', 'MESH:D009362', (3, 19))	('brain metastases', 'Disease', (3, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('TKD tyrosine', 'Var', (382, 394))	('NSCLC', 'Phenotype', 'HP:0030358', (297, 302))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (303, 329))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
10026	28697764	In the present study, we found high linc00673 expression was associated with poor prognosis of NSCLC patients.	('patients', 'Species', '9606', (101, 109))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('linc00673', 'Gene', (36, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('high', 'Var', (31, 35))	('linc00673', 'Gene', '100499467', (36, 45))	('expression', 'MPA', (46, 56))	('NSCLC', 'Disease', (95, 100))
10027	28697764	In vitro experiments showed linc00673 knockdown reversed TGF-beta induced EMT, and miR-150-5p was predicted to target linc00673 through bioinformatics tools.	('miR-150', 'Gene', '406942', (83, 90))	('linc00673', 'Gene', (118, 127))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('linc00673', 'Gene', '100499467', (28, 37))	('5p', 'Chemical', '-', (91, 93))	('TGF-beta', 'Gene', '7040', (57, 65))	('EMT', 'CPA', (74, 77))	('TGF-beta', 'Gene', (57, 65))	('linc00673', 'Gene', (28, 37))	('reversed', 'NegReg', (48, 56))	('miR-150', 'Gene', (83, 90))	('linc00673', 'Gene', '100499467', (118, 127))	('knockdown', 'Var', (38, 47))
10064	28697764	The membranes were incubated with primary antibodies at 4  C overnight, including Vimentin (1:1000, Cell signaling Technology, CST), E-cadherin (1:500, Santa Cruz), N-cadherin (1:500, CST), ZEB1 (1:500, CST), Snail (1:500, CST), PARP (1:1000, CST), pro-caspase 3 (1:1000, CST), GAPDH (1:2000, CST), followed by incubation with an HRP-conjugated anti-mouse or anti-rabbit secondary antibody separately.	('ZEB1', 'Gene', (190, 194))	('CST', 'Gene', (243, 246))	('pro-caspase 3', 'Gene', (249, 262))	('E-cadherin', 'Gene', (133, 143))	('N-cadherin', 'Gene', (165, 175))	('CST', 'Gene', (203, 206))	('CST', 'Gene', '106478911', (184, 187))	('N-cadherin', 'Gene', '1000', (165, 175))	('E-cadherin', 'Gene', '999', (133, 143))	('CST', 'Gene', '106478911', (127, 130))	('1:2000', 'Var', (285, 291))	('antibody', 'cellular_component', 'GO:0019815', ('381', '389'))	('CST', 'Gene', '106478911', (223, 226))	('Vimentin', 'cellular_component', 'GO:0045098', ('82', '90'))	('Snail', 'Gene', (209, 214))	('CST', 'Gene', '106478911', (293, 296))	('GAPDH', 'Gene', '2597', (278, 283))	('CST', 'Gene', (272, 275))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('CST', 'Gene', (184, 187))	('1:500', 'Var', (177, 182))	('antibody', 'cellular_component', 'GO:0019814', ('381', '389'))	('CST', 'Gene', (127, 130))	('ZEB1', 'Gene', '6935', (190, 194))	('GAPDH', 'Gene', (278, 283))	('CST', 'Gene', (223, 226))	('cadherin', 'molecular_function', 'GO:0008014', ('135', '143'))	('PARP', 'Gene', '1302', (229, 233))	('CST', 'Gene', '106478911', (243, 246))	('CST', 'Gene', (293, 296))	('rabbit', 'Species', '9986', (364, 370))	('CST', 'Gene', '106478911', (203, 206))	('antibody', 'molecular_function', 'GO:0003823', ('381', '389'))	('Vimentin', 'Gene', '7431', (82, 90))	('CST', 'Gene', '106478911', (272, 275))	('antibody', 'cellular_component', 'GO:0042571', ('381', '389'))	('Snail', 'Gene', '6615', (209, 214))	('Vimentin', 'cellular_component', 'GO:0045099', ('82', '90'))	('pro-caspase 3', 'Gene', '836', (249, 262))	('cadherin', 'molecular_function', 'GO:0008014', ('167', '175'))	('Vimentin', 'Gene', (82, 90))	('mouse', 'Species', '10090', (350, 355))	('PARP', 'Gene', (229, 233))
10084	28697764	Next 8 NOD/SCID mice were divided into two groups and were injected with 1 x 106/0.1 ml linc00673-shRNA or negative control shRNA (sh-nc) transfected A549 cells by tail vein injection, respectively.	('A549', 'CellLine', 'CVCL:0023', (150, 154))	('linc00673', 'Gene', (88, 97))	('transfected', 'Var', (138, 149))	('SCID', 'Disease', 'MESH:D053632', (11, 15))	('linc00673', 'Gene', '100499467', (88, 97))	('SCID', 'Disease', (11, 15))	('mice', 'Species', '10090', (16, 20))
10102	28697764	By performing apoptosis assay, we observed that knockdown linc00673 increased apoptosis slightly in A549 cells (Fig.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('apoptosis', 'CPA', (78, 87))	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('linc00673', 'Gene', '100499467', (58, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('linc00673', 'Gene', (58, 67))	('increased', 'PosReg', (68, 77))	('knockdown', 'Var', (48, 57))
10103	28697764	Consistently, cleaved PARP increased while pro-Caspase 3 decreased after linc00673 knockdown in A549 cells (Fig.	('PARP', 'Gene', (22, 26))	('increased', 'PosReg', (27, 36))	('pro-Caspase 3', 'Gene', (43, 56))	('pro-Caspase 3', 'Gene', '836', (43, 56))	('linc00673', 'Gene', '100499467', (73, 82))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('knockdown', 'Var', (83, 92))	('decreased', 'NegReg', (57, 66))	('cleaved', 'MPA', (14, 21))	('linc00673', 'Gene', (73, 82))	('PARP', 'Gene', '1302', (22, 26))
10105	28697764	Similar growth inhibiting effect was also validated by EdU proliferation assays, where linc00673 knockdown reduced EdU incorporated cell proportion (Fig.	('EdU', 'Chemical', 'MESH:C031086', (115, 118))	('knockdown', 'Var', (97, 106))	('linc00673', 'Gene', '100499467', (87, 96))	('reduced', 'NegReg', (107, 114))	('EdU', 'MPA', (115, 118))	('EdU', 'Chemical', 'MESH:C031086', (55, 58))	('linc00673', 'Gene', (87, 96))
10106	28697764	Beyond that, linc00673 knockdown suppressed colony forming ability of A549 and H1975, as shown in Additional file 4: Figure S2C.	('linc00673', 'Gene', '100499467', (13, 22))	('knockdown', 'Var', (23, 32))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('colony forming ability', 'CPA', (44, 66))	('linc00673', 'Gene', (13, 22))	('suppressed', 'NegReg', (33, 43))	('H1975', 'CellLine', 'CVCL:1511', (79, 84))
10109	28697764	By performing wound scratch assay in A549 and H1975, we found wound closure area was larger after linc00673 knockdown (Fig.	('knockdown', 'Var', (108, 117))	('wound closure area', 'CPA', (62, 80))	('linc00673', 'Gene', (98, 107))	('H1975', 'CellLine', 'CVCL:1511', (46, 51))	('larger', 'PosReg', (85, 91))	('A549', 'CellLine', 'CVCL:0023', (37, 41))	('linc00673', 'Gene', '100499467', (98, 107))
10113	28697764	The tumor formation were significantly inhibited after linc00673 knockdown (P = 0.011 at week 2 and P = 0.008 at week 4; Fig.	('tumor', 'Disease', (4, 9))	('linc00673', 'Gene', (55, 64))	('inhibited', 'NegReg', (39, 48))	('linc00673', 'Gene', '100499467', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('formation', 'biological_process', 'GO:0009058', ('10', '19'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('knockdown', 'Var', (65, 74))
10124	28697764	Moreover, we observed that epithelial marker E-cadherin increased which was accompanied with the decrease of mesenchymal markers Vimentin, N-cadherin, Snail1 and ZEB1 following linc00673 depletion in A549 and H1975 cells (Fig.	('Vimentin', 'cellular_component', 'GO:0045099', ('129', '137'))	('A549', 'CellLine', 'CVCL:0023', (200, 204))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('Snail1', 'Gene', (151, 157))	('linc00673', 'Gene', '100499467', (177, 186))	('N-cadherin', 'Gene', (139, 149))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))	('N-cadherin', 'Gene', '1000', (139, 149))	('depletion', 'Var', (187, 196))	('ZEB1', 'Gene', '6935', (162, 166))	('mesenchymal', 'CPA', (109, 120))	('H1975', 'CellLine', 'CVCL:1511', (209, 214))	('ZEB1', 'Gene', (162, 166))	('Vimentin', 'cellular_component', 'GO:0045098', ('129', '137'))	('linc00673', 'Gene', (177, 186))	('decrease', 'NegReg', (97, 105))	('Vimentin', 'Gene', '7431', (129, 137))	('increased', 'PosReg', (56, 65))	('Vimentin', 'Gene', (129, 137))	('Snail1', 'Gene', '6615', (151, 157))	('cadherin', 'molecular_function', 'GO:0008014', ('141', '149'))
10127	28697764	S4E and S4F), while linc00673 expression did not alter under TNF-alpha stimuli in A549 cells (Additional file 6: Figure S4G).	('linc00673', 'Gene', '100499467', (20, 29))	('TNF-alpha', 'Gene', '7124', (61, 70))	('S4F', 'Var', (8, 11))	('linc00673', 'Gene', (20, 29))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('TNF-alpha', 'Gene', (61, 70))
10128	28697764	Immunofluorescence staining revealed that linc00673 knockdown changed Vimentin distribution in the absence or presence of TGF-beta in A549 and H1975 cells (Fig.	('Vimentin', 'cellular_component', 'GO:0045099', ('70', '78'))	('Vimentin', 'Gene', (70, 78))	('linc00673', 'Gene', '100499467', (42, 51))	('A549', 'CellLine', 'CVCL:0023', (134, 138))	('Vimentin', 'Gene', '7431', (70, 78))	('TGF-beta', 'Gene', '7040', (122, 130))	('Vimentin', 'cellular_component', 'GO:0045098', ('70', '78'))	('knockdown', 'Var', (52, 61))	('linc00673', 'Gene', (42, 51))	('H1975', 'CellLine', 'CVCL:1511', (143, 148))	('TGF-beta', 'Gene', (122, 130))	('changed', 'Reg', (62, 69))
10141	28697764	Meanwhile, miR-150-5p level increased significantly after linc00673 knockdown in A549 cells (Additional file 8: Figure S6C).	('increased', 'PosReg', (28, 37))	('linc00673', 'Gene', '100499467', (58, 67))	('5p', 'Chemical', '-', (19, 21))	('knockdown', 'Var', (68, 77))	('miR-150', 'Gene', (11, 18))	('linc00673', 'Gene', (58, 67))	('miR-150', 'Gene', '406942', (11, 18))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
10145	28697764	First, we constructed ZEB1 3'UTR wild type or mutated (predicted miR-150 binding sites) luciferase plasmids in the pmirGLO dual luciferase reporter vector, and luciferase activity was evaluated after co-transfection of miRNA and luciferase plasmids.	('luciferase', 'Enzyme', (88, 98))	('luciferase activity', 'molecular_function', 'GO:0047077', ('160', '179'))	('mutated', 'Var', (46, 53))	('ZEB1', 'Gene', (22, 26))	('luciferase activity', 'molecular_function', 'GO:0047712', ('160', '179'))	('miR', 'Gene', '220972', (65, 68))	('miR-150', 'Gene', (65, 72))	('miR', 'Gene', (65, 68))	('ZEB1', 'Gene', '6935', (22, 26))	('miR', 'Gene', (219, 222))	('miR', 'Gene', '220972', (219, 222))	('miR-150', 'Gene', '406942', (65, 72))	('luciferase activity', 'molecular_function', 'GO:0045289', ('160', '179'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('160', '179'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('160', '179'))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))
10146	28697764	In 293 T and A549 cells, we observed that over-expression of miR-150-5p could reduce the luciferase activity significantly, while mutation in miR-150-5p binding sites reversed luciferase activity (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('176', '195'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('176', '195'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('176', '195'))	('over-expression', 'PosReg', (42, 57))	('5p', 'Chemical', '-', (69, 71))	('reduce', 'NegReg', (78, 84))	('miR-150', 'Gene', (61, 68))	('mutation', 'Var', (130, 138))	('luciferase activity', 'molecular_function', 'GO:0050397', ('176', '195'))	('binding', 'molecular_function', 'GO:0005488', ('153', '160'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('176', '195'))	('293 T', 'CellLine', 'CVCL:0063', (3, 8))	('A549', 'CellLine', 'CVCL:0023', (13, 17))	('activity', 'MPA', (100, 108))	('miR-150', 'Gene', '406942', (142, 149))	('luciferase activity', 'molecular_function', 'GO:0047077', ('89', '108'))	('activity', 'MPA', (187, 195))	('luciferase activity', 'molecular_function', 'GO:0045289', ('89', '108'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('89', '108'))	('miR-150', 'Gene', '406942', (61, 68))	('luciferase activity', 'molecular_function', 'GO:0050248', ('89', '108'))	('5p', 'Chemical', '-', (150, 152))	('luciferase', 'Enzyme', (89, 99))	('luciferase activity', 'molecular_function', 'GO:0050397', ('89', '108'))	('miR-150', 'Gene', (142, 149))
10149	28697764	This repressive effect was abrogated by mutations of the miR-150-5p-binding seed region in linc00673 (Fig.	('abrogated', 'NegReg', (27, 36))	('miR-150', 'Gene', (57, 64))	('linc00673', 'Gene', (91, 100))	('mutations', 'Var', (40, 49))	('miR-150', 'Gene', '406942', (57, 64))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('5p', 'Chemical', '-', (65, 67))	('linc00673', 'Gene', '100499467', (91, 100))
10152	28697764	In consistent with previous results, linc00673 expression increased after transfected with miR-150-5p inhibitors while decreased after linc00673 knockdown (Fig.	('miR-150', 'Gene', (91, 98))	('decreased', 'NegReg', (119, 128))	('linc00673', 'Gene', (135, 144))	('knockdown', 'Var', (145, 154))	('increased', 'PosReg', (58, 67))	('miR-150', 'Gene', '406942', (91, 98))	('linc00673', 'Gene', (37, 46))	('5p', 'Chemical', '-', (99, 101))	('linc00673', 'Gene', '100499467', (135, 144))	('linc00673', 'Gene', '100499467', (37, 46))	('expression', 'MPA', (47, 57))
10164	28697764	Besides, although we observed promoted apoptosis after linc00673 knockdown in A549, the apoptosis level did not change in H1975 cells significantly.	('linc00673', 'Gene', (55, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('apoptosis', 'CPA', (39, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('promoted', 'PosReg', (30, 38))	('linc00673', 'Gene', '100499467', (55, 64))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('knockdown', 'Var', (65, 74))	('H1975', 'CellLine', 'CVCL:1511', (122, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))
10182	28697764	We found that high linc00673 expression predicted worse overall survival for NSCLC patients, and linc00673 knockdown reversed TGF-beta induced epithelial mesenchymal transition by sponging miR-150-5p and modulate ZEB1 expression indirectly.	('TGF-beta', 'Gene', (126, 134))	('modulate', 'Reg', (204, 212))	('5p', 'Chemical', '-', (197, 199))	('linc00673', 'Gene', '100499467', (97, 106))	('reversed', 'NegReg', (117, 125))	('miR-150', 'Gene', (189, 196))	('ZEB1', 'Gene', (213, 217))	('linc00673', 'Gene', '100499467', (19, 28))	('knockdown', 'Var', (107, 116))	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('overall survival', 'MPA', (56, 72))	('linc00673', 'Gene', (19, 28))	('patients', 'Species', '9606', (83, 91))	('NSCLC', 'Disease', (77, 82))	('linc00673', 'Gene', (97, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('143', '176'))	('TGF-beta', 'Gene', '7040', (126, 134))	('miR-150', 'Gene', '406942', (189, 196))	('worse', 'NegReg', (50, 55))	('ZEB1', 'Gene', '6935', (213, 217))	('SCLC', 'Phenotype', 'HP:0030357', (78, 82))	('expression', 'MPA', (218, 228))	('epithelial mesenchymal transition', 'CPA', (143, 176))
10203	28418844	Furthermore, in an analysis of listed mutations in 500 human protein kinases in 169 primary tumours and 40 cell lines, mutations in ATM emerged at number 3 in terms of frequency.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (55, 60))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('ATM ', 'Gene', '472', (132, 136))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (38, 47))	('mutations', 'Var', (119, 128))	('ATM ', 'Gene', (132, 136))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
10204	28418844	A large proportion of these mutations were found in lung cancers, which exhibited the highest rate of somatic ATM mutations of all tumours analyzed.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('found', 'Reg', (43, 48))	('lung cancers', 'Disease', (52, 64))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('ATM ', 'Gene', '472', (110, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung cancers', 'Disease', 'MESH:D008175', (52, 64))	('ATM ', 'Gene', (110, 114))	('mutations', 'Var', (28, 37))	('lung cancers', 'Phenotype', 'HP:0100526', (52, 64))
10209	28418844	We expect that somatic changes in ATM would lead to a loss of ATM expression that could be detected by quantifying the relative expression of ATM protein within the malignant versus the stromal component of the tumour - a concept introduced here as the ATM expression index (ATM-EI).	('ATM', 'Gene', '472', (62, 65))	('ATM', 'Gene', '472', (142, 145))	('changes', 'Var', (23, 30))	('ATM ', 'Gene', (253, 257))	('ATM', 'Gene', (34, 37))	('ATM', 'Gene', '472', (253, 256))	('ATM ', 'Gene', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('ATM', 'Gene', '472', (275, 278))	('tumour', 'Disease', (211, 217))	('ATM ', 'Gene', '472', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('ATM', 'Gene', (62, 65))	('ATM', 'Gene', (142, 145))	('ATM', 'Gene', (253, 256))	('ATM', 'Gene', (275, 278))	('ATM ', 'Gene', (34, 38))	('ATM ', 'Gene', '472', (142, 146))	('ATM', 'Gene', '472', (34, 37))	('ATM ', 'Gene', '472', (253, 257))	('loss', 'NegReg', (54, 58))	('ATM ', 'Gene', '472', (62, 66))	('ATM ', 'Gene', (142, 146))
10212	28418844	Furthermore, we present data suggesting that patients with low ATM-EI respond more positively to adjuvant chemotherapy.	('ATM', 'Gene', '472', (63, 66))	('positively', 'PosReg', (83, 93))	('patients', 'Species', '9606', (45, 53))	('low', 'Var', (59, 62))	('ATM', 'Gene', (63, 66))
10229	28418844	Median ATM expression in our NSCLC cohort was 4490 (Figure 1C, red line) and fell in the upper end of the normal lung epithelium 95% C.I., indicating moderate overexpression in tumour tissue.	('fell', 'NegReg', (77, 81))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('ATM ', 'Gene', '472', (7, 11))	('NSCLC', 'Disease', (29, 34))	('4490', 'Var', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('ATM ', 'Gene', (7, 11))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))
10269	28418844	The fact that relative ATM deficiency is seen in a proportion of stage I patients suggests that reduced ATM expression is an early event in NSCLC carcinogenesis and supports the hypothesis that tumour progression is associated with a disruption in the ATM-CHK2-p53 pathway in many human cancers, including lung cancer.	('NSCLC carcinogenesis', 'Disease', 'MESH:D063646', (140, 160))	('ATM ', 'Gene', (23, 27))	('ATM', 'Gene', '472', (252, 255))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('ATM', 'Gene', '472', (23, 26))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('ATM', 'Gene', (104, 107))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('reduced', 'NegReg', (96, 103))	('p53', 'Gene', '7157', (261, 264))	('tumour', 'Disease', (194, 200))	('CHK2', 'Gene', (256, 260))	('cancers', 'Phenotype', 'HP:0002664', (287, 294))	('ATM ', 'Gene', '472', (104, 108))	('cancers', 'Disease', (287, 294))	('lung cancer', 'Disease', (306, 317))	('ATM', 'Gene', (252, 255))	('p53', 'Gene', (261, 264))	('ATM', 'Gene', (23, 26))	('CHK2', 'Gene', '11200', (256, 260))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('disruption', 'Var', (234, 244))	('ATM ', 'Gene', (104, 108))	('patients', 'Species', '9606', (73, 81))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('ATM ', 'Gene', '472', (23, 27))	('ATM', 'Gene', '472', (104, 107))	('cancers', 'Disease', 'MESH:D009369', (287, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('human', 'Species', '9606', (281, 286))	('NSCLC carcinogenesis', 'Disease', (140, 160))
10270	28418844	Intriguingly, there was no clear association between ATM deficiency and smoking, perhaps indicating that disruption in the ATM-CHK2-p53 pathway is one of several mechanisms by which lung carcinogenesis can occur.	('ATM ', 'Gene', '472', (53, 57))	('disruption', 'Var', (105, 115))	('lung carcinogenesis', 'Disease', (182, 201))	('CHK2', 'Gene', (127, 131))	('ATM ', 'Gene', (53, 57))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('ATM', 'Gene', (53, 56))	('ATM', 'Gene', (123, 126))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (182, 201))	('CHK2', 'Gene', '11200', (127, 131))	('ATM', 'Gene', '472', (53, 56))	('ATM', 'Gene', '472', (123, 126))
10293	28418844	Slides were processed using a Dako Autostainer and incubated for 60 minutes with a cocktail of three primary antibodies, including: anti-pan-cytokeratin to identify tumour cells, anti-vimentin to identify stromal cells, and anti-ATM (described in Supplementary Table 1).	('anti-vimentin', 'Var', (179, 192))	('ATM ', 'Gene', (229, 233))	('vimentin', 'cellular_component', 'GO:0045099', ('184', '192'))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('vimentin', 'cellular_component', 'GO:0045098', ('184', '192'))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumour', 'Disease', (165, 171))	('anti-pan-cytokeratin', 'Var', (132, 152))	('ATM ', 'Gene', '472', (229, 233))
10302	27698794	Two novel susceptibility loci for non-small cell lung cancer map to low-density lipoprotein receptor-related protein 5 This study investigated the effect of single-nucleotide polymorphisms (SNPs) of low-density lipoprotein receptor-related protein 5 (LRP5) on the risk of developing non-small cell lung cancer (NSCLC).	('low-density lipoprotein receptor-related protein 5', 'Gene', (68, 118))	('low-density lipoprotein receptor-related protein 5', 'Gene', '4041', (199, 249))	('cell lung cancer', 'Disease', 'MESH:D008175', (44, 60))	('low-density lipoprotein', 'molecular_function', 'GO:0005322', ('68', '91'))	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('NSCLC', 'Phenotype', 'HP:0030358', (311, 316))	('single-nucleotide polymorphisms', 'Var', (157, 188))	('non-small cell lung cancer', 'Disease', (34, 60))	('LRP5', 'Gene', (251, 255))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (283, 309))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (287, 309))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('low-density lipoprotein receptor-related protein 5', 'Gene', '4041', (68, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (283, 309))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (34, 60))	('low-density lipoprotein receptor-related protein 5', 'Gene', (199, 249))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell lung cancer', 'Disease', 'MESH:D008175', (293, 309))	('NSCLC', 'Disease', 'MESH:D002289', (311, 316))	('low-density lipoprotein', 'molecular_function', 'GO:0005322', ('199', '222'))	('single-nucleotide', 'Chemical', '-', (157, 174))	('non-small cell lung cancer', 'Disease', (283, 309))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (34, 60))	('NSCLC', 'Disease', (311, 316))
10305	27698794	The frequency of the LRP5 rs3736228 T allele (18.9% in male NSCLC cases and 23.9% in male controls) was statistically different between male NSCLCs and male controls (P=0.03), and the T allele was associated with a lower risk of NSCLC (OR=0.74; 95% CI, 0.56-0.67), whereas the C/C homozygous genotype and the LRP5 rs64843 T/T genotype were associated with an increased risk of NSCLC and squamous cell carcinoma (SCC), respectively (OR=1.43 and 1.77, respectively).	('squamous cell carcinoma', 'Disease', (387, 410))	('rs64843 T/T', 'Var', (314, 325))	('rs3736228 T', 'Var', (26, 37))	('NSCLC', 'Disease', (229, 234))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('LRP5', 'Gene', (21, 25))	('T/T', 'Var', (322, 325))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('SCC', 'Phenotype', 'HP:0002860', (412, 415))	('NSCLC', 'Disease', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (387, 410))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))	('SCC', 'Gene', '6317', (412, 415))	('NSCLC', 'Disease', 'MESH:D002289', (377, 382))	('C/C', 'Var', (277, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (401, 410))	('NSCLC', 'Disease', (60, 65))	('SCC', 'Gene', (412, 415))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (387, 410))	('NSCLC', 'Disease', (377, 382))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (377, 382))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('rs64843', 'Mutation', 'rs64843', (314, 321))	('LRP5', 'Gene', (309, 313))	('rs3736228', 'Mutation', 'rs3736228', (26, 35))
10306	27698794	Using Haploview software, the frequency of the haplotypes of rs312009/rs3120015/rs3120014 CCC was was significantly higher in female SCC cases compared with female controls (0.064 vs. 0.009, P=0.04).	('SCC', 'Gene', '6317', (133, 136))	('rs3120014', 'Mutation', 'rs3120014', (80, 89))	('higher', 'PosReg', (116, 122))	('CCC', 'cellular_component', 'GO:0030896', ('90', '93'))	('rs312009/rs3120015/rs3120014 CCC', 'Var', (61, 93))	('rs312009', 'Mutation', 'rs312009', (61, 69))	('rs3120015', 'Mutation', 'rs3120015', (70, 79))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
10307	27698794	LRP5 rs3736228 and rs64843 SNPs were significantly associated with an increased risk of NSCLC and SCC, respectively.	('rs64843', 'Mutation', 'rs64843', (19, 26))	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('rs3736228', 'Var', (5, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('SCC', 'Gene', '6317', (98, 101))	('associated', 'Reg', (51, 61))	('NSCLC', 'Disease', (88, 93))	('LRP5', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('rs64843 SNPs', 'Var', (19, 31))	('rs3736228', 'Mutation', 'rs3736228', (5, 14))	('SCC', 'Gene', (98, 101))
10324	27698794	Thus, in this study, we hypothesized that LRP5 polymorphisms may play a role in susceptibility to NSCLC.	('polymorphisms', 'Var', (47, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('NSCLC', 'Disease', (98, 103))	('susceptibility', 'Reg', (80, 94))	('play', 'Reg', (65, 69))	('LRP5', 'Gene', (42, 46))
10336	27698794	All patients and controls were subjected to genotyping of 11 LRP5 tag SNPs (i.e., rs4930573, rs312009, rs312014, rs3781590, rs312015, rs491347, rs1784235, rs648438, rs3736228, rs624947 and rs607887).	('rs624947', 'Var', (176, 184))	('rs607887', 'Var', (189, 197))	('rs648438', 'Mutation', 'rs648438', (155, 163))	('rs624947', 'Mutation', 'rs624947', (176, 184))	('rs3736228', 'Mutation', 'rs3736228', (165, 174))	('rs312009', 'Var', (93, 101))	('rs1784235', 'Mutation', 'rs1784235', (144, 153))	('rs3736228', 'Var', (165, 174))	('rs3781590', 'Mutation', 'rs3781590', (113, 122))	('rs312015', 'Var', (124, 132))	('patients', 'Species', '9606', (4, 12))	('LRP5', 'Gene', (61, 65))	('rs312009', 'Mutation', 'rs312009', (93, 101))	('rs312015', 'Mutation', 'rs312015', (124, 132))	('rs648438', 'Var', (155, 163))	('rs491347', 'Mutation', 'rs491347', (134, 142))	('rs3781590', 'Var', (113, 122))	('rs1784235', 'Var', (144, 153))	('rs4930573', 'Var', (82, 91))	('rs491347', 'Var', (134, 142))	('rs312014', 'Mutation', 'rs312014', (103, 111))	('rs607887', 'Mutation', 'rs607887', (189, 197))	('rs312014', 'Var', (103, 111))	('rs4930573', 'Mutation', 'rs4930573', (82, 91))
10337	27698794	The frequency of the rs3736228 T allele was 18.9% and that of the C allele was 81.1% in the male NSCLC patients, whereas they were 23.9% and 76.1%, respectively, for the male controls (P=0.03).	('NSCLC', 'Disease', (97, 102))	('rs3736228', 'Mutation', 'rs3736228', (21, 30))	('patients', 'Species', '9606', (103, 111))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('rs3736228 T', 'Var', (21, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
10339	27698794	In contrast, the frequency of rs3736228 was similar between NSCLC patients and controls and between female NSCLC patients and female controls (P>0.05).	('rs3736228', 'Mutation', 'rs3736228', (30, 39))	('NSCLC', 'Disease', (107, 112))	('patients', 'Species', '9606', (113, 121))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('rs3736228', 'Var', (30, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('NSCLC', 'Disease', (60, 65))	('patients', 'Species', '9606', (66, 74))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
10340	27698794	The differences in allele frequencies in the other 10 Tag SNPs (i.e., rs4930573, rs312009, rs312014, rs3781590, rs312015, rs491347, rs1784235, rs648438, rs624947 and rs607887) between cases and controls, male patients and male controls, as well as female patients and female controls were not statistically significant (Table III).	('rs312015', 'Var', (112, 120))	('rs3781590', 'Var', (101, 110))	('rs607887', 'Var', (166, 174))	('rs312009', 'Mutation', 'rs312009', (81, 89))	('rs312015', 'Mutation', 'rs312015', (112, 120))	('rs491347', 'Mutation', 'rs491347', (122, 130))	('rs312014', 'Mutation', 'rs312014', (91, 99))	('rs624947', 'Var', (153, 161))	('rs312014', 'Var', (91, 99))	('rs648438', 'Var', (143, 151))	('rs624947', 'Mutation', 'rs624947', (153, 161))	('rs491347', 'Var', (122, 130))	('rs1784235', 'Var', (132, 141))	('rs4930573', 'Var', (70, 79))	('patients', 'Species', '9606', (255, 263))	('rs4930573', 'Mutation', 'rs4930573', (70, 79))	('patients', 'Species', '9606', (209, 217))	('rs607887', 'Mutation', 'rs607887', (166, 174))	('rs3781590', 'Mutation', 'rs3781590', (101, 110))	('rs648438', 'Mutation', 'rs648438', (143, 151))	('rs312009', 'Var', (81, 89))	('rs1784235', 'Mutation', 'rs1784235', (132, 141))
10341	27698794	For rs3736228 polymorphisms, logistic regression analysis revealed that the C/C major allele homozygote was associated with an increased risk of NSCLC in the male population (C/C frequencies were 64.9% and 56.4% in male NSCLC patients and controls, respectively; OR=1.43; 95% CI, 0.33-1.99; P=0.03; Table IV).	('C/C', 'Var', (76, 79))	('NSCLC', 'Disease', (220, 225))	('rs3736228', 'Mutation', 'rs3736228', (4, 13))	('NSCLC', 'Disease', (145, 150))	('rs3736228 polymorphisms', 'Var', (4, 27))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('polymorphisms', 'Var', (14, 27))	('patients', 'Species', '9606', (226, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))
10342	27698794	For rs64843 polymorphisms, the T/T major allele homozygote had a 1.77-fold greater risk of developing SCC compared with the C/C and C/T genotypes (95% CI, 1.02-3.04; P=0.04).	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('rs64843', 'Var', (4, 11))	('rs64843', 'Mutation', 'rs64843', (4, 11))	('SCC', 'Gene', (102, 105))
10344	27698794	Haploview software identified two blocks among NSCLCs, ADCs and controls, and male NSCLCs, male ADCs and male controls: the haplotypes were CG, TC and CC in Block 1 (the length of one block was 6 kb, including rs312009 and 3120015), and TTC, CCT and TTT in Block 2 (the length of the other block was 27 kb, including rs491347, rs1784235 and rs607887).	('CCT', 'Gene', '907', (242, 245))	('3120015', 'Var', (223, 230))	('NSCLC', 'Disease', (83, 88))	('rs607887', 'Var', (341, 349))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('rs1784235', 'Var', (327, 336))	('rs312009', 'Var', (210, 218))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('rs312009', 'Mutation', 'rs312009', (210, 218))	('NSCLC', 'Disease', (47, 52))	('rs1784235', 'Mutation', 'rs1784235', (327, 336))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('CCT', 'Gene', (242, 245))	('rs491347', 'Var', (317, 325))	('rs607887', 'Mutation', 'rs607887', (341, 349))	('rs491347', 'Mutation', 'rs491347', (317, 325))
10345	27698794	Two blocks were identified among female NSCLCs, female ADCs and female controls: the haplotypes were CG, TC and CC in Block 1 (the length of one block was 6 kb, including rs312009 and 3120015), and TTCC, CCTT, TTTC and TTTT in Block 3 (the length of the other block was 31 kb, including rs491347, rs1784235, rs607887 and rs3736228).	('rs3736228', 'Mutation', 'rs3736228', (321, 330))	('rs491347', 'Var', (287, 295))	('rs607887', 'Mutation', 'rs607887', (308, 316))	('CCT', 'Gene', '907', (204, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('rs491347', 'Mutation', 'rs491347', (287, 295))	('rs3736228', 'Var', (321, 330))	('rs607887', 'Var', (308, 316))	('rs1784235', 'Var', (297, 306))	('rs1784235', 'Mutation', 'rs1784235', (297, 306))	('rs312009', 'Mutation', 'rs312009', (171, 179))	('NSCLC', 'Disease', (40, 45))	('CCT', 'Gene', (204, 207))	('rs312009', 'Var', (171, 179))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
10346	27698794	Two blocks were identified among SCCs and controls, and male SCCs and male controls: the haplotypes were CGC, TCG, CCG and CGG in Block 4 (the length of one block was 7 kb, including rs312009, rs3120014 and rs3120015), and TTC, CCT and TTT in Block 2 (the length of the other block was 27 kb, including rs491347, rs1784235 and rs607887).	('rs3120015', 'Var', (207, 216))	('rs3120014', 'Var', (193, 202))	('rs312009', 'Mutation', 'rs312009', (183, 191))	('SCC', 'Gene', '6317', (61, 64))	('rs3120015', 'Mutation', 'rs3120015', (207, 216))	('SCC', 'Gene', (61, 64))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('rs491347', 'Mutation', 'rs491347', (303, 311))	('TCG', 'Chemical', '-', (110, 113))	('rs1784235', 'Var', (313, 322))	('CCT', 'Gene', '907', (228, 231))	('rs491347', 'Var', (303, 311))	('rs607887', 'Mutation', 'rs607887', (327, 335))	('SCC', 'Gene', '6317', (33, 36))	('rs3120014', 'Mutation', 'rs3120014', (193, 202))	('SCC', 'Gene', (33, 36))	('rs607887', 'Var', (327, 335))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('rs312009', 'Var', (183, 191))	('rs1784235', 'Mutation', 'rs1784235', (313, 322))	('CCT', 'Gene', (228, 231))
10347	27698794	Two blocks were identified among female SCCs and female controls: the haplotypes were CGC, TCG, CCG, CGG and CCC in Block 4 (the length of one block was 7 kb, including rs312009, rs3120015 and rs3120014), and TTCC, CCTT, TTTC and TTTT in Block 3 (the length of the other block was 31 kb, including rs491347, rs1784235, rs607887 and rs3736228).	('rs3120014', 'Var', (193, 202))	('rs491347', 'Var', (298, 306))	('CCT', 'Gene', '907', (215, 218))	('rs312009', 'Mutation', 'rs312009', (169, 177))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))	('rs3736228', 'Mutation', 'rs3736228', (332, 341))	('rs3120015', 'Var', (179, 188))	('rs3736228', 'Var', (332, 341))	('rs1784235', 'Mutation', 'rs1784235', (308, 317))	('rs3120015', 'Mutation', 'rs3120015', (179, 188))	('SCC', 'Gene', '6317', (40, 43))	('TCG', 'Chemical', '-', (91, 94))	('rs3120014', 'Mutation', 'rs3120014', (193, 202))	('rs607887', 'Mutation', 'rs607887', (319, 327))	('SCC', 'Gene', (40, 43))	('CCT', 'Gene', (215, 218))	('rs491347', 'Mutation', 'rs491347', (298, 306))	('rs312009', 'Var', (169, 177))	('CCC', 'cellular_component', 'GO:0030896', ('109', '112'))	('rs1784235', 'Var', (308, 317))	('rs607887', 'Var', (319, 327))
10348	27698794	Among these results, only the frequency of haplotypes rs312009/rs3120015/rs3120014 CCC were significantly higher in female SCC patients vs. female controls (0.064 vs. 0.009; P=0.04; Table VI).	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('rs312009/rs3120015/rs3120014', 'Var', (54, 82))	('rs312009', 'Mutation', 'rs312009', (54, 62))	('SCC', 'Gene', '6317', (123, 126))	('rs3120015', 'Mutation', 'rs3120015', (63, 72))	('higher', 'PosReg', (106, 112))	('patients', 'Species', '9606', (127, 135))	('CCC', 'cellular_component', 'GO:0030896', ('83', '86'))	('rs3120014', 'Mutation', 'rs3120014', (73, 82))	('SCC', 'Gene', (123, 126))
10349	27698794	In the current study, we investigated the association between LRP5 polymorphisms and NSCLC risk.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('association', 'Interaction', (42, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('polymorphisms', 'Var', (67, 80))	('LRP5', 'Gene', (62, 66))
10350	27698794	We observed that LRP5 rs3736228 and rs648438 polymorphisms were strongly associated with the risk of NSCLC and lung SCC.	('SCC', 'Gene', (116, 119))	('rs3736228', 'Mutation', 'rs3736228', (22, 31))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('NSCLC', 'Disease', (101, 106))	('rs3736228', 'Var', (22, 31))	('SCC', 'Gene', '6317', (116, 119))	('rs648438', 'Mutation', 'rs648438', (36, 44))	('associated', 'Reg', (73, 83))	('LRP5', 'Gene', (17, 21))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('rs648438', 'Var', (36, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
10351	27698794	Based on this finding, rs3736228 and rs648438 are two novel susceptibility loci that were associated with an increased risk of developing NSCLC in this Chinese male population.	('NSCLC', 'Disease', (138, 143))	('rs3736228', 'Var', (23, 32))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('associated', 'Reg', (90, 100))	('rs648438', 'Mutation', 'rs648438', (37, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('rs648438', 'Var', (37, 45))	('rs3736228', 'Mutation', 'rs3736228', (23, 32))
10352	27698794	To the best of our knowledge, this is the first study describing the association of rs3736228 and rs648438 SNPs with NSCLC risk in humans.	('humans', 'Species', '9606', (131, 137))	('NSCLC', 'Disease', (117, 122))	('rs3736228', 'Var', (84, 93))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('association', 'Interaction', (69, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('rs648438 SNPs', 'Var', (98, 111))	('rs648438', 'Mutation', 'rs648438', (98, 106))	('rs3736228', 'Mutation', 'rs3736228', (84, 93))
10355	27698794	Moreover, dominant-negative LRP5 inhibits the growth and metastasis of osteosarcoma in animal models and reduces the expression of cancer cell invasion-associated markers (including N-cadherin, Snail and matrix metalloprotease-2).	('cancer', 'Disease', (131, 137))	('cadherin', 'molecular_function', 'GO:0008014', ('184', '192'))	('N-cadherin', 'Gene', (182, 192))	('metastasis of osteosarcoma', 'Disease', (57, 83))	('expression', 'MPA', (117, 127))	('metastasis of osteosarcoma', 'Disease', 'MESH:D009362', (57, 83))	('LRP5', 'Gene', (28, 32))	('dominant-negative', 'Var', (10, 27))	('N-cadherin', 'Gene', '1000', (182, 192))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('matrix', 'Protein', (204, 210))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('inhibits', 'NegReg', (33, 41))	('reduces', 'NegReg', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('Snail', 'Gene', '6615', (194, 199))	('Snail', 'Gene', (194, 199))
10356	27698794	In the current study, we analyzed rs3736228 and rs648438 SNPs, which are localized in the region of the LRP5 gene on 11q13.2.	('rs648438', 'Mutation', 'rs648438', (48, 56))	('rs648438', 'Var', (48, 56))	('rs3736228', 'Mutation', 'rs3736228', (34, 43))	('rs3736228', 'Var', (34, 43))	('LRP5', 'Gene', (104, 108))
10359	27698794	By selecting the Tag SNPs across the LRP5 gene from the HapMap CHB database using the approach of Carlson et al, the criteria for the selection of Tag SNPs enabled us to maximize the power to detect SNPs (the statistical power of our study was >80%); thus, 11 SNPs were selected and two SNPs (rs3736228 and rs648438) were associated with NSCLC risk, which indicated that this methodology is useful in identifying susceptibility loci for NSCLC.	('rs3736228', 'Var', (293, 302))	('rs648438', 'Mutation', 'rs648438', (307, 315))	('associated with', 'Reg', (322, 337))	('NSCLC', 'Phenotype', 'HP:0030358', (437, 442))	('NSCLC', 'Disease', (338, 343))	('LRP5', 'Gene', (37, 41))	('rs648438', 'Var', (307, 315))	('NSCLC', 'Disease', 'MESH:D002289', (338, 343))	('NSCLC', 'Disease', (437, 442))	('rs3736228', 'Mutation', 'rs3736228', (293, 302))	('NSCLC', 'Disease', 'MESH:D002289', (437, 442))	('NSCLC', 'Phenotype', 'HP:0030358', (338, 343))
10360	27698794	Furthermore, rs3736228 is a SNP in LRP5, which is also known as Ala1330Val or A1330V; the more common C allele encodes Ala, while the rarer T allele encodes Val, and the latter is the risk allele.	('Ala1330Val', 'SUBSTITUTION', 'None', (64, 74))	('A1330V', 'SUBSTITUTION', 'None', (78, 84))	('Ala1330Val', 'Var', (64, 74))	('rs3736228', 'Mutation', 'rs3736228', (13, 22))	('LRP5', 'Gene', (35, 39))	('Val', 'Chemical', 'MESH:D014633', (71, 74))	('Ala', 'Chemical', 'MESH:D000409', (119, 122))	('Ala', 'Chemical', 'MESH:D000409', (64, 67))	('rs3736228', 'Var', (13, 22))	('Val', 'Chemical', 'MESH:D014633', (157, 160))	('A1330V', 'Var', (78, 84))
10361	27698794	In the LRP5 gene, a C T transition at rs3736228 results in a substitution of Val for Ala, and this transition significantly decreases the response to canonical Wnt signaling.	('substitution', 'MPA', (61, 73))	('rs3736228', 'Mutation', 'rs3736228', (38, 47))	('decreases', 'NegReg', (124, 133))	('rs3736228', 'Var', (38, 47))	('response to canonical Wnt signaling', 'MPA', (138, 173))	('Ala', 'Chemical', 'MESH:D000409', (85, 88))	('Val', 'Chemical', 'MESH:D014633', (77, 80))	('Val for Ala', 'MPA', (77, 88))	('LRP5', 'Gene', (7, 11))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))
10362	27698794	Published data have identified that polymorphisms of rs3736228 are associated with a decrease in bone mineral density in postmenopausal Maya-mestizo females, Mexican females, healthy fertile French females, Japanese male workers, Chinese patients, and Chinese patients with osteoporosis.	('polymorphisms', 'Var', (36, 49))	('osteoporosis', 'Phenotype', 'HP:0000939', (274, 286))	('rs3736228', 'Var', (53, 62))	('patients', 'Species', '9606', (260, 268))	('decrease', 'NegReg', (85, 93))	('decrease in bone mineral density', 'Phenotype', 'HP:0004349', (85, 117))	('bone mineral density', 'CPA', (97, 117))	('osteoporosis', 'Disease', 'MESH:D010024', (274, 286))	('osteoporosis', 'Disease', (274, 286))	('patients', 'Species', '9606', (238, 246))	('rs3736228', 'Mutation', 'rs3736228', (53, 62))
10363	27698794	However, to date, there are no studies describing an association between rs3736228 polymorphisms and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('rs3736228', 'Mutation', 'rs3736228', (73, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('rs3736228', 'Var', (73, 82))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
10364	27698794	In the present study, we noted that individuals with the rs3736228 C allele had a lower risk of developing NSCLC compared with those carrying the T allele.	('rs3736228', 'Mutation', 'rs3736228', (57, 66))	('NSCLC', 'Disease', (107, 112))	('rs3736228 C', 'Var', (57, 68))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))
10365	27698794	Compared with the C/C homozygote, other genotypes (C/T and T/T) had a greater risk of developing NSCLC in the male population, but not in the female population.	('NSCLC', 'Disease', (97, 102))	('C/T', 'Var', (51, 54))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
10366	27698794	Polymorphisms of rs3736228 have a combined effect with cigarette smoking; people that smoke cigarettes (current and former smokers) with rs3736228 polymorphisms have a 4.1-fold greater (95% CI, 1.6-10.2) risk of having metabolic syndrome.	('rs3736228 polymorphisms', 'Var', (137, 160))	('polymorphisms', 'Var', (147, 160))	('rs3736228', 'Mutation', 'rs3736228', (17, 26))	('greater', 'PosReg', (177, 184))	('people', 'Species', '9606', (74, 80))	('metabolic syndrome', 'Disease', 'MESH:D008659', (219, 237))	('metabolic syndrome', 'Disease', (219, 237))	('rs3736228', 'Mutation', 'rs3736228', (137, 146))
10368	27698794	Our results suggest that, among smokers, East Asian males with the rs3736228 SNP have a higher susceptibility to develop NSCLC.	('rs3736228', 'Var', (67, 76))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('develop', 'PosReg', (113, 120))	('rs3736228', 'Mutation', 'rs3736228', (67, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
10369	27698794	Another potential susceptibility locus for NSLCL risk was determined to be rs648438 in our current study.	('NSLCL', 'Disease', (43, 48))	('rs648438', 'Var', (75, 83))	('rs648438', 'Mutation', 'rs648438', (75, 83))
10370	27698794	Rs648438 is located in the intron region of LRP5, which has not been reported to be associated with any diseases.	('LRP5', 'Gene', (44, 48))	('Rs648438', 'Var', (0, 8))	('Rs648438', 'Mutation', 'Rs648438', (0, 8))
10371	27698794	The present study reveals that an rs648438 polymorphism was associated with lung SCC development in males carrying at least one C allele (C/C and C/T) compared with those carrying the T/T homozygote.	('SCC', 'Gene', '6317', (81, 84))	('rs648438', 'Var', (34, 42))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('rs648438', 'Mutation', 'rs648438', (34, 42))	('associated with', 'Reg', (60, 75))
10373	27698794	The current data indicated that among smokers, East Asian males with rs648438 had a higher susceptibility of developing SCC.	('rs648438', 'Mutation', 'rs648438', (69, 77))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('rs648438', 'Var', (69, 77))	('SCC', 'Gene', '6317', (120, 123))	('SCC', 'Gene', (120, 123))
10382	33379141	At the plasma membrane level, HPF prevents cytosol alkalization and extracellular acidification by allowing protons to re-enter the cells.	('HPF', 'Chemical', 'MESH:C001654', (30, 33))	('extracellular', 'cellular_component', 'GO:0005576', ('68', '81'))	('cytosol alkalization', 'MPA', (43, 63))	('cytosol', 'cellular_component', 'GO:0005829', ('43', '50'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('7', '22'))	('HPF', 'Var', (30, 33))	('protons', 'MPA', (108, 115))	('acidification', 'biological_process', 'GO:0045851', ('82', '95'))	('prevents', 'NegReg', (34, 42))	('extracellular acidification', 'MPA', (68, 95))	('allowing', 'Reg', (99, 107))
10391	33379141	Oncogenesis involves dysregulation of proto-oncogenes or tumor suppressor genes, which upon mutation can modify key cellular processes linked to cell proliferation and its control.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('mutation', 'Var', (92, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('modify', 'Reg', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Oncogenesis', 'Disease', (0, 11))	('proto-oncogenes', 'Gene', (38, 53))	('Oncogenesis', 'biological_process', 'GO:0007048', ('0', '11'))	('dysregulation', 'Var', (21, 34))	('rat', 'Species', '10116', (157, 160))	('cell proliferation', 'CPA', (145, 163))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))
10422	33379141	However, if ROS amount exceeds a certain threshold, serious damages occur in cells, like DNA deletions, insertions, single- and double-strand breaks that, if not repaired, might lead to either tumor transformation or cell death.	('DNA', 'Gene', (89, 92))	('lead to', 'Reg', (178, 185))	('cell death', 'biological_process', 'GO:0008219', ('217', '227'))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cell death', 'CPA', (217, 227))	('insertions', 'Var', (104, 114))	('deletions', 'Var', (93, 102))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('tumor', 'Disease', (193, 198))
10424	33379141	When the Deltapsim is high, like in cancer cells, the electron transfer is slowed down, as protons have to be pumped against an enhanced electrochemical force, so that an electron leakage and, consequently, high ROS production are favored (Figure 1).	('slowed down', 'NegReg', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('ROS', 'Chemical', 'MESH:D017382', (212, 215))	('Deltapsim', 'Var', (9, 18))	('ROS production', 'MPA', (212, 226))	('electron leakage', 'MPA', (171, 187))	('cancer', 'Disease', (36, 42))	('electron transfer', 'MPA', (54, 71))	('electron transfer', 'biological_process', 'GO:0006118', ('54', '71'))	('favored', 'PosReg', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('electron transfer', 'biological_process', 'GO:0022904', ('54', '71'))	('protons', 'MPA', (91, 98))
10426	33379141	In this regard, tumor cells have a more negative mitochondrial membrane potential inside the matrix (Deltapsim ~ -210 mV), than normal cells (Deltapsim ~ -140 mV) (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mitochondrial membrane potential', 'MPA', (49, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Deltapsim ~ -210 mV', 'Var', (101, 120))	('tumor', 'Disease', (16, 21))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('49', '71'))	('negative', 'NegReg', (40, 48))
10431	33379141	Thus, H2O2 can operate as a bona fide second messenger for the intracellular transduction signaling of hormones, growth factors, cytokines and other inflammatory mediators, by oxidizing the thiol groups of cysteine residues of target proteins, including tyrosine phosphatases (PTPs).	('rat', 'Species', '10116', (18, 21))	('tyrosine', 'Chemical', 'MESH:D014443', (254, 262))	('H2O2', 'Var', (6, 10))	('P', 'Chemical', 'MESH:D010758', (277, 278))	('thiol', 'Chemical', 'MESH:D013438', (190, 195))	('transduction', 'biological_process', 'GO:0009293', ('77', '89'))	('thiol groups', 'MPA', (190, 202))	('P', 'Chemical', 'MESH:D010758', (279, 280))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('oxidizing', 'MPA', (176, 185))	('H2O2', 'Chemical', 'MESH:D006861', (6, 10))	('cysteine', 'Chemical', 'MESH:D003545', (206, 214))	('intracellular', 'cellular_component', 'GO:0005622', ('63', '76'))
10437	33379141	At the same time, cancer cells can utilize ROS signaling to enhance growth by promoting the activity of pro-survival kinases (i.e., PI3K, Akt, ERK1/2, mTOR).	('ERK1', 'molecular_function', 'GO:0004707', ('143', '147'))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('pro-survival', 'biological_process', 'GO:0043066', ('104', '116'))	('P', 'Chemical', 'MESH:D010758', (132, 133))	('cancer', 'Disease', (18, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('132', '136'))	('growth', 'MPA', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('enhance', 'PosReg', (60, 67))	('mTOR', 'Gene', (151, 155))	('ERK1/2', 'Gene', (143, 149))	('ERK1/2', 'Gene', '5595;5594', (143, 149))	('Akt', 'Gene', (138, 141))	('ROS signaling', 'MPA', (43, 56))	('Akt', 'Gene', '207', (138, 141))	('activity', 'MPA', (92, 100))	('mTOR', 'Gene', '2475', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('PI3K', 'Var', (132, 136))	('promoting', 'PosReg', (78, 87))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))
10447	33379141	Indeed, although it has been well documented that polyphenols and other natural compounds are able to inhibit tumorigenesis and tumor growth in several animal models, a putative ROS-dependent pro-oxidant mechanism in such in vivo inhibition has not been elucidated yet.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('polyphenols', 'Var', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ROS', 'Chemical', 'MESH:D017382', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inhibit', 'NegReg', (102, 109))	('tumor', 'Disease', (128, 133))	('polyphenols', 'Chemical', 'MESH:D059808', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
10455	33379141	Importantly, both pharmacological and phytochemical inhibitors of these channels were found to revert or at least attenuate the malignant phenotype of cancer cells, suggesting that a crucial role is played by pH and ion concentration changes in tumor development, as reviewed in.	('rat', 'Species', '10116', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', (151, 157))	('attenuate', 'NegReg', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', (245, 250))	('inhibitors', 'Var', (52, 62))
10457	33379141	In this way, pH dysregulation can simultaneously modify charge and function of many protein targets, facilitating gain- or loss-of-function of mutated proteins as it occurs in the R337H substitution of the tumor suppressor p53 in cancer.	('loss-of-function', 'NegReg', (123, 139))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('R337H', 'Mutation', 'p.R337H', (180, 185))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('R337H', 'Var', (180, 185))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('charge', 'MPA', (56, 62))	('gain-', 'PosReg', (114, 119))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor suppressor', 'biological_process', 'GO:0051726', ('206', '222'))	('modify', 'Reg', (49, 55))	('function', 'MPA', (67, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('206', '222'))
10486	33379141	Moreover, it should be stressed that HPF is able to induce long-lasting changes in the cell signaling and transcriptional pathways even after being withdrawn from the cell culture medium following a pre-incubation period.	('transcriptional pathways', 'Pathway', (106, 130))	('HPF', 'Chemical', 'MESH:C001654', (37, 40))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('pre', 'molecular_function', 'GO:0003904', ('199', '202'))	('HPF', 'Var', (37, 40))	('cell signaling', 'Pathway', (87, 101))	('changes', 'Reg', (72, 79))
10492	33379141	In our laboratory, we observed that, in pancreatic beta cells as well as in rat and human pancreatic islets, SJW and HPF are able to markedly inhibit both IFN-gamma-elicited STAT-1 and TNF-alpha/IL-1beta-triggered NF-kappaB activities, leading to prevention of iNOS gene expression and protection against beta-cell damage.	('gene expression', 'biological_process', 'GO:0010467', ('266', '281'))	('SJW', 'Chemical', '-', (109, 112))	('iNOS gene', 'Gene', (261, 270))	('inhibit', 'NegReg', (142, 149))	('IFN-gamma', 'Gene', '3458', (155, 164))	('IFN-gamma', 'Gene', (155, 164))	('rat', 'Species', '10116', (76, 79))	('STAT-1', 'Gene', '6772', (174, 180))	('activities', 'MPA', (224, 234))	('human', 'Species', '9606', (84, 89))	('rat', 'Species', '10116', (11, 14))	('HPF', 'Chemical', 'MESH:C001654', (117, 120))	('SJW', 'Var', (109, 112))	('STAT-1', 'Gene', (174, 180))	('prevention', 'NegReg', (247, 257))	('IL-1', 'molecular_function', 'GO:0005149', ('195', '199'))
10496	33379141	Additionally, 1 microM HPF triggers differentiation in primary cultures of human keratinocytes and in derived HaCaT cell lines and inhibits their proliferation.	('rat', 'Species', '10116', (83, 86))	('HPF', 'Chemical', 'MESH:C001654', (23, 26))	('proliferation', 'CPA', (146, 159))	('rat', 'Species', '10116', (153, 156))	('HPF', 'Var', (23, 26))	('triggers', 'Reg', (27, 35))	('inhibits', 'NegReg', (131, 139))	('differentiation', 'CPA', (36, 51))	('human', 'Species', '9606', (75, 80))	('HaCaT', 'CellLine', 'CVCL:0038', (110, 115))
10517	33379141	Indeed, the ability of HPF to increase proton conductance of plasmatic and organelle membranes was firstly disclosed by Roz and Rehavi to explain its inhibitory action on neurotransmitter reuptake by a non-competitive mechanism.	('HPF', 'Chemical', 'MESH:C001654', (23, 26))	('HPF', 'Var', (23, 26))	('neurotransmitter reuptake', 'biological_process', 'GO:0098810', ('171', '196'))	('organelle', 'cellular_component', 'GO:0043226', ('75', '84'))	('increase', 'PosReg', (30, 38))	('neurotransmitter reuptake', 'MPA', (171, 196))
10522	33379141	observed that HPF, likewise the protonophore and uncoupler FCCP, cause a concentration-dependent drop in the mitochondrial membrane potential.	('rat', 'Species', '10116', (80, 83))	('drop', 'NegReg', (97, 101))	('mitochondrial membrane potential', 'MPA', (109, 141))	('FCCP', 'Chemical', 'MESH:D002259', (59, 63))	('HPF', 'Chemical', 'MESH:C001654', (14, 17))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('109', '131'))	('HPF', 'Var', (14, 17))
10523	33379141	Thus, HPF is also able to affect mitochondrial function, as well as mitochondrial (mt)ROS production.	('ROS', 'Chemical', 'MESH:D017382', (86, 89))	('affect', 'Reg', (26, 32))	('HPF', 'Chemical', 'MESH:C001654', (6, 9))	('HPF', 'Var', (6, 9))	('mitochondrial function', 'MPA', (33, 55))
10525	33379141	As already mentioned, HPF suppresses 5-LO and COX-1 activity and PGE2 production both in human whole blood at low concentrations range (0.03-2 microM) and in a number of in vivo models.	('human', 'Species', '9606', (89, 94))	('5-LO and', 'MPA', (37, 45))	('HPF', 'Var', (22, 25))	('suppresses', 'NegReg', (26, 36))	('COX-1', 'Gene', '4512', (46, 51))	('COX-1', 'Gene', (46, 51))	('PGE2', 'Chemical', 'MESH:D015232', (65, 69))	('PGE2 production', 'MPA', (65, 80))	('HPF', 'Chemical', 'MESH:C001654', (22, 25))	('rat', 'Species', '10116', (121, 124))
10530	33379141	Actually, the anti-genotoxic ability of HPF has been verified by measuring the amount of bacterial gene mutations (Ames' test), the occurrence of DNA strand breaks in human lymphocytes (comet assay) and the induction of chromosome aberrations in a mammalian cell line.	('chromosome aberrations', 'CPA', (220, 242))	('bacterial gene', 'Gene', (89, 103))	('mutations', 'Var', (104, 113))	('rat', 'Species', '10116', (235, 238))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('human', 'Species', '9606', (167, 172))	('chromosome', 'cellular_component', 'GO:0005694', ('220', '230'))	('HPF', 'Chemical', 'MESH:C001654', (40, 43))	('mammalian', 'Species', '9606', (248, 257))
10536	33379141	In fact, intracellular alkalization was detected in rat hepatic epithelial F258 cells quickly upon exposure to B[a]P, resulting in alteration of pH dynamics in different cell compartments including mitochondria and affecting mitochondrial function.	('rat', 'Species', '10116', (52, 55))	('alteration', 'Reg', (131, 141))	('affecting', 'Reg', (215, 224))	('mitochondria', 'MPA', (198, 210))	('rat', 'Species', '10116', (135, 138))	('B[a]P', 'Var', (111, 116))	('B[a]P', 'Chemical', 'MESH:D001564', (111, 116))	('pH dynamics in different cell compartments', 'MPA', (145, 187))	('F258', 'CellLine', 'CVCL:L976', (75, 79))	('mitochondria', 'cellular_component', 'GO:0005739', ('198', '210'))	('mitochondrial function', 'MPA', (225, 247))	('intracellular', 'cellular_component', 'GO:0005622', ('9', '22'))
10542	33379141	In this model, at molecular level, it has been observed that NF-kappaB and ERK1/2 pathways are hampered by SJW, with a reduction in the mRNA expression level of NF-kappaB-elicited genes, such as TNF-alpha, IL-1beta, MMP-7 and -9 and iNOS.	('mRNA expression level', 'MPA', (136, 157))	('TNF-alpha', 'Gene', (195, 204))	('SJW', 'Var', (107, 110))	('MMP-7', 'molecular_function', 'GO:0004235', ('216', '221'))	('IL-1', 'molecular_function', 'GO:0005149', ('206', '210'))	('ERK1', 'molecular_function', 'GO:0004707', ('75', '79'))	('ERK1/2', 'Gene', (75, 81))	('ERK1/2', 'Gene', '5595;5594', (75, 81))	('hampered', 'NegReg', (95, 103))	('SJW', 'Chemical', '-', (107, 110))	('reduction', 'NegReg', (119, 128))	('NF-kappaB', 'Pathway', (61, 70))	('MMP-7 and -9', 'Gene', '4316;4318', (216, 228))
10545	33379141	Mechanistically, DPI decreases ROS production in the colon, resulting in inhibition of TNF-alpha, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production, as well as ERK1/2, STAT-3 and NF-kappaB signaling, finally exerting a strong anti-inflammatory effect.	('inhibition', 'NegReg', (73, 83))	('monocyte chemoattractant protein-1', 'Gene', '6347', (107, 141))	('ROS production', 'MPA', (31, 45))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('decreases', 'NegReg', (21, 30))	('decreases ROS production', 'Phenotype', 'HP:0025464', (21, 45))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('MCP-1) production', 'biological_process', 'GO:0071605', ('143', '160'))	('IL-6', 'Gene', '3569', (98, 102))	('signaling', 'biological_process', 'GO:0023052', ('202', '211'))	('MCP', 'molecular_function', 'GO:0004298', ('143', '146'))	('DPI', 'Chemical', 'MESH:C007517', (17, 20))	('ERK1/2', 'Gene', (173, 179))	('IL-6', 'Gene', (98, 102))	('TNF-alpha', 'MPA', (87, 96))	('ERK1/2', 'Gene', '5595;5594', (173, 179))	('ERK1', 'molecular_function', 'GO:0004707', ('173', '177'))	('NF-kappaB', 'MPA', (192, 201))	('monocyte chemoattractant protein-1', 'Gene', (107, 141))	('IL-6', 'molecular_function', 'GO:0005138', ('98', '102'))	('DPI', 'Var', (17, 20))
10547	33379141	It is meaningful to remark that the presence of HPF in SJW extract can affect the pharmacokinetics of many co-administered drugs by inducing a number of liver cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C19, CYP2D2.	('CYP3A4', 'Gene', '1576', (199, 205))	('CYP', 'Gene', '4051', (216, 219))	('CYP2C19', 'Gene', (207, 214))	('CYP', 'Gene', '4051', (176, 179))	('CYP3A4', 'Gene', (199, 205))	('CYP', 'Gene', '4051', (207, 210))	('CYP2C19', 'Gene', '1557', (207, 214))	('HPF', 'Chemical', 'MESH:C001654', (48, 51))	('CYP', 'Gene', '4051', (199, 202))	('pharmacokinetics', 'MPA', (82, 98))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('159', '174'))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('159', '174'))	('cytochrome P450', 'Gene', (159, 174))	('presence', 'Var', (36, 44))	('CYP', 'Gene', (216, 219))	('inducing', 'Reg', (132, 140))	('CYP', 'Gene', (176, 179))	('CYP', 'Gene', (207, 210))	('CYP3A4', 'molecular_function', 'GO:0033780', ('199', '205'))	('affect', 'Reg', (71, 77))	('SJW extract', 'Chemical', '-', (55, 66))	('cytochrome P450', 'Gene', '4051', (159, 174))	('CYP', 'Gene', (199, 202))
10550	33379141	Nevertheless, at variance of most in vitro studies showing carcinogen activation by CYPs, in vivo experiments performed after gene deletion of P450 isozymes have often revealed that these metabolizing enzymes have a major role in detoxification rather than activation of carcinogens.	('gene deletion', 'Var', (126, 139))	('CYP', 'Gene', (84, 87))	('rat', 'Species', '10116', (245, 248))	('CYP', 'Gene', '4051', (84, 87))	('P', 'Chemical', 'MESH:D010758', (143, 144))	('P450', 'Enzyme', (143, 147))	('P', 'Chemical', 'MESH:D010758', (86, 87))	('detoxification', 'MPA', (230, 244))	('detoxification', 'biological_process', 'GO:0098754', ('230', '244'))
10561	33379141	When tumor has already grown, SJW and HPF can still exert therapeutic effects by down-modulating survival signaling and/or inducing apoptosis.	('apoptosis', 'CPA', (132, 141))	('SJW', 'Chemical', '-', (30, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('down-modulating', 'NegReg', (81, 96))	('survival signaling', 'Pathway', (97, 115))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('HPF', 'Chemical', 'MESH:C001654', (38, 41))	('SJW', 'Var', (30, 33))	('tumor', 'Disease', (5, 10))	('inducing', 'Reg', (123, 131))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
10562	33379141	Remarkably, in rats injected subcutaneously with MT-450 breast cancer cells and administered HPF daily at the site of the cell transfer, in vivo tumor growth was inhibited in the absence of any side effect.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MT-450', 'Chemical', '-', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('breast cancer', 'Disease', (56, 69))	('tumor', 'Disease', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('MT-450', 'Var', (49, 55))	('HPF', 'Chemical', 'MESH:C001654', (93, 96))	('inhibited', 'NegReg', (162, 171))	('rats', 'Species', '10116', (15, 19))
10566	33379141	reported that in two glioblastoma cell lines, HPF prompts apoptosis, increase of cytosolic [Ca2+], loss of Deltapsim, suppression of EGFR/ERK/NF-kappaB signaling, and decrease of anti-apoptotic proteins expression.	('glioblastoma', 'Disease', (21, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('EGFR', 'Gene', '1956', (133, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('cytosolic [Ca2+]', 'MPA', (81, 97))	('anti-apoptotic', 'MPA', (179, 193))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))	('ERK', 'Gene', (138, 141))	('increase', 'PosReg', (69, 77))	('suppression', 'NegReg', (118, 129))	('loss', 'NegReg', (99, 103))	('ERK', 'molecular_function', 'GO:0004707', ('138', '141'))	('HPF', 'Chemical', 'MESH:C001654', (46, 49))	('HPF', 'Var', (46, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('apoptosis', 'CPA', (58, 67))	('EGFR', 'Gene', (133, 137))	('decrease', 'NegReg', (167, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('Deltapsim', 'Protein', (107, 116))	('ERK', 'Gene', '5594', (138, 141))
10567	33379141	also showed that HPF can directly impair viability of mitochondria isolated from HL-60 cells by affecting mitochondrial proton-motive force.	('impair', 'NegReg', (34, 40))	('HPF', 'Chemical', 'MESH:C001654', (17, 20))	('HL-60', 'CellLine', 'CVCL:0002', (81, 86))	('viability', 'CPA', (41, 50))	('affecting', 'Reg', (96, 105))	('HPF', 'Var', (17, 20))	('mitochondria', 'cellular_component', 'GO:0005739', ('54', '66'))	('mitochondrial proton-motive force', 'MPA', (106, 139))
10568	33379141	Again, in hepatocellular carcinoma cell line, HPF significantly inhibits cell viability and cyclin D1 expression and induces loss of Deltapsim and downregulation of the anti-apoptotic proteins fetal liver LKB1 interacting protein c (c-FLIP), X linked inhibitor of apoptosis protein (XIAP) and myeloid leukemia cell differentiation protein (Mcl-1), finally triggering apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('367', '376'))	('apoptosis', 'biological_process', 'GO:0006915', ('367', '376'))	('loss', 'NegReg', (125, 129))	('hepatocellular carcinoma', 'Disease', (10, 34))	('XIAP', 'Gene', (283, 287))	('c-FLIP', 'Gene', '8837', (233, 239))	('myeloid leukemia', 'Disease', 'MESH:D007951', (293, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (293, 309))	('leukemia', 'Phenotype', 'HP:0001909', (301, 309))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('Mcl-1', 'Gene', (340, 345))	('cell viability', 'CPA', (73, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('protein', 'cellular_component', 'GO:0003675', ('331', '338'))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('HPF', 'Chemical', 'MESH:C001654', (46, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (10, 34))	('Deltapsim', 'Protein', (133, 142))	('HPF', 'Var', (46, 49))	('cyclin', 'molecular_function', 'GO:0016538', ('92', '98'))	('downregulation', 'NegReg', (147, 161))	('cyclin D1', 'Gene', (92, 101))	('XIAP', 'Gene', '331', (283, 287))	('c-FLIP', 'Gene', (233, 239))	('protein', 'cellular_component', 'GO:0003675', ('274', '281'))	('cyclin D1', 'Gene', '595', (92, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (10, 34))	('expression', 'MPA', (102, 112))	('myeloid leukemia', 'Disease', (293, 309))	('inhibits', 'NegReg', (64, 72))	('cell differentiation', 'biological_process', 'GO:0030154', ('310', '330'))	('Mcl-1', 'Gene', '4170', (340, 345))	('X linked inhibitor of apoptosis protein', 'Gene', '331', (242, 281))	('X linked inhibitor of apoptosis protein', 'Gene', (242, 281))
10571	33379141	In fact, HPF-induced severe dissipation of Deltapsim provokes pore formation and Cyt c release, sensitizing cancer cells to death.	('Deltapsim', 'Protein', (43, 52))	('pore formation', 'MPA', (62, 76))	('pore formation', 'biological_process', 'GO:0046931', ('62', '76'))	('Cyt c release', 'MPA', (81, 94))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('pore', 'cellular_component', 'GO:0046930', ('62', '66'))	('sensitizing', 'Reg', (96, 107))	('HPF', 'Chemical', 'MESH:C001654', (9, 12))	('provokes', 'Reg', (53, 61))	('severe dissipation', 'Var', (21, 39))
10573	33379141	As reported above, mitochondrial membranes incorporate lipophilic HPF, so that, while in normal condition the inner membrane is impervious to protons, in the presence of HPF, protons can shuttle into the matrix following their concentration and electric gradients (as described in Figure 2), with consequent breakdown of Deltapsim.	('breakdown', 'biological_process', 'GO:0009056', ('308', '317'))	('shuttle into the', 'MPA', (187, 203))	('protons', 'MPA', (175, 182))	('HPF', 'Var', (170, 173))	('rat', 'Species', '10116', (50, 53))	('HPF', 'Chemical', 'MESH:C001654', (66, 69))	('Deltapsim', 'MPA', (321, 330))	('rat', 'Species', '10116', (234, 237))	('membrane', 'cellular_component', 'GO:0016020', ('116', '124'))	('breakdown', 'NegReg', (308, 317))	('HPF', 'Chemical', 'MESH:C001654', (170, 173))
10585	33379141	show that HPF inhibits Akt kinase activity, determining dephosphorylation of Bad, an Akt substrate, and activation of its pro-apoptotic function.	('rat', 'Species', '10116', (94, 97))	('activation', 'PosReg', (104, 114))	('inhibits', 'NegReg', (14, 22))	('pro-apoptotic function', 'MPA', (122, 144))	('Akt', 'Gene', '207', (85, 88))	('Akt', 'Gene', '207', (23, 26))	('kinase activity', 'molecular_function', 'GO:0016301', ('27', '42'))	('HPF', 'Chemical', 'MESH:C001654', (10, 13))	('dephosphorylation', 'MPA', (56, 73))	('Akt', 'Gene', (23, 26))	('Akt', 'Gene', (85, 88))	('HPF', 'Var', (10, 13))	('dephosphorylation', 'biological_process', 'GO:0016311', ('56', '73'))
10590	33379141	HPF induces apoptosis in the B-CLL cells by eliciting a drop in mitochondrial transmembrane potential and activation of caspase 3.	('transmembrane', 'cellular_component', 'GO:0044214', ('78', '91'))	('transmembrane', 'cellular_component', 'GO:0016021', ('78', '91'))	('mitochondrial transmembrane potential', 'MPA', (64, 101))	('drop', 'NegReg', (56, 60))	('HPF', 'Chemical', 'MESH:C001654', (0, 3))	('apoptosis', 'biological_process', 'GO:0006915', ('12', '21'))	('caspase 3', 'Gene', (120, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('12', '21'))	('activation', 'PosReg', (106, 116))	('HPF', 'Var', (0, 3))	('caspase 3', 'Gene', '836', (120, 129))
10591	33379141	In this study, the anti-apoptotic factors Bcl-2 and Mcl-1 as well as the protein expressions of iNOS and p27kip1b are downregulated.	('Bcl-2', 'Gene', (42, 47))	('Bcl-2', 'Gene', '596', (42, 47))	('Mcl-1', 'Gene', '4170', (52, 57))	('iNOS', 'Gene', (96, 100))	('anti-apoptotic factors', 'CPA', (19, 41))	('Bcl-2', 'molecular_function', 'GO:0015283', ('42', '47'))	('protein expressions', 'MPA', (73, 92))	('Mcl-1', 'Gene', (52, 57))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('downregulated', 'NegReg', (118, 131))	('p27kip1b', 'Var', (105, 113))
10603	33379141	Alike other protonophore, HPF elicits proton influx in tumor cells restoring cytosolic acidity and allowing apoptosis.	('proton influx', 'MPA', (38, 51))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('HPF', 'Chemical', 'MESH:C001654', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('HPF', 'Var', (26, 29))	('cytosolic acidity', 'MPA', (77, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('restoring', 'PosReg', (67, 76))	('tumor', 'Disease', (55, 60))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('elicits', 'Reg', (30, 37))	('apoptosis', 'CPA', (108, 117))
10608	33379141	At the present state of our knowledge, the hypothesis that HPF can change the proton flux in function of the proton gradient could explain why HPF is not cytotoxic for normal cells, whereas it can induce apoptosis in cancer cells.	('induce', 'Reg', (197, 203))	('proton flux in function of the proton gradient', 'MPA', (78, 124))	('HPF', 'Chemical', 'MESH:C001654', (143, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('HPF', 'Chemical', 'MESH:C001654', (59, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('HPF', 'Var', (143, 146))	('change', 'Reg', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('apoptosis', 'CPA', (204, 213))
10609	33379141	In cancer cells, both at the plasma membrane level, in which DeltapH favors high proton influx, and at the hyperpolarized inner mitochondria membrane, the presence of HPF could counteract malignant phenotype, or at higher concentration, promote cell death by collapsing inner mitochondrial membrane.	('mitochondria', 'cellular_component', 'GO:0005739', ('128', '140'))	('presence', 'Var', (155, 163))	('membrane', 'cellular_component', 'GO:0016020', ('141', '149'))	('inner mitochondrial membrane', 'cellular_component', 'GO:0005743', ('270', '298'))	('high proton influx', 'MPA', (76, 94))	('HPF', 'Chemical', 'MESH:C001654', (167, 170))	('inner mitochondrial membrane', 'MPA', (270, 298))	('rat', 'Species', '10116', (229, 232))	('promote', 'PosReg', (237, 244))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('plasma membrane', 'cellular_component', 'GO:0005886', ('29', '44'))	('DeltapH', 'Var', (61, 68))	('cancer', 'Disease', (3, 9))	('collapsing', 'NegReg', (259, 269))	('cell death', 'CPA', (245, 255))	('cell death', 'biological_process', 'GO:0008219', ('245', '255'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
10612	33379141	On the other hand, activated AMPK stabilizes the tumor suppressor p53 favoring cellular sensitization to mitochondrial apoptosis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('sensitization', 'biological_process', 'GO:0046960', ('88', '101'))	('p53', 'Gene', '7157', (66, 69))	('AMPK', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cellular sensitization to mitochondrial apoptosis', 'MPA', (79, 128))	('stabilizes', 'Var', (34, 44))	('AMPK', 'Gene', '5564', (29, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('tumor', 'Disease', (49, 54))	('AMPK', 'molecular_function', 'GO:0050405', ('29', '33'))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('AMPK', 'molecular_function', 'GO:0004691', ('29', '33'))	('AMPK', 'molecular_function', 'GO:0047322', ('29', '33'))	('p53', 'Gene', (66, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
10618	33379141	showed that HPF can inhibit angiogenesis both in bovine aortic endothelial (BAE) cells in vitro and in chorioallantoid membrane in vivo.	('angiogenesis', 'biological_process', 'GO:0001525', ('28', '40'))	('HPF', 'Var', (12, 15))	('bovine', 'Species', '9913', (49, 55))	('membrane', 'cellular_component', 'GO:0016020', ('119', '127'))	('angiogenesis', 'CPA', (28, 40))	('inhibit', 'NegReg', (20, 27))	('HPF', 'Chemical', 'MESH:C001654', (12, 15))
10619	33379141	HPF also inhibits MMP-2 and urokinase secretion from BAE cells and restrains their invasive capability in a Matrigel layer.	('invasive capability in a Matrigel layer', 'CPA', (83, 122))	('restrains', 'NegReg', (67, 76))	('HPF', 'Chemical', 'MESH:C001654', (0, 3))	('secretion', 'biological_process', 'GO:0046903', ('38', '47'))	('inhibits', 'NegReg', (9, 17))	('MMP-2', 'molecular_function', 'GO:0004228', ('18', '23'))	('MMP-2', 'Protein', (18, 23))	('HPF', 'Var', (0, 3))
10622	33379141	Lorusso et al., using hyperforin-DCHA in human umbilical vascular endothelial cells (HUVEC), showed that HPF induces cytostatic but not cytotoxic effects, significantly reducing HUVEC cell migration triggered by chemoattractant stimuli.	('HPF', 'Chemical', 'MESH:C001654', (105, 108))	('hyperforin-DCHA', 'Chemical', '-', (22, 37))	('human', 'Species', '9606', (41, 46))	('HPF', 'Var', (105, 108))	('cell migration', 'biological_process', 'GO:0016477', ('184', '198'))	('rat', 'Species', '10116', (192, 195))	('HUVEC', 'CellLine', 'CVCL:2959', (178, 183))	('reducing', 'NegReg', (169, 177))	('HUVEC', 'CellLine', 'CVCL:2959', (85, 90))	('HUVEC cell migration', 'CPA', (178, 198))
10623	33379141	Again, the authors showed that in the presence of 1-3 microM HPF, the chemokine-elicited migration of neutrophils and monocytes as well as the TNF-alpha-stimulated nuclear translocation of NF-kappaB were markedly inhibited in HUVEC cells.	('HUVEC', 'CellLine', 'CVCL:2959', (226, 231))	('nuclear translocation', 'MPA', (164, 185))	('HPF', 'Chemical', 'MESH:C001654', (61, 64))	('inhibited', 'NegReg', (213, 222))	('rat', 'Species', '10116', (92, 95))	('chemokine-elicited migration of neutrophils', 'CPA', (70, 113))	('HPF', 'Var', (61, 64))	('NF-kappaB', 'Protein', (189, 198))
10643	33379141	Furthermore, non-cytotoxic HPF concentrations can hinder cell invasiveness by downregulating the activities of MMP-2 and -9, elastase and cathepsin G, highly expressed in inflammatory and tumor cells.	('tumor', 'Disease', (188, 193))	('elastase', 'Enzyme', (125, 133))	('cell invasiveness', 'CPA', (57, 74))	('MMP-2', 'molecular_function', 'GO:0004228', ('111', '116'))	('cathepsin G', 'Gene', (138, 149))	('HPF', 'Chemical', 'MESH:C001654', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('activities', 'MPA', (97, 107))	('MMP-2 and -9', 'Gene', '4313;4318', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('concentrations', 'Var', (31, 45))	('rat', 'Species', '10116', (38, 41))	('downregulating', 'NegReg', (78, 92))	('hinder', 'NegReg', (50, 56))	('cathepsin G', 'Gene', '1511', (138, 149))
10658	33379141	The HPF ability to drop off mitochondrial membrane hyperpolarization and consequently mtROS generation inhibits cell proliferation and favors apoptosis induction.	('mitochondrial membrane hyperpolarization', 'MPA', (28, 68))	('cell proliferation', 'CPA', (112, 130))	('mtROS', 'Var', (86, 91))	('rat', 'Species', '10116', (124, 127))	('drop off', 'NegReg', (19, 27))	('favors', 'PosReg', (135, 141))	('membrane hyperpolarization', 'biological_process', 'GO:0060081', ('42', '68'))	('HPF', 'Chemical', 'MESH:C001654', (4, 7))	('inhibits', 'NegReg', (103, 111))	('apoptosis induction', 'CPA', (142, 161))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('rat', 'Species', '10116', (96, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('28', '50'))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))
10661	33379141	Thus, low doses of SJW/HPF, likely insufficient to induce cancer cell death, can nevertheless block ROS-elicited tumor growth and spread by hindering activity of pro-survival protein kinases and angiogenesis.	('SJW', 'Chemical', '-', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('angiogenesis', 'biological_process', 'GO:0001525', ('195', '207'))	('block', 'NegReg', (94, 99))	('pro-survival', 'biological_process', 'GO:0043066', ('162', '174'))	('spread', 'CPA', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('activity', 'MPA', (150, 158))	('tumor', 'Disease', (113, 118))	('HPF', 'Chemical', 'MESH:C001654', (23, 26))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('protein kinases', 'Enzyme', (175, 190))	('SJW/HPF', 'Var', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('hindering', 'NegReg', (140, 149))	('angiogenesis', 'CPA', (195, 207))	('cancer', 'Disease', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
10664	33379141	Additionally, SJW/HPF, acting against different types of tumor cells, can be a broad-spectrum anti-tumor compound and should be tested in association with current chemotherapy drugs to achieve additive effects.	('SJW/HPF', 'Var', (14, 21))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('HPF', 'Chemical', 'MESH:C001654', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SJW', 'Chemical', '-', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (57, 62))
10677	33479213	We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability.	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('EGFR', 'Gene', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ZFHX3', 'Gene', '463', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('patients', 'Species', '9606', (151, 159))	('ZFHX3', 'Gene', (28, 33))	('tumor', 'Disease', (200, 205))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('brain tumor', 'Disease', (65, 76))	('lung', 'Disease', (50, 54))	('mutations', 'Var', (179, 188))	('brain tumor', 'Disease', 'MESH:D001932', (65, 76))	('tumor', 'Disease', (71, 76))	('brain tumor', 'Phenotype', 'HP:0030692', (65, 76))
10689	33479213	Tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangements, targetable mutant genes commonly used to guide personalized targeted therapies for primary lung tumor, has shown high response rates for BM.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (91, 110))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('38', '61'))	('mutation', 'Var', (78, 86))	('anaplastic lymphoma kinase', 'Gene', (91, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'Gene', '1956', (72, 76))	('epidermal growth factor receptor', 'Gene', (38, 70))	('ALK', 'Gene', (119, 122))	('lung tumor', 'Disease', (231, 241))	('epidermal growth factor receptor', 'Gene', '1956', (38, 70))	('lung tumor', 'Disease', 'MESH:D008175', (231, 241))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('EGFR', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('ALK', 'Gene', '238', (119, 122))	('lung tumor', 'Phenotype', 'HP:0100526', (231, 241))	('anaplastic lymphoma kinase', 'Gene', '238', (91, 117))
10694	33479213	A recently published genomic characterization demonstrated clonally dominant and nearly universal genetic variations of BM and matched diverse primary tumor samples.	('genetic variations', 'Var', (98, 116))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))
10709	33479213	EGFR and TP53 mutations affected 71% (n = 17) of total.	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
10710	33479213	Of these, 4 had EGFR/TP53 co-mutations, less than those with exclusive EGFR or TP53.	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('co-mutations', 'Var', (26, 38))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('EGFR', 'Gene', (71, 75))	('EGFR', 'Gene', (16, 20))	('TP53', 'Gene', '7157', (21, 25))
10713	33479213	EGFR and TP53 mutations affected 72% (n = 23) of patients.	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('affected', 'Reg', (24, 32))	('patients', 'Species', '9606', (49, 57))	('EGFR', 'Gene', '1956', (0, 4))
10714	33479213	Of them, increased EGFR/TP53 co-mutations (n = 8, 25%), although with no statistical difference compared to primary tumor.	('co-mutations', 'Var', (29, 41))	('TP53', 'Gene', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('increased', 'PosReg', (9, 18))	('EGFR', 'Gene', '1956', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EGFR', 'Gene', (19, 23))	('tumor', 'Disease', (116, 121))	('TP53', 'Gene', '7157', (24, 28))
10723	33479213	Fourteen (58%) had shared mutations with inconsistent CCF in primary tumor or BM (Fig.	('tumor', 'Disease', (69, 74))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
10726	33479213	RBM10, LRP1B, and EPAS1 mutations were all subclonal in lung tumors and BMs (Fig.	('lung tumors', 'Phenotype', 'HP:0100526', (56, 67))	('lung tumors', 'Disease', (56, 67))	('lung tumor', 'Phenotype', 'HP:0100526', (56, 66))	('BMs', 'Disease', (72, 75))	('EPAS1', 'Gene', '2034', (18, 23))	('LRP1B', 'Gene', (7, 12))	('lung tumors', 'Disease', 'MESH:D008175', (56, 67))	('EPAS1', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('RBM10', 'Gene', '8241', (0, 5))	('mutations', 'Var', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RBM10', 'Gene', (0, 5))	('LRP1B', 'Gene', '53353', (7, 12))
10741	33479213	Seven cases (85.7%) were PD-L1 bi-positive in lung and BM and 17 bi-negative cases (Fig.	('PD-L1', 'Gene', '29126', (25, 30))	('PD-L1', 'Gene', (25, 30))	('bi-positive', 'Var', (31, 42))
10751	33479213	Considering the influences of the dominant pathological type of adenocarcinoma and most of the patients with EGFR mutations receiving EGFR-TKI targeted therapy after BM resection, we classified patients into TKI (n = 12, 100% LUAD) and non-TKI (n = 15) groups to further assess the clinical and molecular factors.	('patients', 'Species', '9606', (194, 202))	('EGFR', 'Gene', (134, 138))	('adenocarcinoma', 'Disease', (64, 78))	('mutations', 'Var', (114, 123))	('patients', 'Species', '9606', (95, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('EGFR', 'Gene', '1956', (109, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('EGFR', 'Gene', (109, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('EGFR', 'Gene', '1956', (134, 138))
10752	33479213	Within TKI group, patients with ZFH3X mutation, higher Shannon index, and higher MOI between lung tumor and BM had poor outcome, while higher TCR clonality and more CD8+ TILs indicated prolonged OS and lower hazard ratio (Fig.	('TCR', 'Gene', (142, 145))	('hazard ratio', 'MPA', (208, 220))	('lung tumor', 'Disease', 'MESH:D008175', (93, 103))	('Shannon index', 'MPA', (55, 68))	('lower', 'NegReg', (202, 207))	('TCR', 'cellular_component', 'GO:0042101', ('142', '145'))	('lung tumor', 'Phenotype', 'HP:0100526', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CD8', 'Gene', (165, 168))	('higher', 'PosReg', (48, 54))	('CD8', 'Gene', '925', (165, 168))	('TCR', 'Gene', '6962', (142, 145))	('patients', 'Species', '9606', (18, 26))	('TCR', 'biological_process', 'GO:0006283', ('142', '145'))	('higher', 'PosReg', (135, 141))	('ZFH3X mutation', 'Var', (32, 46))	('lung tumor', 'Disease', (93, 103))
10759	33479213	Those clonal mutations with the highest CCF in both primary and brain tumors indicated the retention of dominance during the evolutionary process, while those mutations with inconsistent CCF suggested genetic selection events of tumor clone.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('brain tumors', 'Disease', 'MESH:D001932', (64, 76))	('brain tumors', 'Phenotype', 'HP:0030692', (64, 76))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('brain tumor', 'Phenotype', 'HP:0030692', (64, 75))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (229, 234))	('brain tumors', 'Disease', (64, 76))	('retention', 'biological_process', 'GO:0051235', ('91', '100'))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
10764	33479213	In addition, subclonal LRP1B and EPAS1 enriched in lung tumor with synchronous BM indicated the relation of lung cancer with the risk of synchronous BM.	('EPAS1', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung tumor', 'Disease', 'MESH:D008175', (51, 61))	('lung tumor', 'Phenotype', 'HP:0100526', (51, 61))	('LRP1B', 'Gene', '53353', (23, 28))	('relation', 'Reg', (96, 104))	('subclonal', 'Var', (13, 22))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('EPAS1', 'Gene', '2034', (33, 38))	('LRP1B', 'Gene', (23, 28))	('lung tumor', 'Disease', (51, 61))
10769	33479213	Correspondingly, in our cohort, LUADs carrying the ZFHX3 mutation and receiving EGFR-TKI had a higher risk of death.	('mutation', 'Var', (57, 65))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('ZFHX3', 'Gene', '463', (51, 56))	('death', 'Disease', 'MESH:D003643', (110, 115))	('ZFHX3', 'Gene', (51, 56))	('death', 'Disease', (110, 115))
10770	33479213	These results provided pieces of evidence of the relation of ZFHX3 and BM and worse outcome of mutant patients.	('ZFHX3', 'Gene', (61, 66))	('patients', 'Species', '9606', (102, 110))	('ZFHX3', 'Gene', '463', (61, 66))	('mutant', 'Var', (95, 101))
10783	33479213	BM ZFHX3 mutation, CD8+ TILs, and TCR clonality level were potential factors of prognostic stratification for the surgery of oligometastatic brain tumor.	('mutation', 'Var', (9, 17))	('CD8', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CD8', 'Gene', '925', (19, 22))	('TCR', 'biological_process', 'GO:0006283', ('34', '37'))	('ZFHX3', 'Gene', '463', (3, 8))	('ZFHX3', 'Gene', (3, 8))	('oligometastatic brain tumor', 'Disease', (125, 152))	('TCR', 'Gene', '6962', (34, 37))	('oligometastatic brain tumor', 'Disease', 'MESH:D001932', (125, 152))	('brain tumor', 'Phenotype', 'HP:0030692', (141, 152))	('TCR', 'Gene', (34, 37))	('TCR', 'cellular_component', 'GO:0042101', ('34', '37'))
10808	33066157	The development of cancer is a multistage process that begins with genetic alteration and is followed by abnormal cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('114', '132'))	('genetic alteration', 'Var', (67, 85))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (105, 132))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cell proliferation', 'CPA', (114, 132))	('men', 'Species', '9606', (11, 14))
10809	33066157	Carcinogenesis is strictly related to the activation of oncogenes (induction of cell growth) and the inactivation of tumor suppressor genes (repression of cell growth), resulting in a loss of control of cell cycle progression.	('Carcinogenesis', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('control', 'MPA', (192, 199))	('tumor', 'Disease', (117, 122))	('loss', 'NegReg', (184, 188))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('cell growth', 'biological_process', 'GO:0016049', ('155', '166'))	('activation', 'PosReg', (42, 52))	('control of cell cycle progression', 'biological_process', 'GO:0051726', ('192', '225'))	('inactivation', 'Var', (101, 113))	('oncogenes', 'Gene', (56, 65))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cell cycle progression', 'CPA', (203, 225))
10810	33066157	This initiation stage is followed by progression related to additive mutation within cells, some of which are implicated in even more rapid growth, and the suppression of cancer cell death.	('death', 'Disease', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cell death', 'biological_process', 'GO:0008219', ('178', '188'))	('cancer', 'Disease', (171, 177))	('additive mutation', 'Var', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('death', 'Disease', 'MESH:D003643', (183, 188))
10811	33066157	As a result of these changes, mature epithelial cancer cells may undergo epithelial-mesenchymal transition (EMT), which is characterized by the reduction of adhesion among cells and increased cell motility.	('cell motility', 'biological_process', 'GO:0048870', ('192', '205'))	('increased', 'PosReg', (182, 191))	('EMT', 'biological_process', 'GO:0001837', ('108', '111'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epithelial cancer', 'Phenotype', 'HP:0031492', (37, 54))	('cell motility', 'CPA', (192, 205))	('epithelial-mesenchymal transition', 'CPA', (73, 106))	('adhesion among', 'CPA', (157, 171))	('undergo', 'Reg', (65, 72))	('changes', 'Var', (21, 28))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('reduction', 'NegReg', (144, 153))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('73', '106'))
10830	33066157	Cancer occurs by a series of successive mutations in the relevant genes, leading to changes in cell function.	('cell function', 'MPA', (95, 108))	('changes', 'Reg', (84, 91))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
10831	33066157	Various physical and chemical factors play an obvious role in the formation of gene mutations and the appearance of cancer cells.	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gene mutations', 'Var', (79, 93))
10845	33066157	Among others, important common driver gene mutations in patients with NSCLC are as follows: tumor suppressor genes TP53 and PTEN; EGFR, which encodes protein, is involved in cell growth and survival.	('patients', 'Species', '9606', (56, 64))	('PTEN', 'Gene', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('EGFR', 'Gene', (130, 134))	('PTEN', 'Gene', '5728', (124, 128))	('NSCLC', 'Disease', (70, 75))	('cell growth', 'biological_process', 'GO:0016049', ('174', '185'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TP53', 'Gene', (115, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('EGFR', 'Gene', '1956', (130, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('TP53', 'Gene', '7157', (115, 119))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (92, 97))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))
10851	33066157	In turn, mutations in the BRCA1 and BRCA2 genes cause as much as 80% of genetic breast cancer.	('BRCA1', 'Gene', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('mutations', 'Var', (9, 18))	('genetic breast cancer', 'Disease', 'MESH:D001943', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('BRCA2', 'Gene', (36, 41))	('cause', 'Reg', (48, 53))	('genetic breast cancer', 'Disease', (72, 93))	('BRCA1', 'Gene', '672', (26, 31))	('BRCA2', 'Gene', '675', (36, 41))
10859	33066157	Inherited mutations in specific genes, such as BRCA1, BRCA2, and HOXB13, are the cause of some hereditary prostate cancer cases.	('cause', 'Reg', (81, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('HOXB13', 'Gene', (65, 71))	('BRCA1', 'Gene', (47, 52))	('BRCA1', 'Gene', '672', (47, 52))	('hereditary prostate cancer', 'Disease', (95, 121))	('hereditary prostate cancer', 'Disease', 'MESH:C537243', (95, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BRCA2', 'Gene', (54, 59))	('HOXB13', 'Gene', '10481', (65, 71))	('mutations', 'Var', (10, 19))	('BRCA2', 'Gene', '675', (54, 59))
10861	33066157	Men with mutations in these genes are at high risk of developing prostate cancer and, in some cases, other cancers during their lifetime.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (9, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('Men', 'Species', '9606', (0, 3))
10862	33066157	Additionally, other different genes have been implicated in prostate cancer by genetic alteration, depending on types (familial, sporadic, hereditary): TP53, PTEN, and protooncogenes MYC, which also constitute molecular targets for compounds from the Lamiaceae family.	('MYC', 'Gene', '4609', (183, 186))	('prostate cancer', 'Disease', (60, 75))	('implicated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('MYC', 'Gene', (183, 186))	('TP53', 'Gene', '7157', (152, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('TP53', 'Gene', (152, 156))	('PTEN', 'Gene', (158, 162))	('PTEN', 'Gene', '5728', (158, 162))	('alteration', 'Var', (87, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
10865	33066157	Colorectal cancer has been attributed to a number of mutations: mutational inactivation of tumor suppressor genes such as TP53, and activation of the oncogene pathway PI3K.	('TP53', 'Gene', (122, 126))	('activation', 'PosReg', (132, 142))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('oncogene pathway PI3K', 'Pathway', (150, 171))	('mutational inactivation', 'Var', (64, 87))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Colorectal cancer', 'Disease', (0, 17))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('TP53', 'Gene', '7157', (122, 126))	('tumor', 'Disease', (91, 96))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
10866	33066157	Genetically, colorectal cancer is divided into three categories: sporadic (about 60%) for patients with no family history, family (about 30%) for patients with at least one relative with colorectal cancer or adenoma, and hereditary forms (about 10%) due to the germline inheritance of mutations.	('colorectal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (285, 294))	('adenoma', 'Disease', (208, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('colorectal cancer', 'Disease', (13, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (146, 154))	('adenoma', 'Disease', 'MESH:D000236', (208, 215))
10888	33066157	Polyphenols are believed to cause cancer cell death by apoptosis through several mechanisms, such as DNA fragmentation, alteration of the level of apoptotic proteins, and mitochondrial membrane potential and cell cycle arrest.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('level of apoptotic proteins', 'MPA', (138, 165))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('101', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('death', 'Disease', (46, 51))	('arrest', 'Disease', (219, 225))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (208, 225))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('171', '193'))	('mitochondrial membrane potential', 'CPA', (171, 203))	('Polyphenols', 'Chemical', 'MESH:D059808', (0, 11))	('alteration', 'Reg', (120, 130))	('death', 'Disease', 'MESH:D003643', (46, 51))	('men', 'Species', '9606', (109, 112))	('arrest', 'Disease', 'MESH:D006323', (219, 225))	('Polyphenols', 'Var', (0, 11))	('DNA fragmentation', 'CPA', (101, 118))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('cancer', 'Disease', (34, 40))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('208', '225'))
10911	33066157	Satureja khuzistanica extract enriched with rosmarinic acid was found to increase the size of the apoptotic sub-G0/G1 population in MCF-7 cells.	('increase', 'PosReg', (73, 81))	('rosmarinic acid', 'Var', (44, 59))	('rosmarinic acid', 'Chemical', 'MESH:C041376', (44, 59))	('Satureja khuzistanica', 'Species', '1114304', (0, 21))	('MCF-7', 'CellLine', 'CVCL:0031', (132, 137))	('apoptotic sub-G0/G1 population', 'CPA', (98, 128))
10932	33066157	The insertion of Bax/Bak into the mitochondrial membrane results in the formation of a pore complex and release of cytochrome c into the cytosol from the intermembrane space.	('cytochrome c', 'molecular_function', 'GO:0045155', ('115', '127'))	('cytochrome c', 'Gene', (115, 127))	('cytosol', 'cellular_component', 'GO:0005829', ('137', '144'))	('results in', 'Reg', (57, 67))	('insertion', 'Var', (4, 13))	('formation of a pore complex', 'MPA', (72, 99))	('cytochrome c', 'Gene', '54205', (115, 127))	('cytochrome c', 'molecular_function', 'GO:0009461', ('115', '127'))	('Bax', 'Gene', (17, 20))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('pore complex', 'cellular_component', 'GO:0046930', ('87', '99'))	('Bak', 'Gene', (21, 24))	('Bak', 'Gene', '578', (21, 24))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('34', '56'))	('Bax', 'Gene', '581', (17, 20))
10948	33066157	Caspase-8 induction was found to induce apoptosis in MCF-7 and HCT-116 cells following Micromeria fruticose aerial part extract administration, as well as treatment with Vitex rotundifolia leaf extract in T-47D cells, Stachys pilifera leaf extract in the HT-29 cell line, and for Teucrium chamaedrys aerial flowering part extract in SW480 cells.	('apoptosis', 'CPA', (40, 49))	('Vitex rotundifolia', 'Species', '413484', (170, 188))	('flowering', 'biological_process', 'GO:0010228', ('307', '316'))	('SW480', 'CellLine', 'CVCL:0546', (333, 338))	('Caspase-8', 'Gene', '841', (0, 9))	('fruticose', 'Chemical', '-', (98, 107))	('flowering', 'Species', '3398', (307, 316))	('men', 'Species', '9606', (160, 163))	('MCF-7', 'CellLine', 'CVCL:0031', (53, 58))	('HT-29', 'CellLine', 'CVCL:0320', (255, 260))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('T-47D', 'CellLine', 'CVCL:0553', (205, 210))	('Micromeria', 'Species', '306389', (87, 97))	('Caspase-8', 'Gene', (0, 9))	('Stachys pilifera', 'Species', '1541664', (218, 234))	('induction', 'Var', (10, 19))	('Teucrium chamaedrys', 'Species', '53176', (280, 299))	('HCT-116', 'CellLine', 'CVCL:0291', (63, 70))
10960	33066157	DNA damage occurs due to metabolic processes and environmental factors including ROS and results in an increase in the levels of tumor suppressor protein p53.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('129', '145'))	('increase', 'PosReg', (103, 111))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('men', 'Species', '9606', (56, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('129', '145'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p53', 'Gene', (154, 157))	('ROS', 'Var', (81, 84))	('p53', 'Gene', '7157', (154, 157))	('tumor', 'Disease', (129, 134))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
10970	33066157	That PI3K signaling cascade induces protein kinase B, which is also known as PKB or Akt.	('signaling cascade', 'biological_process', 'GO:0007165', ('10', '27'))	('Akt', 'Gene', '207', (84, 87))	('PI3K signaling', 'biological_process', 'GO:0014065', ('5', '19'))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('protein kinase B', 'Gene', (36, 52))	('Akt', 'Gene', (84, 87))	('induces', 'Reg', (28, 35))	('PI3K', 'Var', (5, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('5', '9'))	('PKB', 'Gene', '207', (77, 80))	('protein kinase B', 'Gene', '2185', (36, 52))	('PKB', 'Gene', (77, 80))
10974	33066157	Akt may inactivate mammalian target of rapamycin complex 1 (mTORC1), p70S6 kinase, and p21, which are known to stimulate cell growth and proliferation.	('mTORC1', 'Gene', '382056', (60, 66))	('p21', 'Gene', (87, 90))	('mammalian', 'MPA', (19, 28))	('p70S6', 'Var', (69, 74))	('mTORC1', 'Gene', (60, 66))	('p21', 'Gene', '644914', (87, 90))	('Akt', 'Gene', '207', (0, 3))	('cell growth', 'biological_process', 'GO:0016049', ('121', '132'))	('mTORC1', 'cellular_component', 'GO:0031931', ('60', '66'))	('stimulate', 'PosReg', (111, 120))	('target of rapamycin complex', 'cellular_component', 'GO:0038201', ('29', '56'))	('Akt', 'Gene', (0, 3))	('cell growth', 'CPA', (121, 132))	('inactivate', 'NegReg', (8, 18))
11002	33066157	The first elongation step involves the enrollment of numerous autophagy-related (Atg) proteins by PI3P.	('men', 'Species', '9606', (45, 48))	('autophagy', 'biological_process', 'GO:0016236', ('62', '71'))	('enrollment', 'MPA', (39, 49))	('PI3P', 'Var', (98, 102))	('autophagy', 'biological_process', 'GO:0006914', ('62', '71'))	('PI3P', 'Chemical', '-', (98, 102))
11060	33066157	Acetyl-macrocalin B induces apoptosis in an ROS-dependent manner in A549 cells and then upregulates the p38 MAPK signaling pathway that mediates caspase-9 release.	('p38', 'Gene', (104, 107))	('caspase-9', 'Gene', (145, 154))	('p38 MAPK signaling', 'biological_process', 'GO:0051403', ('104', '122'))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('Acetyl-macrocalin B', 'Var', (0, 19))	('upregulates', 'PosReg', (88, 99))	('apoptosis', 'CPA', (28, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('signaling pathway', 'biological_process', 'GO:0007165', ('113', '130'))	('caspase-9', 'Gene', '842', (145, 154))	('p38', 'Gene', '5594', (104, 107))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))
11081	33066157	Nepeta rtanjensis essential oils rich in trans,cis-nepetalactone induced programmed cell death against A549 and MDA-MB-231 cells, as did Origanum onites essential oil, which is rich in carvacrol, against Ht-29 cells.	('oil', 'Chemical', 'MESH:D009821', (163, 166))	('death', 'Disease', 'MESH:D003643', (89, 94))	('carvacrol', 'Chemical', 'MESH:C073316', (185, 194))	('Origanum onites', 'Species', '452416', (137, 152))	('essential oils', 'Chemical', 'MESH:D009822', (18, 32))	('cis-nepetalactone', 'Var', (47, 64))	('trans,cis-nepetalactone', 'Chemical', '-', (41, 64))	('death', 'Disease', (89, 94))	('Nepeta rtanjensis', 'Species', '2721193', (0, 17))	('oil', 'Chemical', 'MESH:D009821', (28, 31))	('programmed cell death', 'biological_process', 'GO:0012501', ('73', '94'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('Ht-29', 'CellLine', 'CVCL:C834', (204, 209))
11083	33066157	Salvia aurea, S. judaica, and S. viscosa essential oils containing caryophyllene oxide as a main constituent induced apoptosis triggered by excessive ROS formation in DU-145 cells, as did Zataria multiflora essential oils in HCT-116 and SW48 cell lines.	('S. judaica', 'Var', (14, 24))	('apoptosis', 'CPA', (117, 126))	('caryophyllene oxide', 'Chemical', 'MESH:C515179', (67, 86))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))	('ROS formation', 'MPA', (150, 163))	('Zataria multiflora essential oils', 'Disease', (188, 221))	('ROS formation', 'biological_process', 'GO:1903409', ('150', '163'))	('DU-145', 'CellLine', 'CVCL:0105', (167, 173))	('SW48', 'CellLine', 'CVCL:1724', (237, 241))	('induced', 'Reg', (109, 116))	('Salvia aurea', 'Disease', 'None', (0, 12))	('HCT-116', 'CellLine', 'CVCL:0291', (225, 232))	('S. viscosa', 'Species', '718', (30, 40))	('Zataria multiflora essential oils', 'Disease', 'MESH:D020329', (188, 221))	('Salvia aurea', 'Disease', (0, 12))	('essential oils', 'Chemical', 'MESH:D009822', (41, 55))	('essential oils', 'Chemical', 'MESH:D009822', (207, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))
11088	33066157	Stachys viticina essential oils, with their main components being endo-borneol, eucalyptol, and epizonarene, inhibit mediators of apoptosis suppression COX-2 in COLO 205 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('COX-2', 'Gene', (152, 157))	('Stachys viticina', 'Species', '1007651', (0, 16))	('eucalyptol', 'Chemical', 'MESH:D000077591', (80, 90))	('COX-2', 'Gene', '5743', (152, 157))	('inhibit', 'NegReg', (109, 116))	('epizonarene', 'Chemical', '-', (96, 107))	('COLO', 'Species', '307630', (161, 165))	('epizonarene', 'Var', (96, 107))	('endo-borneol', 'Chemical', 'MESH:C022871', (66, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('essential oils', 'Chemical', 'MESH:D009822', (17, 31))
11116	31053602	Various immune and tumor genomic metrics are associated with sensitivity to PD-1 axis blockers including tumor PD-L1 expression, measurement of tumor infiltrating lymphocytes (TILs) or inflammation-related mRNA expression profiles, tumor mutational burden and microsatellite instability.	('PD-1', 'Gene', (76, 80))	('microsatellite instability', 'Var', (260, 286))	('tumor', 'Disease', (19, 24))	('PD-1', 'Gene', '5133', (76, 80))	('PD-L1', 'Gene', (111, 116))	('PD-L1', 'Gene', '29126', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('TIL', 'Gene', '7096', (176, 179))	('inflammation', 'Disease', 'MESH:D007249', (185, 197))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('inflammation', 'biological_process', 'GO:0006954', ('185', '197'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TIL', 'Gene', (176, 179))	('inflammation', 'Disease', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
11126	31053602	Additional candidate ligands have also shown to be able to modulate TIM-3 functions including phosphatidyl serine (PtdSer) and high mobility group protein B1 (HMGB1).Clinical studies assessing the safety and anti-tumor effect of TIM-3 blockers alone or in combination with other therapies are currently ongoing: NCT02817633, NCT03099109, NCT03066648.	('tumor', 'Disease', (213, 218))	('TIM-3', 'Gene', (68, 73))	('high mobility group protein B1', 'Gene', '3146', (127, 157))	('NCT02817633', 'Var', (312, 323))	('TIM-3', 'Gene', '84868', (68, 73))	('PtdSer', 'Chemical', 'MESH:D010718', (115, 121))	('NCT03099109', 'Var', (325, 336))	('high mobility group protein B1', 'Gene', (127, 157))	('NCT03066648', 'Var', (338, 349))	('serine', 'Chemical', 'MESH:D012694', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('TIM-3', 'Gene', (229, 234))	('HMGB1', 'Gene', (159, 164))	('HMGB1', 'Gene', '3146', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('TIM-3', 'Gene', '84868', (229, 234))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
11137	31053602	Another TMA-based cohort from Yale (cohort #4) including retrospective samples from 108 lung adenocarcinomas clinically tested for EGFR and KRAS mutations was also studied.	('KRAS', 'Gene', '3845', (140, 144))	('mutations', 'Var', (145, 154))	('lung adenocarcinomas', 'Disease', (88, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (88, 108))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (88, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('KRAS', 'Gene', (140, 144))	('TMA', 'Chemical', '-', (8, 11))
11140	31053602	All the studies were conducted in accordance with recognized ethical guidelines (e.g., Declaration of Helsinki, CIOMS, Belmont Report, U.S. Common Rule) and tissue and clinical information were used after approval from the Yale Human Investigation Committee protocols #9505008219, #1412015109, #1608018220 and #1603017333 or local institutional protocols, which approved the patient consent forms or waiver of consent.	('patient', 'Species', '9606', (375, 382))	('#1603017333', 'Var', (310, 321))	('#1412015109', 'Var', (281, 292))	('Human', 'Species', '9606', (228, 233))	('#1608018220', 'Var', (294, 305))
11187	31053602	Overall, simultaneous co-expression of PD-1, LAG-3 and TIM-3 was seen in 5.4% of CD3+ TILs.	('PD-1', 'Gene', (39, 43))	('PD-1', 'Gene', '5133', (39, 43))	('TIL', 'Gene', '7096', (86, 89))	('TIM-3', 'Gene', (55, 60))	('TIM-3', 'Gene', '84868', (55, 60))	('CD3+', 'Var', (81, 85))	('TIL', 'Gene', (86, 89))
11198	31053602	As shown in Figure 4A, the level of PD-1 and TIM-3 were significantly lower in tumor harboring KRAS mutations than in cases with wild type EGFR and KRAS.	('KRAS', 'Gene', '3845', (95, 99))	('mutations', 'Var', (100, 109))	('KRAS', 'Gene', (148, 152))	('tumor', 'Disease', (79, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('TIM-3', 'Gene', '84868', (45, 50))	('TIM-3', 'Gene', (45, 50))	('KRAS', 'Gene', '3845', (148, 152))	('EGFR', 'Gene', '1956', (139, 143))	('lower', 'NegReg', (70, 75))	('KRAS', 'Gene', (95, 99))	('EGFR', 'Gene', (139, 143))	('PD-1', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('PD-1', 'Gene', '5133', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
11199	31053602	EGFR mutated lung adenocarcinomas showed significantly lower TIM-3 than tumors lacking mutations in both oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (13, 32))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('lung adenocarcinomas', 'Disease', (13, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lower', 'NegReg', (55, 60))	('mutated', 'Var', (5, 12))	('TIM-3', 'Gene', (61, 66))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (13, 33))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (13, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('EGFR', 'Gene', '1956', (0, 4))	('TIM-3', 'Gene', '84868', (61, 66))
11204	31053602	Notably, cases with high LAG-3 and low tumor PD-L1 expression (<50% tumor proportion score [TPS]) showed a markedly lower progression free survival than cases with low LAG-3 and high ( 50% TPS) tumor PD-L1 expression (Figure 6D).	('lower', 'NegReg', (116, 121))	('PD-L1', 'Gene', (200, 205))	('low tumor', 'Disease', 'MESH:D009800', (35, 44))	('PD-L1', 'Gene', '29126', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('expression', 'MPA', (51, 61))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('low tumor', 'Disease', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('LAG-3', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('high', 'Var', (20, 24))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PD-L1', 'Gene', (45, 50))	('progression free survival', 'CPA', (122, 147))	('PD-L1', 'Gene', '29126', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (39, 44))
11221	31053602	In our study, we found lower levels of PD-1, LAG-3 and TIM-3 in KRAS and EGFR mutant tumors than in cases lacking mutations in both genes.	('PD-1', 'Gene', (39, 43))	('EGFR', 'Gene', '1956', (73, 77))	('PD-1', 'Gene', '5133', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('levels', 'MPA', (29, 35))	('TIM-3', 'Gene', (55, 60))	('EGFR', 'Gene', (73, 77))	('KRAS', 'Gene', (64, 68))	('TIM-3', 'Gene', '84868', (55, 60))	('LAG-3', 'MPA', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('KRAS', 'Gene', '3845', (64, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutant', 'Var', (78, 84))	('lower', 'NegReg', (23, 28))	('tumors', 'Disease', (85, 91))
11223	31053602	However, a fraction of NSCLCs with KRAS driver mutations may also harbor other genomic variants which could alter the tumor-immune microenvironment.	('NSCLCs', 'Disease', 'MESH:D002289', (23, 29))	('KRAS', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (47, 56))	('KRAS', 'Gene', '3845', (35, 39))	('tumor', 'Disease', (118, 123))	('NSCLCs', 'Disease', (23, 29))	('alter', 'Reg', (108, 113))
11227	31053602	Consistent with this notion, expression of PD-1, LAG-3 and TIM-3 was associated with elevated expression of key pro-apoptotic targets in lung carcinomas.	('PD-1', 'Gene', '5133', (43, 47))	('expression', 'Var', (29, 39))	('PD-1', 'Gene', (43, 47))	('TIM-3', 'Gene', '84868', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('lung carcinomas', 'Disease', 'MESH:D008175', (137, 152))	('elevated', 'PosReg', (85, 93))	('expression', 'MPA', (94, 104))	('LAG-3', 'Gene', (49, 54))	('lung carcinomas', 'Disease', (137, 152))	('TIM-3', 'Gene', (59, 64))
11232	31053602	Here, LAG-3 positivity by IHC in pre-treatment tumor samples is associated with higher response rate supporting a predictive role of LAG-3 expression.	('pre', 'molecular_function', 'GO:0003904', ('33', '36'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('LAG-3', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('positivity', 'Var', (12, 22))	('response', 'CPA', (87, 95))	('higher', 'PosReg', (80, 86))	('tumor', 'Disease', (47, 52))
11241	31053602	In addition, single-cell studies show that simultaneous co-expression of these immune inhibitory receptors is associated with prominent TIL activation, but also with acquisition of a pro-apoptotic phenotype.	('TIL', 'Gene', (136, 139))	('TIL', 'Gene', '7096', (136, 139))	('co-expression', 'Var', (56, 69))
11281	32575664	The alpha-helix peptides, containing alanine, leucine and lysine residues to stabilize the helix but not cysteine residues, are the most studied class of AMPs.	('alpha-helix peptides', 'Protein', (4, 24))	('leucine', 'Var', (46, 53))	('lysine residues', 'Var', (58, 73))	('alanine', 'Var', (37, 44))	('cysteine', 'Chemical', 'MESH:D003545', (105, 113))	('helix', 'MPA', (91, 96))	('leucine', 'Chemical', 'MESH:D007930', (46, 53))	('peptides', 'Chemical', 'MESH:D010455', (16, 24))	('alanine', 'Chemical', 'MESH:D000409', (37, 44))	('lysine', 'Chemical', 'MESH:D008239', (58, 64))	('AMPs', 'Chemical', '-', (154, 158))
11288	32575664	The AMPs have been shown first to destabilize the bacterial envelope and then to interact electrostatically with the anionic part of the membrane.	('AMPs', 'Var', (4, 8))	('AMPs', 'Chemical', '-', (4, 8))	('bacterial envelope', 'CPA', (50, 68))	('destabilize', 'NegReg', (34, 45))	('envelope', 'cellular_component', 'GO:0031975', ('60', '68'))	('membrane', 'cellular_component', 'GO:0016020', ('137', '145'))	('envelope', 'cellular_component', 'GO:0009274', ('60', '68'))	('interact', 'Interaction', (81, 89))
11295	32575664	In this model, the aggregation forces peptides into the hydrophobic center of the membrane and prevents exposure of the hydrophilic parts of the peptide to the hydrophobic parts of the inner membrane.	('prevents', 'NegReg', (95, 103))	('peptides', 'Chemical', 'MESH:D010455', (38, 46))	('membrane', 'cellular_component', 'GO:0016020', ('82', '90'))	('membrane', 'cellular_component', 'GO:0016020', ('191', '199'))	('peptides', 'Protein', (38, 46))	('aggregation', 'Var', (19, 30))	('exposure', 'MPA', (104, 112))
11306	32575664	In fact, peptides are described to bind the cell membrane and to form a significant curvature which allows the formation of transient pores in the membrane.	('peptides', 'Var', (9, 17))	('membrane', 'cellular_component', 'GO:0016020', ('147', '155'))	('bind', 'Interaction', (35, 39))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('cell membrane', 'cellular_component', 'GO:0005886', ('44', '57'))	('transient pores in the membrane', 'MPA', (124, 155))	('peptides', 'Chemical', 'MESH:D010455', (9, 17))
11316	32575664	In this model, AMPs can induce localized changes of the lipid phase by altering the lipid packaging in the double layer.	('lipid phase', 'MPA', (56, 67))	('lipid', 'Chemical', 'MESH:D008055', (56, 61))	('AMPs', 'Var', (15, 19))	('lipid packaging in the double layer', 'MPA', (84, 119))	('AMPs', 'Chemical', '-', (15, 19))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('altering', 'Reg', (71, 79))
11326	32575664	Cyclic peptides, which have reduced conformational freedom, also decrease the chances of degradation.	('Cyclic peptides', 'Var', (0, 15))	('degradation', 'biological_process', 'GO:0009056', ('89', '100'))	('Cyclic peptides', 'Chemical', 'MESH:D010456', (0, 15))	('conformational freedom', 'MPA', (36, 58))	('decrease', 'NegReg', (65, 73))	('degradation', 'MPA', (89, 100))
11327	32575664	For example, the susceptibility of Polybia-CP, a alpha-helical peptide with antitumor, antibacterial and antifungal activity, to proteases has been inhibited by replacing lysine with D-lysine (D-Lys-CP).	('lysine', 'Chemical', 'MESH:D008239', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('susceptibility', 'MPA', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('D-lysine', 'Chemical', '-', (183, 191))	('tumor', 'Disease', (80, 85))	('replacing', 'Var', (161, 170))	('Polybia-CP', 'Chemical', '-', (35, 45))	('Polybia-CP', 'Gene', (35, 45))	('lysine', 'Chemical', 'MESH:D008239', (171, 177))	('inhibited', 'NegReg', (148, 157))	('D-Lys-CP', 'Chemical', '-', (193, 201))
11328	32575664	Polybia-CP containing all D-aminoacid residues (D-CP) or only D-Lys-CP both showed a comparable antimicrobial activity but only D-Lys-CP was resistant to the degradation either by trypsin or chymotrypsin.	('degradation', 'biological_process', 'GO:0009056', ('158', '169'))	('D-CP', 'Chemical', 'MESH:C580746', (48, 52))	('D-aminoacid residues', 'Var', (26, 46))	('D-Lys-CP', 'Var', (62, 70))	('D-Lys-CP', 'Chemical', '-', (128, 136))	('antimicrobial activity', 'MPA', (96, 118))	('Polybia-CP', 'Chemical', '-', (0, 10))	('D-Lys-CP', 'Chemical', '-', (62, 70))	('D-aminoacid', 'Chemical', '-', (26, 37))
11330	32575664	demonstrated that AMP pegylation was also able to inhibit the proteolysis.	('proteolysis', 'biological_process', 'GO:0006508', ('62', '73'))	('inhibit', 'NegReg', (50, 57))	('AMP pegylation', 'Var', (18, 32))	('proteolysis', 'MPA', (62, 73))	('AMP', 'Chemical', '-', (18, 21))
11333	32575664	demonstrated that liposomal formulation increased the administration efficiency of the HCC-targeting peptide SP94 (SFSIIHTPILPL) in a HCC xenograft mouse model.	('SP94', 'Var', (109, 113))	('mouse', 'Species', '10090', (148, 153))	('SP94', 'Chemical', '-', (109, 113))	('increased', 'PosReg', (40, 49))	('administration efficiency', 'MPA', (54, 79))
11334	32575664	Particularly, SP94-mediated targeting improved anti-tumor efficacy by enhancing pharmacokinetics and tissue distribution, allowing the accumulation of a vast amount of anti-cancer drug in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tissue distribution', 'MPA', (101, 120))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Disease', (192, 197))	('improved', 'PosReg', (38, 46))	('cancer', 'Disease', (173, 179))	('tumor', 'Disease', (52, 57))	('pharmacokinetics', 'MPA', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('enhancing', 'PosReg', (70, 79))	('accumulation', 'PosReg', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('SP94-mediated', 'Var', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('SP94', 'Chemical', '-', (14, 18))
11338	32575664	The lipotripeptide C16-KKK-NH2 and lipotetrapeptide C16-PCatPHexPHexPCat-NH2 ((L-4R-aminoproline (PCat), L-4R-hexyloxyproline (PHex)) showed diverse anticancer activities such as caspase-mediated apoptosis and caspases independent cell death, respectively.	('cancer', 'Disease', (153, 159))	('PCat', 'Chemical', '-', (56, 60))	('cell death', 'biological_process', 'GO:0008219', ('231', '241'))	('-KKK-NH2', 'Chemical', '-', (22, 30))	('PHex', 'Gene', '5251', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('C16-KKK-NH2', 'Var', (19, 30))	('caspases independent cell death', 'CPA', (210, 241))	('PHex', 'Gene', (64, 68))	('PHex', 'Gene', (127, 131))	('caspase-mediated apoptosis', 'CPA', (179, 205))	('PCat', 'Chemical', '-', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('-PCatPHexPHexPCat-NH2', 'Chemical', '-', (55, 76))	('PHex', 'Gene', '5251', (64, 68))	('(L-4R-aminoproline', 'Chemical', '-', (78, 96))	('PHex', 'Gene', '5251', (127, 131))	('lipotripeptide', 'Chemical', '-', (4, 18))	('PCat', 'Chemical', '-', (98, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('PHex', 'Gene', (60, 64))	('L-4R-hexyloxyproline', 'Chemical', '-', (105, 125))
11339	32575664	The difference between the two moieties, besides the cationic and amphiphilic properties, was in the secondary conformation with the polyproline peptide having a more rigid structure.	('polyproline', 'Var', (133, 144))	('polyproline', 'Chemical', 'MESH:C011083', (133, 144))	('secondary conformation', 'MPA', (101, 123))	('rigid', 'MPA', (167, 172))
11353	32575664	Moreover, Ag-MNP and Au-MNP peptides are more stable, more effective against cancer cells and less toxic to normal cells.	('peptides', 'Chemical', 'MESH:D010455', (28, 36))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Ag-MNP', 'Var', (10, 16))	('Au-MNP', 'Var', (21, 27))	('Au', 'Chemical', 'MESH:D006046', (21, 23))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('effective', 'MPA', (59, 68))
11355	32575664	Moreover, the MNP-CSA-13 showed a pro-apoptotic activity stronger than MNP-LL-37 on colon cancer cells.	('CSA-13', 'Chemical', '-', (18, 24))	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('LL-37', 'Gene', '820', (75, 80))	('pro-apoptotic activity', 'MPA', (34, 56))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Disease', (84, 96))	('MNP-CSA-13', 'Var', (14, 24))	('LL-37', 'Gene', (75, 80))
11356	32575664	observed that MNP-CSA-13 reduced the viability and inhibited proliferation of MCF-7 and MDA-MB-231 breast cancer cells through the disruption of the oxidative balance.	('CSA-13', 'Chemical', '-', (18, 24))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('reduced', 'NegReg', (25, 32))	('proliferation', 'CPA', (61, 74))	('breast cancer', 'Disease', (99, 112))	('MCF-7', 'CellLine', 'CVCL:0031', (78, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('MNP-CSA-13', 'Var', (14, 24))	('oxidative balance', 'MPA', (149, 166))	('disruption', 'MPA', (131, 141))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (88, 98))	('viability', 'CPA', (37, 46))	('inhibited', 'NegReg', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
11360	32575664	AMPs are less likely to induce resistance to pathogens or transformed cells than current antibiotics or cancer drugs.	('AMPs', 'Chemical', '-', (0, 4))	('induce', 'Reg', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('AMPs', 'Var', (0, 4))
11374	32575664	The leucine-leucine-37 (LL-37; named for the first two amino acids and with a total of 37 amino acids), derived from the cleavage of the human cationic antimicrobial peptide 18 (hCAP-18; 18 for its approximate molecular weight of 18 kDa) by proteinase 3, plays a crucial role in the adaptive immunity, growth inhibition, chemotaxis, and wound healing.	('proteinase', 'molecular_function', 'GO:0004175', ('241', '251'))	('human', 'Species', '9606', (137, 142))	('LL-37', 'Gene', (24, 29))	('proteinase 3', 'Gene', '5657', (241, 253))	('wound healing', 'CPA', (337, 350))	('leucine', 'Chemical', 'MESH:D007930', (4, 11))	('leucine', 'Chemical', 'MESH:D007930', (12, 19))	('hCAP-18', 'Gene', '820', (178, 185))	('LL-37', 'Gene', '820', (24, 29))	('chemotaxis', 'biological_process', 'GO:0006935', ('321', '331'))	('proteinase 3', 'Gene', (241, 253))	('adaptive immunity', 'CPA', (283, 300))	('growth inhibition', 'CPA', (302, 319))	('hCAP-18', 'Gene', (178, 185))	('leucine-leucine-37', 'Var', (4, 22))	('wound healing', 'biological_process', 'GO:0042060', ('337', '350'))
11379	32575664	Immunohistochemical staining of tissue arrays revealed that LL-37 is highly expressed in normal colon mucosa, while it is downregulated in colon cancer tissues because of DNA methylation in the CAMP gene promoter.	('downregulated', 'NegReg', (122, 135))	('LL-37', 'Gene', '820', (60, 65))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('CAMP', 'Gene', (194, 198))	('CAMP', 'Gene', '820', (194, 198))	('colon cancer', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('LL-37', 'Gene', (60, 65))	('DNA methylation', 'Var', (171, 186))	('colon mucosa', 'Disease', 'MESH:D003110', (96, 108))	('DNA methylation', 'biological_process', 'GO:0006306', ('171', '186'))	('colon mucosa', 'Disease', (96, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
11392	32575664	LTX-315 was shown to induce cell death by a dual effect, namely cytolysis and immunogenicity.	('LTX-315', 'Var', (0, 7))	('LTX-315', 'Chemical', 'MESH:C000609766', (0, 7))	('cell death', 'CPA', (28, 38))	('cell death', 'biological_process', 'GO:0008219', ('28', '38'))	('cytolysis', 'biological_process', 'GO:0019835', ('64', '73'))
11396	32575664	Thereafter, LTX-315 has been evaluated in a phase I in human clinical study and demonstrated to cause changes in the tumor microenvironment, increase of T effector cells, decrease in immunosuppressive cells, and finally tumor necrosis.	('tumor', 'Disease', (220, 225))	('T effector cells', 'CPA', (153, 169))	('LTX-315', 'Var', (12, 19))	('necrosis', 'biological_process', 'GO:0070265', ('226', '234'))	('necrosis', 'biological_process', 'GO:0019835', ('226', '234'))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('necrosis', 'biological_process', 'GO:0001906', ('226', '234'))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor necrosis', 'Disease', 'MESH:D009336', (220, 234))	('increase', 'PosReg', (141, 149))	('decrease', 'NegReg', (171, 179))	('changes', 'Reg', (102, 109))	('tumor necrosis', 'Disease', (220, 234))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('human', 'Species', '9606', (55, 60))	('iron', 'Chemical', 'MESH:D007501', (131, 135))	('LTX-315', 'Chemical', 'MESH:C000609766', (12, 19))	('necrosis', 'biological_process', 'GO:0008219', ('226', '234'))	('immunosuppressive cells', 'MPA', (183, 206))	('tumor', 'Disease', (117, 122))	('necrosis', 'biological_process', 'GO:0008220', ('226', '234'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
11413	32575664	Recent studies have also shown that MG2 may represent a novel anti-cancer strategy being cytotoxic and anti-proliferative in bladder cancer cells, through the formation of pores on cell membranes, but has no effect on normal human or murine fibroblasts.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('MG2', 'Var', (36, 39))	('cancer', 'Disease', (67, 73))	('MG2', 'Chemical', '-', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('formation', 'biological_process', 'GO:0009058', ('159', '168'))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (225, 230))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('murine', 'Species', '10090', (234, 240))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('pores', 'MPA', (172, 177))
11419	32575664	Buforin IIb is a histone H2A-derived antimicrobial peptide, a synthetic analog of buforin II derived from buforin I, that was isolated from the stomach tissue of the Asian toad Bufo bufo garagrizans, Buforin IIb has a alpha-helical sequence at C terminus and interacts with gangliosides of cancer cells surface causing destruction of membrane and mitochondria-dependent apoptosis.	('gangliosides', 'Chemical', 'MESH:D005732', (274, 286))	('interacts', 'Interaction', (259, 268))	('apoptosis', 'biological_process', 'GO:0097194', ('370', '379'))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('destruction', 'NegReg', (319, 330))	('cancer', 'Disease', (290, 296))	('apoptosis', 'biological_process', 'GO:0006915', ('370', '379'))	('membrane', 'cellular_component', 'GO:0016020', ('334', '342'))	('mitochondria', 'cellular_component', 'GO:0005739', ('347', '359'))	('Buforin', 'Var', (200, 207))	('Bufo bufo', 'Species', '8384', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
11422	32575664	The hypothetical toxic mechanism is based on a lysosomal death pathway (LDP) demonstrated by the fact that inhibitors of lysosomal membrane permeabilization prevented brevinin 2R from inducing cell death.	('cell death', 'CPA', (193, 203))	('prevented', 'NegReg', (157, 166))	('LDP', 'Gene', (72, 75))	('brevinin', 'Var', (167, 175))	('cell death', 'biological_process', 'GO:0008219', ('193', '203'))	('lysosomal membrane', 'cellular_component', 'GO:0005765', ('121', '139'))	('brevinin 2R', 'Chemical', '-', (167, 178))	('lysosomal death pathway', 'Disease', (47, 70))	('LDP', 'Gene', '10404', (72, 75))
11427	32575664	In fact, LFB reduced the proliferation rate of HCT116 cells in a dose-dependent manner and at high concentrations caused cell death through membrane disruption, without inducing apoptosis.	('membrane disruption', 'CPA', (140, 159))	('HCT116', 'CellLine', 'CVCL:0291', (47, 53))	('proliferation rate', 'CPA', (25, 43))	('LFB', 'Chemical', '-', (9, 12))	('membrane', 'cellular_component', 'GO:0016020', ('140', '148'))	('cell death', 'biological_process', 'GO:0008219', ('121', '131'))	('LFB', 'Var', (9, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('cell death', 'CPA', (121, 131))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('reduced', 'NegReg', (13, 20))
11433	32575664	R2PLx was demonstrated to be more potent against cancer cells than against bacteria and selective against cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('R2PLx', 'Var', (0, 5))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
11439	32575664	DRS-B1-B2, DRS-S1-S5 DRS-O1, DRS-CA1 DRS-DU1 are effective against fungi in vitro demonstrating cytotoxicity on Candida albicans cultures, with DRS-S3 triggering apopotosis.	('DRS-CA1 DRS-DU1', 'Var', (29, 44))	('cytotoxicity', 'Disease', (96, 108))	('Candida albicans', 'Species', '5476', (112, 128))	('DRS-S1-S5', 'Var', (11, 20))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))
11441	32575664	Moreover, DRS-S4 and DRS-S9 were shown to inhibit HIV-1 attachment to endometrial cells, the uptake by dendritic cells and subsequent viral spread to T-cells.	('DRS-S4', 'Var', (10, 16))	('viral spread', 'CPA', (134, 146))	('DRS-S9', 'Var', (21, 27))	('uptake', 'biological_process', 'GO:0098739', ('93', '99'))	('uptake', 'biological_process', 'GO:0098657', ('93', '99'))	('attachment', 'CPA', (56, 66))	('HIV-1', 'Species', '11676', (50, 55))	('HIV-1', 'Gene', (50, 55))	('inhibit', 'NegReg', (42, 49))	('uptake by dendritic cells', 'CPA', (93, 118))
11445	32575664	In addition, its analog K8, 23-DPT9, in which Asp8 and Glu23 were substituted by lysine residues, displayed high anti-proliferative activity against cancer cells, and weak activity against the normal human microvascular endothelial cell line HMEC-1.	('cancer', 'Disease', (149, 155))	('activity', 'MPA', (172, 180))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('anti-proliferative activity', 'CPA', (113, 140))	('DPT9', 'Chemical', '-', (31, 35))	('Glu23 were substituted by lysine', 'SUBSTITUTION', 'None', (55, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('human', 'Species', '9606', (200, 205))	('Glu23 were substituted by lysine', 'Var', (55, 87))	('Asp8 and Glu23 were substituted by lysine', 'Mutation', 'p.D,E8,23K', (46, 87))	('HMEC-1', 'CellLine', 'CVCL:0307', (242, 248))
11446	32575664	Both DPT9 and K8, 23-DPT9 peptides showed an increased ability to damage the cell membrane of human lung cancer cell lines NCI-H125 and H157, human prostate cancer cell line PC-3 as well as the human pancreatic cancer cell line PANC-1.	('DPT9', 'Chemical', '-', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DPT9', 'Var', (5, 9))	('DPT9', 'Chemical', '-', (5, 9))	('peptides', 'Chemical', 'MESH:D010455', (26, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (200, 217))	('cell membrane', 'cellular_component', 'GO:0005886', ('77', '90'))	('human', 'Species', '9606', (142, 147))	('lung cancer', 'Disease', (100, 111))	('damage', 'Reg', (66, 72))	('cell membrane', 'MPA', (77, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (200, 217))	('human', 'Species', '9606', (94, 99))	('PC-3', 'CellLine', 'CVCL:0035', (174, 178))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PANC-1', 'CellLine', 'CVCL:0480', (228, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('pancreatic cancer', 'Disease', (200, 217))	('prostate cancer', 'Disease', 'MESH:D011471', (148, 163))	('human', 'Species', '9606', (194, 199))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('NCI-H125', 'CellLine', 'CVCL:3968', (123, 131))	('H157', 'CellLine', 'CVCL:2458', (136, 140))	('prostate cancer', 'Disease', (148, 163))
11449	32575664	The AMP chrysophsin-1 is able to disrupt the plasma membrane of several cancer cell lines at much lower concentrations compared to the CA-MA-2 peptide.	('AMP', 'Var', (4, 7))	('plasma membrane', 'MPA', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('AMP', 'Chemical', '-', (4, 7))	('disrupt', 'NegReg', (33, 40))	('plasma membrane', 'cellular_component', 'GO:0005886', ('45', '60'))	('cancer', 'Disease', (72, 78))
11458	32575664	D-K6L9 is an engineered membranolytic anticancer peptide made of only lysine and leucine aminoacids.	('D-K6L9', 'Chemical', '-', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('leucine', 'Chemical', 'MESH:D007930', (81, 88))	('D-K6L9', 'Var', (0, 6))	('lysine', 'Chemical', 'MESH:D008239', (70, 76))
11459	32575664	demonstrated selective binding of D-K6L9 to negatively charged PS and induction of cell membrane depolarization.	('D-K6L9', 'Chemical', '-', (34, 40))	('cell membrane', 'cellular_component', 'GO:0005886', ('83', '96'))	('PS', 'Chemical', 'MESH:D010718', (63, 65))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('cell', 'CPA', (83, 87))	('negatively charged PS', 'MPA', (44, 65))	('D-K6L9', 'Var', (34, 40))	('binding', 'Interaction', (23, 30))	('membrane depolarization', 'biological_process', 'GO:0051899', ('88', '111'))
11461	32575664	The D-K6L9 administration to immunodeficient mice, implanted with breast and prostate cancer cell lines showed reduced neovascularization.	('D-K6L9', 'Var', (4, 10))	('mice', 'Species', '10090', (45, 49))	('D-K6L9', 'Chemical', '-', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('reduced', 'NegReg', (111, 118))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (66, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('immunodeficient', 'Disease', 'MESH:D007153', (29, 44))	('immunodeficient', 'Disease', (29, 44))	('neovascularization', 'CPA', (119, 137))
11462	32575664	Moreover, the direct administration of D-K6L9 and glycyrrhizin, a HMGB1 protein inhibitor, into B16-F10 murine melanoma tumors inhibited the growth but only during the period of the treatment and did not enhance animal survival.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('D-K6L9', 'Var', (39, 45))	('melanoma tumors', 'Disease', (111, 126))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('inhibited', 'NegReg', (127, 136))	('melanoma tumors', 'Disease', 'MESH:D008545', (111, 126))	('D-K6L9', 'Chemical', '-', (39, 45))	('growth', 'MPA', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('murine', 'Species', '10090', (104, 110))	('glycyrrhizin', 'Chemical', 'MESH:D019695', (50, 62))
11466	32575664	Furthermore, the treatment of nude mice bearing MDA-MB435S breast cancer tumors with (KLAKLAK)2 for 60 days showed that those receiving peptide survived 16 days longer in comparison to the control mice.	('breast cancer tumors', 'Disease', (59, 79))	('MDA-MB435S', 'Var', (48, 58))	('MDA-MB435S', 'CellLine', 'CVCL:0622', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('breast cancer tumors', 'Disease', 'MESH:D001943', (59, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('longer', 'PosReg', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mice', 'Species', '10090', (35, 39))	('nude mice', 'Species', '10090', (30, 39))	('mice', 'Species', '10090', (197, 201))
11486	32575664	evaluated the effect of Tv1 in vitro in the mouse liver cancer cells 1MEA and in vivo in the Balb/c mice implanted with 1MEA and observed that the peptide induced apoptosis by inhibiting the calcium influx into tumor cells via TRPCs.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('liver cancer', 'Disease', (50, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('peptide', 'Var', (147, 154))	('calcium', 'Chemical', 'MESH:D002118', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('mice', 'Species', '10090', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('inhibiting', 'NegReg', (176, 186))	('PC', 'Chemical', 'MESH:D010713', (229, 231))	('tumor', 'Disease', (211, 216))	('liver cancer', 'Disease', 'MESH:D006528', (50, 62))	('liver cancer', 'Phenotype', 'HP:0002896', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mouse', 'Species', '10090', (44, 49))
11496	32575664	They demonstrated that in the HCC xenograft mouse model the SP94-LD accumulated significantly in HCC tumors with low toxicity to normal cells and that the SP94-LD plasma pharmacokinetics was similar to LD.	('SP94-LD', 'Var', (60, 67))	('SP94', 'Chemical', '-', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('SP94', 'Chemical', '-', (60, 64))	('toxicity', 'Disease', (117, 125))	('HCC tumors', 'Disease', 'MESH:D006528', (97, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('HCC tumors', 'Disease', (97, 107))	('mouse', 'Species', '10090', (44, 49))
11497	32575664	R-Tf-D-LP4 (KWTWKNSNGATWALNVATELKKEWTWSHRPYIAH) is a cell-penetrating peptide derived from the voltage-dependent anion channel 1 (VDAC1), which is a beta-barrel protein located in the outer mitochondrial membrane.	('R-Tf-D-LP4', 'Var', (0, 10))	('outer mitochondrial membrane', 'cellular_component', 'GO:0005741', ('184', '212'))	('VDAC1', 'Gene', (130, 135))	('voltage-dependent anion channel 1', 'Gene', '7416', (95, 128))	('VDAC1', 'Gene', '7416', (130, 135))	('voltage-dependent anion channel 1', 'Gene', (95, 128))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
11500	32575664	demonstrated that R-Tf-D-LP4 dramatically inhibits tumor growth in three different HCC mouse models.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mouse', 'Species', '10090', (87, 92))	('inhibits', 'NegReg', (42, 50))	('R-Tf-D-LP4', 'Var', (18, 28))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
11501	32575664	The authors observed that R-Tf-D-LP4 induced cell energy perturbation and antagonized VDAC1 for the interaction with Bcl- 2, Bcl-xL and hexokinase II (HK) thus inducing apoptosis in diethylnitrosamine-induced HCC, metabolically (high-fat diet-32) induced HCC, and subcutaneous Hep-G2 cell xenograft mice models.	('Bcl- 2', 'Gene', '596', (117, 123))	('apoptosis', 'CPA', (169, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('169', '178'))	('VDAC1', 'Gene', '7416', (86, 91))	('interaction', 'Interaction', (100, 111))	('Bcl-xL', 'Gene', '598', (125, 131))	('Bcl- 2', 'molecular_function', 'GO:0015283', ('117', '123'))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (182, 200))	('mice', 'Species', '10090', (299, 303))	('apoptosis', 'biological_process', 'GO:0006915', ('169', '178'))	('cell', 'MPA', (45, 49))	('inducing', 'PosReg', (160, 168))	('R-Tf-D-LP4', 'Var', (26, 36))	('Bcl-xL', 'Gene', (125, 131))	('Hep-G2', 'CellLine', 'CVCL:0027', (277, 283))	('VDAC1', 'Gene', (86, 91))	('Bcl- 2', 'Gene', (117, 123))
11502	32575664	The R-Tf-D-LP4 peptide, besides apoptosis, caused the attenuation of processes associated with liver cancer microenvironment, as well as steatosis, inflammation, and fibrosis.	('inflammation', 'Disease', 'MESH:D007249', (148, 160))	('liver cancer', 'Disease', (95, 107))	('steatosis', 'Disease', (137, 146))	('fibrosis', 'Disease', 'MESH:D005355', (166, 174))	('processes', 'CPA', (69, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('inflammation', 'Disease', (148, 160))	('attenuation', 'NegReg', (54, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('fibrosis', 'Disease', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('liver cancer', 'Phenotype', 'HP:0002896', (95, 107))	('inflammation', 'biological_process', 'GO:0006954', ('148', '160'))	('R-Tf-D-LP4 peptide', 'Var', (4, 22))	('steatosis', 'Phenotype', 'HP:0001397', (137, 146))	('steatosis', 'Disease', 'MESH:D005234', (137, 146))	('liver cancer', 'Disease', 'MESH:D006528', (95, 107))	('iron', 'Chemical', 'MESH:D007501', (116, 120))
11505	32575664	These peptides were able also to inhibit tumor growth in vivo in a mouse xenograft tumor model.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('peptides', 'Chemical', 'MESH:D010455', (6, 14))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (83, 88))	('inhibit', 'NegReg', (33, 40))	('peptides', 'Var', (6, 14))	('mouse', 'Species', '10090', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
11508	32575664	The treatment with beta3 peptide of nude mice transplanted with LCI-D20 HCC tumors caused inhibited of tumor recurrence and prolonged survival time.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('survival time', 'CPA', (134, 147))	('tumor', 'Disease', (103, 108))	('HCC tumors', 'Disease', (72, 82))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('nude mice', 'Species', '10090', (36, 45))	('LCI-D20', 'Var', (64, 71))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('prolonged', 'PosReg', (124, 133))	('HCC tumors', 'Disease', 'MESH:D006528', (72, 82))	('inhibited', 'NegReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
11510	32575664	observed that CecropinXJ inhibits the growth of hepatocellular carcinoma Huh-7 cells in a dose- and time-dependent manner, by inducing cell cycle arrest in S phase and apoptosis by caspase-3.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (48, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('168', '177'))	('arrest', 'Disease', 'MESH:D006323', (146, 152))	('apoptosis', 'biological_process', 'GO:0006915', ('168', '177'))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('135', '152'))	('caspase-3', 'Gene', '836', (181, 190))	('S phase', 'biological_process', 'GO:0051320', ('156', '163'))	('Huh-7', 'CellLine', 'CVCL:0336', (73, 78))	('hepatocellular carcinoma', 'Disease', (48, 72))	('caspase-3', 'Gene', (181, 190))	('growth', 'CPA', (38, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('arrest', 'Disease', (146, 152))	('inducing', 'PosReg', (126, 134))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (48, 72))	('inhibits', 'NegReg', (25, 33))	('CecropinXJ', 'Var', (14, 24))	('apoptosis', 'CPA', (168, 177))
11515	32575664	Moreover, GW-H1 was shown to inhibit the metastatic progression of J5 HCC cells.	('GW-H1', 'Var', (10, 15))	('J5 HCC', 'CellLine', 'CVCL:N186', (67, 73))	('metastatic progression', 'CPA', (41, 63))	('inhibit', 'NegReg', (29, 36))
11521	32575664	Many limitations in the use of peptides, such as poor stability, proteolytic degradation, potential toxicity, low bioavailability, specific delivery to tumor cell, have been overcome by the chemical modifications including amino acids substitution, nanoparticles loading, fusion with cell penetrating peptides.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('peptides', 'Chemical', 'MESH:D010455', (31, 39))	('degradation', 'biological_process', 'GO:0009056', ('77', '88'))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('toxicity', 'Disease', 'MESH:D064420', (100, 108))	('toxicity', 'Disease', (100, 108))	('tumor', 'Disease', (152, 157))	('stability', 'MPA', (54, 63))	('amino acids substitution', 'Var', (223, 247))	('fusion', 'Interaction', (272, 278))	('bioavailability', 'MPA', (114, 129))	('peptides', 'Chemical', 'MESH:D010455', (301, 309))	('proteolytic', 'MPA', (65, 76))
11523	32575664	A large number of AMPs are already in the pre-clinical stage and several are under evaluation in clinical trial as antibacterial but only few as anticancer peptides (Table 2).	('cancer', 'Disease', (149, 155))	('pre', 'molecular_function', 'GO:0003904', ('42', '45'))	('AMPs', 'Chemical', '-', (18, 22))	('AMPs', 'Var', (18, 22))	('peptides', 'Chemical', 'MESH:D010455', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
11590	32651686	Cancer treatment for patients who are COVID-19 positive should be as conservative as possible, using stent placement for stenosing cancer and performing surgery after the resolution of infection.	('cancer', 'Disease', (131, 137))	('positive', 'Var', (47, 55))	('infection', 'Disease', (185, 194))	('infection', 'Disease', 'MESH:D007239', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('patients', 'Species', '9606', (21, 29))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('COVID-19', 'Disease', 'MESH:C000657245', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('COVID-19', 'Disease', (38, 46))
11592	32651686	This can be achieved by minimizing the creation of a plume (reduce power setting) through the use of electrocautery or ultrasonic scalpels, limiting CO2 release into the operating room by lowering the pneumoperitoneum pressure, reducing the Trendelenburg position, or deflating the abdomen before retrieving a specimen or before removing the trocars.	('reducing', 'NegReg', (228, 236))	('limiting', 'NegReg', (140, 148))	('pneumoperitoneum pressure', 'MPA', (201, 226))	('deflating', 'Var', (268, 277))	('lowering', 'NegReg', (188, 196))	('minimizing', 'NegReg', (24, 34))	('CO2', 'Chemical', 'MESH:D002245', (149, 152))	('CO2', 'Protein', (149, 152))	('release', 'MPA', (153, 160))
11681	32651686	Cases have been reported of patients undergoing lung cancer surgery, who tested PCR-positive for COVID-19 when their symptoms worsened postoperatively.	('COVID-19', 'Disease', (97, 105))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('PCR-positive', 'Var', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('COVID-19', 'Disease', 'MESH:C000657245', (97, 105))	('patients', 'Species', '9606', (28, 36))
11756	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))	('metabolism', 'biological_process', 'GO:0008152', ('178', '188'))	('synthesis', 'biological_process', 'GO:0009058', ('167', '176'))	('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))
11758	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))
11759	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))
11760	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))	('CDH13', 'Gene', '1012', (65, 70))	('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))	('rs35859010', 'Mutation', 'rs35859010', (71, 81))	('rs254315', 'Mutation', 'rs254315', (92, 100))
11761	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))
11762	32238407	Genetic variants of APOB and CDH13 in the cholesterol pathway were associated with NSCLC survival, possibly by affecting their gene expression.	('CDH13', 'Gene', (29, 34))	('cholesterol pathway', 'Pathway', (42, 61))	('NSCLC', 'Disease', (83, 88))	('gene expression', 'biological_process', 'GO:0010467', ('127', '142'))	('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))
11763	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))
11773	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))	('metabolism', 'biological_process', 'GO:0008152', ('79', '89'))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cholesterol', 'Chemical', 'MESH:D002784', (23, 34))	('synthesis', 'biological_process', 'GO:0009058', ('68', '77'))	('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))
11775	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))	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('70', '91'))	('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))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('mTOR', 'Gene', (173, 177))	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('212', '233'))	('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))
11780	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))
11786	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))
11801	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))
11803	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))	('rs254315', 'Mutation', 'rs254315', (81, 89))	('CDH13', 'Gene', '1012', (45, 50))	('rs425904T>C', 'Var', (98, 109))	('rs425904T>C', 'DBSNP_MENTION', 'None', (98, 109))	('rs254315 T>C', 'Var', (81, 93))	('APOB', 'Gene', (21, 25))	('NSCLC', 'Disease', (225, 230))	('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))	('CDH13', 'Gene', (45, 50))	('rs1801701C>T', 'Var', (27, 39))
11804	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))
11805	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))
11806	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))
11808	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))
11809	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))	('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', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('NSCLC OS', 'Disease', (60, 68))	('NSCLC', 'Disease', (60, 65))	('Haplotypes', 'Var', (0, 10))	('associated', 'Reg', (146, 156))
11811	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))
11815	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.	('UGH', 'Chemical', '-', (104, 107))	('improved', 'PosReg', (50, 58))	('NUGH', 'Gene', (103, 107))	('addition', 'Var', (91, 99))
11821	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.	('GTEx', 'Chemical', '-', (49, 53))	('rs1801701', 'Mutation', 'rs1801701', (80, 89))	('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))
11822	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))
11823	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))	('RNA', 'cellular_component', 'GO:0005562', ('7', '10'))	('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))
11828	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))	('rs254315T>C', 'DBSNP_MENTION', 'None', (42, 53))	('motifs', 'MPA', (123, 129))	('DNAse', 'MPA', (113, 118))	('CDH13', 'Gene', (36, 41))	('rs1801701C>T', 'Var', (19, 31))	('APOB', 'Gene', (14, 18))	('effects', 'Reg', (78, 85))	('rs35859010C>T', 'Var', (143, 156))	('rs1801701C>T', 'DBSNP_MENTION', 'None', (19, 31))	('rs35859010C>T', 'DBSNP_MENTION', 'None', (143, 156))	('CDH13', 'Gene', '1012', (36, 41))	('CDH13', 'Gene', (137, 142))	('enhancer histone marks', 'MPA', (89, 111))	('rs254315T>C', 'Var', (42, 53))	('enhancer histone marks', 'MPA', (179, 201))
11829	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))
11830	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))
11838	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.	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('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))	('NSCLC', 'Disease', (275, 280))	('associated', 'Reg', (220, 230))	('CDH13', 'Gene', (102, 107))	('NSCLC tumor', 'Disease', 'MESH:D009369', (122, 133))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('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))
11841	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))
11843	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))
11848	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.	('gene expression', 'biological_process', 'GO:0010467', ('231', '246'))	('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))
11852	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))
11854	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))	('metabolism', 'biological_process', 'GO:0008152', ('208', '218'))	('genetic variants', 'Var', (60, 76))	('cholesterol', 'Chemical', 'MESH:D002784', (84, 95))	('metabolism', 'MPA', (208, 218))	('transport', 'biological_process', 'GO:0006810', ('194', '203'))	('cholesterol', 'Chemical', 'MESH:D002784', (222, 233))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', (306, 311))	('synthesis', 'biological_process', 'GO:0009058', ('183', '192'))	('CDH13', 'Gene', '1012', (119, 124))	('synthesis', 'MPA', (183, 192))	('APOB', 'Gene', (110, 114))	('CDH13', 'Gene', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (306, 311))	('modulation', 'Reg', (165, 175))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('transport', 'MPA', (194, 203))
11855	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))	('NSCLC', 'Disease', (541, 546))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (551, 573))	('GTEx', 'Chemical', '-', (296, 300))	('LDL', 'molecular_function', 'GO:0005322', ('454', '457'))	('DSS', 'Chemical', '-', (199, 202))	('Harvard Lung Cancer', 'Disease', (376, 395))	('UGH', 'Chemical', '-', (575, 578))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (682, 696))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (512, 540))	('lung squamous cell carcinoma', 'Disease', (512, 540))	('CDH13', 'Gene', (147, 152))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (547, 573))	('Cancer', 'Phenotype', 'HP:0002664', (869, 875))	('Cancer', 'Disease', 'MESH:D009369', (690, 696))	('Harvard Lung Cancer', 'Disease', 'MESH:D008175', (376, 395))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('16', '30'))	('single nucleotide polymorphisms', 'Var', (756, 787))	('carcinoma', 'Phenotype', 'HP:0030731', (531, 540))	('Cancer', 'Disease', (869, 875))	('low density lipoprotein', 'molecular_function', 'GO:0005322', ('458', '481'))	('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))	('false', 'biological_process', 'GO:0071877', ('106', '111'))	('protein', 'cellular_component', 'GO:0003675', ('852', '859'))	('Lung Cancer', 'Phenotype', 'HP:0100526', (384, 395))	('carcinoma', 'Phenotype', 'HP:0030731', (497, 506))	('Colorectal and Ovarian Cancer', 'Disease', 'MESH:D015179', (667, 696))	('cadherin', 'molecular_function', 'GO:0008014', ('164', '172'))	('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))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('16', '30'))	('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))	('binding', 'molecular_function', 'GO:0005488', ('844', '851'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (487, 506))	('false', 'biological_process', 'GO:0071878', ('106', '111'))	('Cancer', 'Disease', (690, 696))	('APOB            apolipoprotein B', 'Phenotype', 'HP:0031798', (0, 32))	('Cancer', 'Disease', 'MESH:D009369', (389, 395))	('SREBP', 'Gene', (801, 806))	('OS', 'Chemical', '-', (622, 624))
11856	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))	('EGFR', 'Gene', (92, 96))	('cancer', 'Disease', (159, 165))	('AKT', 'Gene', '207', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('drug resistance', 'biological_process', 'GO:0009315', ('43', '58'))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('drug resistance', 'biological_process', 'GO:0042493', ('43', '58'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('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))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('drug resistance', 'CPA', (43, 58))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', (200, 206))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
11860	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))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('mTOR', 'Gene', '2475', (101, 105))	('protein kinase B', 'Gene', (47, 63))	('mammalian target of rapamycin', 'Gene', '2475', (70, 99))	('AKT', 'Gene', '207', (65, 68))	('EGFR', 'Gene', '1956', (180, 184))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('146', '169'))	('CD109', 'Gene', (31, 36))	('association', 'Interaction', (125, 136))	('mammalian target of rapamycin', 'Gene', (70, 99))	('CD109', 'Chemical', '-', (31, 36))	('expression', 'Var', (17, 27))	('epidermal growth factor receptor', 'Gene', (146, 178))	('epidermal growth factor receptor', 'Gene', '1956', (146, 178))	('mTOR', 'Gene', (101, 105))	('AKT', 'Gene', (65, 68))	('EGFR', 'Gene', (180, 184))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))
11861	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))	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('EGFR', 'molecular_function', 'GO:0005006', ('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))	('EGF', 'molecular_function', 'GO:0005154', ('63', '66'))	('activation', 'MPA', (76, 86))	('CD109', 'Gene', (14, 19))	('CD109', 'Chemical', '-', (14, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('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))
11863	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))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('mTOR', 'Gene', (65, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('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))
11870	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))
11887	32133706	shRNAs for human CD109 (TRCN0000073649 and TRCN0000073650) were obtained from the National RNAi Core Facility (Academia Sinica, Taipei, Taiwan).	('TRCN0000073649', 'Var', (24, 38))	('human', 'Species', '9606', (11, 16))	('RNAi', 'biological_process', 'GO:0016246', ('91', '95'))	('CD109', 'Chemical', '-', (17, 22))	('TRCN0000073650', 'Var', (43, 57))
11912	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))
11913	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))
11916	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))	('silencing', 'Var', (110, 119))	('tumor', 'Disease', (262, 267))	('CL1-5', 'Gene', (39, 44))	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (39, 44))	('CD109', 'Chemical', '-', (123, 128))	('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))
11917	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))	('PC9', 'Gene', '255738', (75, 78))	('invasion', 'CPA', (63, 71))	('CD109', 'Chemical', '-', (34, 39))	('PC9', 'Gene', (75, 78))	('enhanced', 'PosReg', (40, 48))
11922	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))
11923	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).	('CD109', 'Chemical', '-', (19, 24))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 188))	('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))
11925	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))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('CD109', 'Chemical', '-', (38, 43))	('A549', 'CellLine', 'CVCL:0023', (137, 141))	('CD109-promoted', 'Var', (38, 52))
11926	32133706	Results showed that the AKT signaling cascade, including mTOR, 70S6K, and GSK3beta, was downregulated after knocking-down CD109 (Figure 3A).	('AKT signaling cascade', 'biological_process', 'GO:0043491', ('24', '45'))	('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))	('GSK', 'molecular_function', 'GO:0050321', ('74', '77'))	('AKT', 'Gene', '207', (24, 27))	('downregulated', 'NegReg', (88, 101))
11927	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))
11934	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))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('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))
11938	32133706	We hypothesized that the presence of CD109 might enhance activation of the EGFR towards its ligand, including EGF.	('EGF', 'Gene', '1950', (110, 113))	('activation', 'MPA', (57, 67))	('EGF', 'Gene', (75, 78))	('CD109', 'Gene', (37, 42))	('CD109', 'Chemical', '-', (37, 42))	('ligand', 'molecular_function', 'GO:0005488', ('92', '98'))	('EGF', 'Gene', '1950', (75, 78))	('enhance', 'PosReg', (49, 56))	('EGF', 'molecular_function', 'GO:0005154', ('110', '113'))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGF', 'Gene', (110, 113))	('EGFR', 'Gene', '1956', (75, 79))	('presence', 'Var', (25, 33))	('EGFR', 'Gene', (75, 79))
11939	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('EGF', 'Gene', (39, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('CD109', 'Chemical', '-', (22, 27))	('diminished', 'NegReg', (28, 38))	('AKT', 'Gene', '207', (98, 101))	('EGF', 'Gene', '1950', (74, 77))	('phosphorylation', 'MPA', (51, 66))	('EGF', 'Gene', '1950', (39, 42))	('EGFR', 'Gene', '1956', (74, 78))	('EGF', 'molecular_function', 'GO:0005154', ('39', '42'))	('inhibition', 'Var', (8, 18))	('AKT', 'Gene', (98, 101))	('EGFR', 'Gene', (74, 78))
11942	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))	('gefitinib', 'Chemical', 'MESH:D000077156', (147, 156))	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (86, 91))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', (62, 66))	('sensitive', 'MPA', (134, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('resistance', 'MPA', (48, 58))	('KRAS', 'Gene', (20, 24))
11943	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))
11944	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))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('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))
11945	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', 'molecular_function', 'GO:0005006', ('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))	('AKT signaling', 'biological_process', 'GO:0043491', ('70', '83'))	('sensitivity', 'MPA', (50, 61))
11949	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))	('phosphatidylinositol 3-kinase signaling', 'biological_process', 'GO:0014065', ('49', '88'))	('altered', 'Reg', (121, 128))	('CD109', 'Gene', (148, 153))	('CD109', 'Chemical', '-', (148, 153))
11950	32133706	These data echoed findings of the downregulation of AKT/mTOR/GSK3beta signaling by CD109 silencing (Figure 3).	('mTOR', 'Gene', (56, 60))	('GSK', 'molecular_function', 'GO:0050321', ('61', '64'))	('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))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('silencing', 'Var', (89, 98))	('AKT', 'Gene', '207', (52, 55))
11951	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))
11952	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))
11961	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))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('CD109', 'Chemical', '-', (23, 28))	('inducing', 'PosReg', (145, 153))	('CD109', 'Var', (23, 28))	('TGF-beta', 'Gene', '7039', (217, 225))	('degradation', 'biological_process', 'GO:0009056', ('113', '124'))	('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))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('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))	('transduction', 'biological_process', 'GO:0009293', ('201', '213'))
11966	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))	('EGFR', 'Gene', (63, 67))	('mTOR', 'Gene', (125, 129))	('AKT', 'Gene', (121, 124))	('EGFR', 'Gene', '1956', (81, 85))	('enhanced', 'PosReg', (72, 80))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('CD109', 'Var', (33, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('associated', 'Reg', (43, 53))	('AKT', 'Gene', '207', (121, 124))	('EGFR', 'Gene', (81, 85))
11969	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))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('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))
11972	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))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('mutant', 'Var', (137, 143))	('lung tumor', 'Phenotype', 'HP:0100526', (144, 154))	('CD109', 'Gene', (32, 37))
11977	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))	('expression', 'MPA', (47, 57))	('adenocarcinomas', 'Disease', (105, 120))	('high', 'Var', (36, 40))	('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))
11978	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))
11981	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))
11982	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.	('H-Ras', 'Gene', '15461', (103, 108))	('CD109', 'Chemical', '-', (162, 167))	('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', (103, 108))
11983	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))
11984	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))
11991	31953485	Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions.	('mutations', 'Var', (66, 75))	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('evolutionary', 'CPA', (223, 235))	('CRC', 'Disease', 'MESH:D015179', (120, 123))	('metastases', 'Disease', (136, 146))	('CRC', 'Disease', (120, 123))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('affect', 'Reg', (202, 208))	('RAS', 'Gene', (92, 95))
12001	31953485	Current analyses of primary and metastatic CRC indicate low rates of variation between tumor sites for the clinically-relevant mutations that may impact upon treatment decisions.	('CRC', 'Disease', 'MESH:D015179', (43, 46))	('impact', 'Reg', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('CRC', 'Disease', (43, 46))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutations', 'Var', (127, 136))
12016	31953485	Loci harboring clinically-relevant mutations of TP53 (codons 175, 213, 245, 248, 273 and 306), APC (codons 1378 and 1450), KRAS (codons 12, 13, 22, 61, 117 and 146), NRAS (codons 12, 13 and 61), PIK3CA (codons 539, 542, 545 and 1047), and BRAF (codon 600) were captured by multiplex amplification on Fluidigm access arrays (South San Francisco, CA) using 50 ng of DNA.	('PIK3CA', 'Gene', (195, 201))	('TP53', 'Gene', '7157', (48, 52))	('NRAS', 'Gene', (166, 170))	('APC', 'Disease', (95, 98))	('BRAF', 'Gene', (239, 243))	('BRAF', 'Gene', '673', (239, 243))	('TP53', 'Gene', (48, 52))	('NRAS', 'Gene', '4893', (166, 170))	('PIK3CA', 'Gene', '5290', (195, 201))	('APC', 'cellular_component', 'GO:0005680', ('95', '98'))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', '3845', (123, 127))	('DNA', 'cellular_component', 'GO:0005574', ('364', '367'))	('APC', 'Disease', 'MESH:D011125', (95, 98))	('mutations', 'Var', (35, 44))
12023	31953485	In cases of copy neutral loss of heterozygosity, we add half of alternate reads to the number of reference reads and use it as the new value for reference read counts (Copy Neutral LOH: Ref' = Ref + Alt/2; Alt' = Alt/2).	('copy neutral', 'Var', (12, 24))	('Alt', 'molecular_function', 'GO:0004021', ('206', '209'))	('Alt/2', 'Gene', '84706', (213, 218))	('Alt/2', 'Gene', '84706', (199, 204))	('Alt', 'molecular_function', 'GO:0004021', ('199', '202'))	('Alt', 'molecular_function', 'GO:0004021', ('213', '216'))	('loss', 'NegReg', (25, 29))	('Alt/2', 'Gene', (199, 204))	('Alt/2', 'Gene', (213, 218))
12029	31953485	As reported recently, mutational signatures can shed light on mutagenic processes that affect cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutational', 'Var', (22, 32))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
12030	31953485	We observed that the primary tumor in patient-009 (REACT-009-A) and metastatic samples REACT-010-B and E are enriched for signature 6 (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patient', 'Species', '9606', (38, 45))	('tumor', 'Disease', (29, 34))	('REACT-010-B', 'Var', (87, 98))
12033	31953485	Our WES results from patient-009's primary tumor confirmed a hypermutated genome in this tumor, with mutations in the MMR genes MSH2 and MSH5 (Supplementary Tables 1 and 4).	('mutations', 'Var', (101, 110))	('hypermutated', 'Var', (61, 73))	('patient', 'Species', '9606', (21, 28))	('MMR', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('MSH5', 'Gene', '4439', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MSH5', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MSH2', 'Gene', (128, 132))	('MMR', 'biological_process', 'GO:0006298', ('118', '121'))	('MSH2', 'Gene', '4436', (128, 132))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
12034	31953485	Next, we focused on non-silent somatic mutations in primary tumors, and identified 1116 such mutations affecting 1019 genes following manual in silico verification of mutations using Integrative Genomics Viewer (IGV) (Supplementary Table 4).	('mutations', 'Var', (93, 102))	('primary tumors', 'Disease', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('primary tumors', 'Disease', 'MESH:D001932', (52, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
12036	31953485	Among these 9 patients, APC and TP53 were the most frequently mutated genes affected by somatic mutations in 78% followed by KRAS which was mutated in 44% of primary tumors (Fig.	('primary tumors', 'Disease', (158, 172))	('APC', 'cellular_component', 'GO:0005680', ('24', '27'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KRAS', 'Gene', (125, 129))	('TP53', 'Gene', '7157', (32, 36))	('KRAS', 'Gene', '3845', (125, 129))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('primary tumors', 'Disease', 'MESH:D001932', (158, 172))	('TP53', 'Gene', (32, 36))	('APC', 'Disease', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (96, 105))
12041	31953485	Notably, these genes were not mutated concurrently in tumors highlighting a mutually-exclusive pattern for RAS pathway mutations (Fig.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('RAS pathway', 'Pathway', (107, 118))	('mutations', 'Var', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
12042	31953485	Three patients were affected with PIK3CA mutations, two of which (E545G and Q546K) have been previously reported in CRC.	('Q546K', 'Mutation', 'rs121913286', (76, 81))	('E545G', 'Var', (66, 71))	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('PIK3CA', 'Gene', (34, 40))	('E545G', 'Mutation', 'rs121913274', (66, 71))	('Q546K', 'Var', (76, 81))	('CRC', 'Disease', 'MESH:D015179', (116, 119))	('affected', 'Reg', (20, 28))	('PIK3CA', 'Gene', '5290', (34, 40))	('patients', 'Species', '9606', (6, 14))	('CRC', 'Disease', (116, 119))
12043	31953485	A third PIK3CA mutation (H665D) with uncertain clinical significance has no previous record in COSMIC database, but was predicted as likely functional based on CADD and fitCons scores.	('H665D', 'Mutation', 'p.H665D', (25, 30))	('H665D', 'Var', (25, 30))	('fitCons', 'Disease', 'None', (169, 176))	('fitCons', 'Disease', (169, 176))	('PIK3CA', 'Gene', (8, 14))	('PIK3CA', 'Gene', '5290', (8, 14))
12044	31953485	Three additional tumors were affected with mutations in PIK3C2G, resulting in a frequency of 55.5% of primary samples affected with PI3K pathway mutations (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('132', '136'))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('PI3K pathway', 'Pathway', (132, 144))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (43, 52))	('PIK3C2G', 'Gene', (56, 63))	('PIK3C2G', 'Gene', '5288', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
12047	31953485	Analysis of the chromosomal copy number alterations (CNAs) revealed highly recurrent amplifications of 13q in 75% (6/8) of primary tumors.	('amplifications', 'Var', (85, 99))	('primary tumors', 'Disease', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('primary tumors', 'Disease', 'MESH:D001932', (123, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))
12048	31953485	This was followed by gains of 11q and 6q in 50% (4/8) and 37.5% (3/8) of primary tumors, respectively.	('primary tumors', 'Disease', (73, 87))	('11q', 'Var', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('primary tumors', 'Disease', 'MESH:D001932', (73, 87))	('gains', 'PosReg', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
12055	31953485	Our results show that patients who had received an interval treatment seem to show a greater decrease in the total number of complete arm aberrations, that is loss or gain of a complete chromosome arm, between their samples (REACT-007, REACT-008 and REACT-014) compared to patients who did not receive any treatment (REACT-011 and REACT-015) (Supplementary Table 5).	('patients', 'Species', '9606', (273, 281))	('loss', 'NegReg', (159, 163))	('patients', 'Species', '9606', (22, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('REACT-014', 'Var', (250, 259))	('decrease', 'NegReg', (93, 101))	('REACT-007', 'Var', (225, 234))	('gain', 'PosReg', (167, 171))
12059	31953485	Analysis of primary tumor and metastases in patients who had received no interval therapy revealed consistency for presence and relative frequency of identified driver mutations.	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('metastases', 'Disease', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (168, 177))	('metastases', 'Disease', 'MESH:D009362', (30, 40))	('tumor', 'Disease', (20, 25))
12060	31953485	For example, in patient REACT-001, where no interval chemotherapy was administered, the relative frequency of main driver mutations (APC E1288*, TP53 L125LH, and KRAS G12A) did not change between the primary and metastatic tumors, suggesting that the cluster of cells disseminated from the primary tumor to form the metastatic tumor harbored the entire set of main driver mutations (i.e.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('KRAS', 'Gene', '3845', (162, 166))	('TP53', 'Gene', '7157', (145, 149))	('patient', 'Species', '9606', (16, 23))	('G12A', 'Mutation', 'rs876658274', (167, 171))	('KRAS', 'Gene', (162, 166))	('APC', 'Disease', 'MESH:D011125', (133, 136))	('tumor', 'Disease', (298, 303))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('APC', 'Disease', (133, 136))	('E1288*', 'SUBSTITUTION', 'None', (137, 143))	('tumor', 'Disease', (327, 332))	('E1288*', 'Var', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('APC', 'cellular_component', 'GO:0005680', ('133', '136'))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('tumor', 'Disease', (223, 228))	('TP53', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))
12065	31953485	TP53 (R114H) and APC (E1379*) mutations exist in a sub-clone present in relatively high frequency in both primary and metastasis.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('E1379*', 'Var', (22, 28))	('APC', 'Disease', 'MESH:D011125', (17, 20))	('APC', 'Disease', (17, 20))	('R114H', 'Mutation', 'rs28934576', (6, 11))	('APC', 'cellular_component', 'GO:0005680', ('17', '20'))	('E1379*', 'SUBSTITUTION', 'None', (22, 28))
12066	31953485	However, relative abundance of a fraction of cells harboring PIK3CA (H665D) and mTOR (V1795M) mutations, which are predicted as likely functional mutations, declined substantially in the lung metastasis compared to the primary tumor (Fig.	('lung metastasis', 'CPA', (187, 202))	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', (227, 232))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('declined', 'NegReg', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('V1795M', 'Mutation', 'p.V1795M', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('H665D', 'Mutation', 'p.H665D', (69, 74))
12067	31953485	This could be due to either cytotoxicity on the metastatic tumor or the absence of these mutations in the cluster of cells that disseminated from the primary tumor to form the lung metastasis.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (59, 64))	('absence', 'NegReg', (72, 79))	('cytotoxicity', 'Disease', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
12068	31953485	Interestingly, the most frequent cell population shows a relatively stable frequency in the metastatic lesion, which may be explained by the presence of the TP53 mutation, possibly conferring resistance to chemotherapy in these cells.	('TP53', 'Gene', (157, 161))	('presence', 'Var', (141, 149))	('metastatic lesion', 'CPA', (92, 109))	('mutation', 'Var', (162, 170))	('TP53', 'Gene', '7157', (157, 161))
12069	31953485	The possible elimination of the sub-clone harboring mutations in mTOR, PIK3CA and a FAT4 due to adjuvant chemotherapy could have happened either in the primary tumor or in the metastasis.	('mTOR', 'Gene', (65, 69))	('mutations', 'Var', (52, 61))	('mTOR', 'Gene', '2475', (65, 69))	('PIK3CA', 'Gene', '5290', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('FAT4', 'Gene', '79633', (84, 88))	('FAT4', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('PIK3CA', 'Gene', (71, 77))
12076	31953485	Metastases in the liver share the same mutational profile for the driver mutations along with some private mutations in each (Fig.	('Metastases', 'Disease', (0, 10))	('mutations', 'Var', (73, 82))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
12078	31953485	In contrast, for two lung metastatic tumors, which are only one-month apart, each harbor an exclusive driver mutation which is absent in the other.	('lung metastatic tumors', 'Disease', (21, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('lung metastatic tumors', 'Disease', 'MESH:D008175', (21, 43))	('mutation', 'Var', (109, 117))
12079	31953485	These are APC Q1349* (depicted by orange color in Fig.	('Q1349*', 'Var', (14, 20))	('APC', 'cellular_component', 'GO:0005680', ('10', '13'))	('APC', 'Disease', 'MESH:D011125', (10, 13))	('APC', 'Disease', (10, 13))	('Q1349*', 'SUBSTITUTION', 'None', (14, 20))
12080	31953485	4), which is present only in REACT-010-C, and a start loss mutation in TP53 (depicted by dark blue in Fig.	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('mutation', 'Var', (59, 67))
12083	31953485	The similar profiles of driver mutations in the liver lesions (B and E) suggest that although these metastases manifested at different times, their founding cell-clusters disseminated around the same time.	('metastases', 'Disease', (100, 110))	('mutations', 'Var', (31, 40))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('liver lesions', 'Disease', 'MESH:D017093', (48, 61))	('liver lesions', 'Disease', (48, 61))
12090	31953485	The tumors did not have mutations in any RAS pathway gene, but they share a missense mutation in the epigenetic modifier gene KMT2C, which shows high allele frequency in both lesions.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('missense mutation', 'Var', (76, 93))	('KMT2C', 'Gene', '58508', (126, 131))	('KMT2C', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
12092	31953485	The shift in the allele frequencies of all the mutations towards higher values in the lung metastasis REACT-011-C suggests that relatively higher allele frequency of the main driver mutations in this tumor could be due to differences in tumor content between the two metastatic samples (40% vs 60%) (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('higher', 'PosReg', (139, 145))	('mutations', 'Var', (182, 191))
12094	31953485	While our findings support previous studies highlighting the persistence of known clinically-relevant mutations between primary and metastatic CRC lesions, we showed that, when present in the primary tumor, clinically-relevant KRAS and NRAS mutations are transmitted to the metastatic lesions of different organs and likely represent ubiquitous driver mutations.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('transmitted', 'Reg', (255, 266))	('KRAS', 'Gene', (227, 231))	('CRC', 'Disease', 'MESH:D015179', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('KRAS', 'Gene', '3845', (227, 231))	('NRAS', 'Gene', (236, 240))	('tumor', 'Disease', (200, 205))	('CRC', 'Disease', (143, 146))	('NRAS', 'Gene', '4893', (236, 240))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('mutations', 'Var', (241, 250))
12098	31953485	In CRC, analysis of cell lines and biopsy tissue from patients with tumors previously wild-type for KRAS mutations has shown that cetuximab treatment results in the emergence of KRAS-mutated sub-clones, as detected by analyzing circulating tumor DNA (ctDNA).	('KRAS', 'Gene', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (105, 114))	('CRC', 'Disease', (3, 6))	('tumor', 'Disease', (68, 73))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('tumor', 'Disease', (240, 245))	('KRAS', 'Gene', '3845', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('KRAS', 'Gene', (178, 182))	('CRC', 'Disease', 'MESH:D015179', (3, 6))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumors', 'Disease', (68, 74))	('KRAS', 'Gene', '3845', (100, 104))
12101	31953485	Notably, however, in the lung metastasis of patient REACT-008 we observed that cells affected by mTOR or PIK3CA mutations were eliminated following chemotherapy.	('PIK3CA', 'Gene', (105, 111))	('patient', 'Species', '9606', (44, 51))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('PIK3CA', 'Gene', '5290', (105, 111))	('mutations', 'Var', (112, 121))
12105	31953485	Interestingly, these tumors exhibited different mutational landscapes as WES revealed a hypermutated genome only in the primary and not in the recurrent tumor.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('hypermutated', 'Var', (88, 100))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
12107	31953485	By examining mutations of candidate genes, it has been suggested that anastomotic recurrences are clonally related to primary tumors.	('primary tumors', 'Disease', 'MESH:D001932', (118, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('primary tumors', 'Disease', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (13, 22))
12108	31953485	However, this study included only microsatellite stable tumors, whereas tumor 9A in our study is a hypermutated tumor with mutations in MSH2 and MSH5 genes, suggesting that this tumor is affected by microsatellite instability.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('MSH2', 'Gene', (136, 140))	('tumors', 'Disease', (56, 62))	('tumor', 'Disease', (178, 183))	('MSH2', 'Gene', '4436', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (56, 61))	('MSH5', 'Gene', '4439', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('MSH5', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (123, 132))
12109	31953485	Development of malignancy through clonal expansion may occur due to somatic mutations in key genes, for example in KRAS and NRAS in CRC, leading to dysregulation of the normal homeostatic mechanisms.	('CRC', 'Disease', (132, 135))	('mutations', 'Var', (76, 85))	('NRAS', 'Gene', '4893', (124, 128))	('KRAS', 'Gene', (115, 119))	('malignancy', 'Disease', 'MESH:D009369', (15, 25))	('KRAS', 'Gene', '3845', (115, 119))	('malignancy', 'Disease', (15, 25))	('CRC', 'Phenotype', 'HP:0003003', (132, 135))	('CRC', 'Disease', 'MESH:D015179', (132, 135))	('leading to', 'Reg', (137, 147))	('dysregulation', 'MPA', (148, 161))	('NRAS', 'Gene', (124, 128))
12110	31953485	Mutations conferring growth advantage are drivers of the carcinogenic and metastatic process and provide clinically-relevant targets for treatment.	('carcinogenic', 'Disease', (57, 69))	('Mutations', 'Var', (0, 9))	('growth advantage', 'CPA', (21, 37))	('carcinogenic', 'Disease', 'MESH:D063646', (57, 69))
12114	31953485	Furthermore, driver gene mutations were constantly present with high frequency in both liver lesions, a pattern which was not the same in lung metastatic tumors.	('lung metastatic tumors', 'Disease', (138, 160))	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('liver lesions', 'Disease', 'MESH:D017093', (87, 100))	('liver lesions', 'Disease', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lung metastatic tumors', 'Disease', 'MESH:D008175', (138, 160))
12120	31953485	Although presence of KRAS mutations using standardized clinical techniques may predict for resistance to anti-EGFR therapy, responses in KRAS wild-type tumors are not universal (single-agent response rates of 10-41%).	('KRAS', 'Gene', '3845', (21, 25))	('predict', 'Reg', (79, 86))	('EGFR', 'Gene', '1956', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('EGFR', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('resistance', 'MPA', (91, 101))	('mutations', 'Var', (26, 35))	('KRAS', 'Gene', (137, 141))	('KRAS', 'Gene', (21, 25))	('tumors', 'Disease', (152, 158))	('KRAS', 'Gene', '3845', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
12121	31953485	Use of alternative technologies may detect low-level, or less frequent, KRAS mutations of uncertain clinical significance, undetectable by standard direct-sequencing and may also detect regional intratumor heterogeneity possibly directing treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('detect', 'Reg', (179, 185))	('KRAS', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('KRAS', 'Gene', '3845', (72, 76))	('tumor', 'Disease', (200, 205))	('mutations', 'Var', (77, 86))
12124	31953485	Data from our patient cohort highlights tumors lacking known clinically-relevant KRAS mutations with a complex, heterogeneous mutational landscape characterized by the presence of non-RAS mutations, as well as other KRAS mutations of uncertain clinical significance.	('KRAS', 'Gene', '3845', (81, 85))	('mutations', 'Var', (86, 95))	('mutations', 'Var', (188, 197))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('patient', 'Species', '9606', (14, 21))	('KRAS', 'Gene', (81, 85))	('KRAS', 'Gene', (216, 220))	('tumors', 'Disease', (40, 46))	('KRAS', 'Gene', '3845', (216, 220))	('non-RAS', 'Protein', (180, 187))
12128	31953485	As there is greater understanding of the molecular landscape of CRC and as non-invasive methods of molecular testing become more frequently ultilised targeted ultra-deep sequencing of driver mutations provides a powerful tool to monitor tumor behavior in clinic, and to identify recurrent lesions, molecularly distinct from primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Disease', (237, 242))	('CRC', 'Disease', 'MESH:D015179', (64, 67))	('mutations', 'Var', (191, 200))	('primary tumors', 'Disease', (324, 338))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('CRC', 'Disease', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('primary tumors', 'Disease', 'MESH:D001932', (324, 338))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('tumor', 'Disease', (332, 337))
12129	31953485	This technique demonstrates high sensitivity for mutation detection and its use in this study has confirmed the persistence of clinically-relevant mutations between primary tumor and metastatic lesions.	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('mutations', 'Var', (147, 156))
12185	31885740	In silico analysis demonstrated that the altered expression of eIF3D was at least regulated by both copy number alterations (CNAs) and the hypomethylation of cg14297023 site.	('cg14297023 site', 'Var', (158, 173))	('cg14297023', 'Chemical', '-', (158, 168))	('eIF3D', 'Gene', (63, 68))	('copy number alterations', 'Var', (100, 123))	('expression', 'MPA', (49, 59))	('eIF3', 'cellular_component', 'GO:0005852', ('63', '67'))	('eIF3D', 'Gene', '8664', (63, 68))	('hypomethylation', 'Var', (139, 154))
12186	31885740	In conclusion, high eIF3D expression might serve as a valuable independent prognostic indicator of shorter OS in patients with LUAD.	('high', 'Var', (15, 19))	('expression', 'MPA', (26, 36))	('eIF3D', 'Gene', (20, 25))	('eIF3', 'cellular_component', 'GO:0005852', ('20', '24'))	('patients', 'Species', '9606', (113, 121))	('eIF3D', 'Gene', '8664', (20, 25))	('shorter OS', 'Disease', (99, 109))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
12193	31885740	Its dysregulation would result in abnormal gene expression and lead to uncontrolled cell growth, which potentially caused tumourigenesis.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('cell growth', 'biological_process', 'GO:0016049', ('84', '95'))	('gene expression', 'MPA', (43, 58))	('result', 'Reg', (24, 30))	('caused', 'Reg', (115, 121))	('dysregulation', 'Var', (4, 17))	('tumour', 'Disease', (122, 128))	('abnormal', 'Reg', (34, 42))	('lead to', 'Reg', (63, 70))	('uncontrolled', 'MPA', (71, 83))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
12203	31885740	The phenotypic data included sample types, histological types, age at initial pathologic diagnosis, gender, pathologic stage, radiation therapy, targeted molecular therapy, residual tumour status, canonical mutations in KRAS/EGFR/ALK, tobacco smoking history, OS status, and OS time (weeks).	('tobacco', 'Species', '4097', (235, 242))	('tumour', 'Disease', (182, 188))	('KRAS', 'Gene', '3845', (220, 224))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('EGFR', 'Gene', '1956', (225, 229))	('ALK', 'Gene', (230, 233))	('mutations', 'Var', (207, 216))	('EGFR', 'Gene', (225, 229))	('KRAS', 'Gene', (220, 224))	('ALK', 'Gene', '238', (230, 233))	('EGFR', 'molecular_function', 'GO:0005006', ('225', '229'))
12216	31885740	The high eIF3D expression group had a significantly larger ratio of patients with residual tumour (13/4 vs. 163/176, p = 0.0257) and targeted molecular therapy (85/65 vs. 138/164, p = 0.0357).	('eIF3D', 'Gene', '8664', (9, 14))	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('patients', 'Species', '9606', (68, 76))	('eIF3D', 'Gene', (9, 14))	('high', 'Var', (4, 8))	('eIF3', 'cellular_component', 'GO:0005852', ('9', '13'))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
12222	31885740	No significant differences in prognosis were observed between patients with high and low eIF3A, eIF3C, eIF3E, eIF3H, eIF3I, and eIF3J expression levels.	('eIF3I', 'Gene', '8668', (117, 122))	('eIF3', 'cellular_component', 'GO:0005852', ('103', '107'))	('eIF3', 'cellular_component', 'GO:0005852', ('89', '93'))	('eIF3', 'cellular_component', 'GO:0005852', ('110', '114'))	('patients', 'Species', '9606', (62, 70))	('eIF3E', 'Gene', (103, 108))	('eIF3C', 'Gene', (96, 101))	('eIF3', 'cellular_component', 'GO:0005852', ('117', '121'))	('eIF3A', 'Gene', '8661', (89, 94))	('low', 'NegReg', (85, 88))	('eIF3C', 'Gene', '8663', (96, 101))	('eIF3I', 'Gene', (117, 122))	('eIF3H', 'Gene', (110, 115))	('high', 'Var', (76, 80))	('eIF3', 'cellular_component', 'GO:0005852', ('128', '132'))	('eIF3J', 'Gene', (128, 133))	('eIF3J', 'Gene', '8669', (128, 133))	('eIF3E', 'Gene', '3646', (103, 108))	('eIF3', 'cellular_component', 'GO:0005852', ('96', '100'))	('eIF3A', 'Gene', (89, 94))	('eIF3H', 'Gene', '8667', (110, 115))
12230	31885740	Besides, Kaplan-Meier survival analysis showed that patients with CNA gains exhibited significantly worse prognosis than those with CNA losses and copy neutral (p = 0.0427, Figure 4(d)).	('CNA', 'Var', (66, 69))	('patients', 'Species', '9606', (52, 60))	('gains', 'PosReg', (70, 75))
12233	31885740	Overall, these results indicated that the expression of eIF3D was at least regulated by both CNAs and cg14297023 methylation.	('eIF3D', 'Gene', '8664', (56, 61))	('cg14297023', 'Chemical', '-', (102, 112))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('methylation', 'Var', (113, 124))	('expression', 'MPA', (42, 52))	('cg14297023 methylation', 'Var', (102, 124))	('eIF3', 'cellular_component', 'GO:0005852', ('56', '60'))	('eIF3D', 'Gene', (56, 61))	('CNAs', 'Gene', (93, 97))
12237	31885740	Deregulation of eIF3 expression and/or function has been proposed to play either a causal role or at least contribute to the etiology of various cancer entities.	('cancer', 'Disease', (145, 151))	('play', 'Reg', (69, 73))	('Deregulation', 'Var', (0, 12))	('eIF3', 'Gene', '8661', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('expression', 'MPA', (21, 31))	('eIF3', 'cellular_component', 'GO:0005852', ('16', '20'))	('eIF3', 'Gene', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('function', 'MPA', (39, 47))
12239	31885740	Studies have revealed that imbalanced expression of single eIF3 subunit may affect the overall expression profiles of the entire eIF3 complex, which may explain why the vast majority of eIF3 subunits were observed to be aberrantly expressed in our study.	('affect', 'Reg', (76, 82))	('eIF3', 'Gene', (59, 63))	('eIF3', 'cellular_component', 'GO:0005852', ('186', '190'))	('imbalanced', 'Var', (27, 37))	('eIF3', 'Gene', '8661', (129, 133))	('eIF3', 'cellular_component', 'GO:0005852', ('59', '63'))	('eIF3', 'Gene', '8661', (59, 63))	('eIF3', 'Gene', (186, 190))	('eIF3', 'Gene', (129, 133))	('expression profiles', 'MPA', (95, 114))	('eIF3', 'cellular_component', 'GO:0005852', ('129', '133'))	('eIF3', 'Gene', '8661', (186, 190))
12240	31885740	The misregulation of eIF3 subunits may contribute to malignancy via several possible means.	('misregulation', 'Var', (4, 17))	('contribute', 'Reg', (39, 49))	('eIF3', 'Gene', '8661', (21, 25))	('malignancy', 'Disease', 'MESH:D009369', (53, 63))	('eIF3', 'cellular_component', 'GO:0005852', ('21', '25'))	('malignancy', 'Disease', (53, 63))	('eIF3', 'Gene', (21, 25))
12241	31885740	First, the altered expression of mammalian eIF3 subunits, especially those in the core regions defined as octamer (a, c, e, f, h, k, l, m) and YLC (Yeast- Like-Core: b, g, i), may impact on the correct assembly of the entire eIF3 complex, leading to irregular mRNA translation and causing disease or its quick progression.	('translation', 'biological_process', 'GO:0006412', ('265', '276'))	('eIF3', 'Gene', '8661', (225, 229))	('disease', 'Disease', (289, 296))	('causing', 'Reg', (281, 288))	('altered', 'Var', (11, 18))	('eIF3', 'Gene', '8661', (43, 47))	('eIF3', 'Gene', (43, 47))	('mammalian', 'Species', '9606', (33, 42))	('mRNA translation', 'MPA', (260, 276))	('leading to', 'Reg', (239, 249))	('core', 'cellular_component', 'GO:0019013', ('82', '86'))	('eIF3', 'Gene', (225, 229))	('impact', 'Reg', (180, 186))	('correct assembly', 'MPA', (194, 210))	('eIF3', 'cellular_component', 'GO:0005852', ('43', '47'))	('eIF3', 'cellular_component', 'GO:0005852', ('225', '229'))
12245	31885740	It is the only subunit whose misregulation affects neither the expression of the other eIF3 subunits nor the integrity of the eIF3 complex but is nonetheless essential for cell proliferation.	('eIF3', 'cellular_component', 'GO:0005852', ('126', '130'))	('eIF3', 'Gene', '8661', (87, 91))	('eIF3', 'Gene', (126, 130))	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('integrity', 'MPA', (109, 118))	('eIF3', 'Gene', (87, 91))	('affects', 'Reg', (43, 50))	('expression', 'MPA', (63, 73))	('eIF3', 'Gene', '8661', (126, 130))	('misregulation', 'Var', (29, 42))	('eIF3', 'cellular_component', 'GO:0005852', ('87', '91'))
12250	31885740	The eIF3D knockdown researches conducted in a series of cancer cell lines involving breast cancer, NSCLC, melanoma, acute myeloid leukaemia, and colon cancer revealed that the deletion of eIF3D caused a significant reduction in cell proliferation and colony formation due to an arrest of cell cycle at G2/M phase, suggesting its key role in cell cycle control and apoptosis.	('deletion', 'Var', (176, 184))	('SCLC', 'Phenotype', 'HP:0030357', (100, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('364', '373'))	('apoptosis', 'biological_process', 'GO:0097194', ('364', '373'))	('eIF3D', 'Gene', '8664', (4, 9))	('eIF3D', 'Gene', '8664', (188, 193))	('colony formation', 'CPA', (251, 267))	('cancer', 'Disease', (56, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (145, 157))	('arrest', 'Disease', 'MESH:D006323', (278, 284))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('formation', 'biological_process', 'GO:0009058', ('258', '267'))	('eIF3D', 'Gene', (4, 9))	('eIF3D', 'Gene', (188, 193))	('M phase', 'biological_process', 'GO:0000279', ('305', '312'))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (151, 157))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))	('colon cancer', 'Disease', 'MESH:D015179', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('288', '298'))	('cell cycle control', 'biological_process', 'GO:1901987', ('341', '359'))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (116, 139))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (122, 139))	('cell proliferation', 'biological_process', 'GO:0008283', ('228', '246'))	('cell proliferation', 'CPA', (228, 246))	('NSCLC', 'Disease', (99, 104))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (116, 139))	('cell cycle at G2/M phase', 'CPA', (288, 312))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('colon cancer', 'Disease', (145, 157))	('arrest', 'Disease', (278, 284))	('cancer', 'Disease', (91, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('reduction', 'NegReg', (215, 224))	('eIF3', 'cellular_component', 'GO:0005852', ('188', '192'))	('eIF3', 'cellular_component', 'GO:0005852', ('4', '8'))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('acute myeloid leukaemia', 'Disease', (116, 139))
12254	31885740	By exploring the modifications of effector proteins in signaling pathways responsible for cell growth and apoptosis, the activations of three cancer-related molecules:AKT, HSP27, and SAPK/JNK:were found to be reduced by eIF3D knockdown in NSCLC cells.	('AKT', 'Gene', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('SAPK', 'Gene', (183, 187))	('HSP27', 'Gene', (172, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('SAPK', 'Gene', '5601', (183, 187))	('knockdown', 'Var', (226, 235))	('eIF3D', 'Gene', '8664', (220, 225))	('cell growth', 'biological_process', 'GO:0016049', ('90', '101'))	('eIF3D', 'Gene', (220, 225))	('JNK', 'Gene', (188, 191))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('AKT', 'Gene', '207', (167, 170))	('JNK', 'molecular_function', 'GO:0004705', ('188', '191'))	('JNK', 'Gene', '5599', (188, 191))	('cancer', 'Disease', (142, 148))	('SCLC', 'Phenotype', 'HP:0030357', (240, 244))	('HSP27', 'Gene', '3315', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('activations', 'MPA', (121, 132))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))	('SAPK', 'molecular_function', 'GO:0004707', ('183', '187'))	('eIF3', 'cellular_component', 'GO:0005852', ('220', '224'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('NSCLC', 'Disease', (239, 244))	('reduced', 'NegReg', (209, 216))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))
12255	31885740	Moreover, a series of phosphorylation upregulation was observed along with downregulation of eIF3D in colon cancer cells, including AMPKalpha, Bad, PRAS409, SAPK/JNK, and GSK3beta, as well as the cleavage of PARP.	('eIF3D', 'Gene', (93, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('colon cancer', 'Disease', (102, 114))	('GSK', 'molecular_function', 'GO:0050321', ('171', '174'))	('PARP', 'Gene', '1302', (208, 212))	('GSK3beta', 'Gene', '2931', (171, 179))	('JNK', 'molecular_function', 'GO:0004705', ('162', '165'))	('upregulation', 'PosReg', (38, 50))	('SAPK', 'Gene', (157, 161))	('phosphorylation', 'MPA', (22, 37))	('downregulation', 'NegReg', (75, 89))	('SAPK', 'Gene', '5601', (157, 161))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('PARP', 'Gene', (208, 212))	('JNK', 'Gene', (162, 165))	('JNK', 'Gene', '5599', (162, 165))	('SAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('GSK3beta', 'Gene', (171, 179))	('PRAS409', 'Var', (148, 155))	('eIF3D', 'Gene', '8664', (93, 98))	('eIF3', 'cellular_component', 'GO:0005852', ('93', '97'))
12258	31885740	Being consistent with our findings, the strong correlations between high eIF3D expression and poor OS outcomes were also observed in patients with GC and GBC, supporting its high potential role to serve as a useful prognostic marker and therapeutic target for the treatment of these cancers.	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('expression', 'MPA', (79, 89))	('high', 'Var', (68, 72))	('eIF3D', 'Gene', '8664', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('cancers', 'Disease', (283, 290))	('patients', 'Species', '9606', (133, 141))	('GC', 'Phenotype', 'HP:0012126', (147, 149))	('GBC', 'Disease', (154, 157))	('eIF3', 'cellular_component', 'GO:0005852', ('73', '77'))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('eIF3D', 'Gene', (73, 78))
12259	31885740	In this study, by assessing the potential mechanisms underlying eIF3D upregulation in LUAD, we found that the eIF3D dysregulation was partly regulated by the CNAs, as well as the hypomethylation of cg14297023 site which locates in the 3'UTR region of eIF3D gene according to the MethHC database (http://methhc.mbc.nctu.edu.tw/php/index.php).	('eIF3D', 'Gene', '8664', (110, 115))	('eIF3D', 'Gene', (64, 69))	('eIF3', 'cellular_component', 'GO:0005852', ('251', '255'))	('eIF3D', 'Gene', (251, 256))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('eIF3', 'cellular_component', 'GO:0005852', ('64', '68'))	('cg14297023', 'Var', (198, 208))	('eIF3D', 'Gene', '8664', (251, 256))	('eIF3D', 'Gene', (110, 115))	('eIF3D', 'Gene', '8664', (64, 69))	('eIF3', 'cellular_component', 'GO:0005852', ('110', '114'))	('cg14297023', 'Chemical', '-', (198, 208))
12260	31885740	Therefore, the specific role of hypomethylation of cg14297023 site on eIF3D expression in LUAD cannot be concluded yet based on these hypotheses.	('eIF3D', 'Gene', '8664', (70, 75))	('cg14297023', 'Var', (51, 61))	('cg14297023', 'Chemical', '-', (51, 61))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('eIF3', 'cellular_component', 'GO:0005852', ('70', '74'))	('eIF3D', 'Gene', (70, 75))
12264	31885740	has revealed that loss-of-function mutations in eIF3L gene resulted in a 40% extension in lifespan in Caenorhabditis elegans, indicating its pivotal functional role in the regulation of cellular and organismal responses to aging.	('aging', 'biological_process', 'GO:0007568', ('223', '228'))	('eIF3', 'cellular_component', 'GO:0005852', ('48', '52'))	('lifespan', 'CPA', (90, 98))	('extension', 'PosReg', (77, 86))	('eIF3L', 'Gene', (48, 53))	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('Caenorhabditis elegans', 'Species', '6239', (102, 124))	('loss-of-function', 'NegReg', (18, 34))	('eIF3L', 'Gene', '51386', (48, 53))	('mutations', 'Var', (35, 44))
12268	31885740	The mutations in KRAS/EGFR/ALK are the most common "driver" mutations detected in LUAD and are considered to play pivotal roles in carcinogenesis at multiple levels, thus acting as important genomic-guided therapeutic targets in LUAD (reviewed by).	('carcinogenesis', 'Disease', (131, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('ALK', 'Gene', (27, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('LUAD', 'Phenotype', 'HP:0030078', (229, 233))	('KRAS', 'Gene', (17, 21))	('EGFR', 'Gene', '1956', (22, 26))	('mutations', 'Var', (4, 13))	('LUAD', 'Disease', (82, 86))	('KRAS', 'Gene', '3845', (17, 21))	('LUAD', 'Phenotype', 'HP:0030078', (82, 86))	('ALK', 'Gene', '238', (27, 30))	('EGFR', 'Gene', (22, 26))
12269	31885740	In our study, the discovery of different expression levels of eIF3J occurring in patients with or without mutations in KRAS/EGFR/ALK (86/46 vs. 47/48, p = 0.0206, Table 1) may provide a clue of its potential impact on LUAD carcinogenesis accompanied by KRAS/EGFR/ALK genomic alterations.	('EGFR', 'Gene', (258, 262))	('eIF3', 'cellular_component', 'GO:0005852', ('62', '66'))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('impact', 'Reg', (208, 214))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('258', '262'))	('ALK', 'Gene', '238', (129, 132))	('KRAS', 'Gene', '3845', (119, 123))	('EGFR', 'Gene', '1956', (258, 262))	('ALK', 'Gene', (129, 132))	('KRAS', 'Gene', (119, 123))	('carcinogenesis', 'Disease', (223, 237))	('ALK', 'Gene', '238', (263, 266))	('KRAS', 'Gene', '3845', (253, 257))	('ALK', 'Gene', (263, 266))	('expression levels', 'MPA', (41, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (223, 237))	('patients', 'Species', '9606', (81, 89))	('EGFR', 'Gene', (124, 128))	('eIF3J', 'Gene', (62, 67))	('KRAS', 'Gene', (253, 257))	('LUAD', 'Phenotype', 'HP:0030078', (218, 222))	('mutations', 'Var', (106, 115))	('eIF3J', 'Gene', '8669', (62, 67))
12282	31402485	Protein-coding genes (PCGs) are the most common biomarkers and involved in the many key biological processes which can be powerful predictors of survival in patients in different cancers.7, 8, 9, 10 Recently, long non-coding RNAs (lncRNAs) are transcripts >200 nucleotides with little coding capacity.	('long non-coding', 'Var', (209, 224))	('ncRNA', 'Gene', (232, 237))	('N', 'Chemical', 'MESH:D009584', (226, 227))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('N', 'Chemical', 'MESH:D009584', (235, 236))	('patients', 'Species', '9606', (157, 165))	('ncRNA', 'Gene', '54719', (232, 237))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Disease', (179, 186))
12294	31402485	We used the R package clusterProfiler to make Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment.25  Expression profiles of 417 samples, along with corresponding clinical data of patients diagnosed with LUAD, were downloaded from GSE31210, GSE37745, and GSE30219.	('GSE30219', 'Var', (284, 292))	('LUAD', 'Disease', (233, 237))	('Gene Ontology', 'biological_process', 'GO:0003673', ('97', '110'))	('GSE31210', 'Var', (260, 268))	('LUAD', 'Disease', 'MESH:C538231', (233, 237))	('GSE37745', 'Var', (270, 278))	('patients', 'Species', '9606', (209, 217))
12305	31402485	When applied the median risk score to the GSE37745 and GSE30219 sets, patients from the two test sets were also divided into two groups, respectively, namely high-risk groups(n = 53/42) and low-risk groups (n = 53/43).Similarly, the survival of patients in the high-risk groups was significantly shorter than those in the low-risk groups (GSE37745 median 2.78, 95% CI: 1.46-4.01 vs 5.94 years, 95% CI: 4.11-7.22, log-rank test P < .001, Figure 2B; GSE30219 median 4.58, 95% CI: 2.33-12.5 vs 16.25 years, 95% CI: 8.58-16.73, log-rank test P = .0063, Figure 2C).	('patients', 'Species', '9606', (70, 78))	('shorter', 'NegReg', (296, 303))	('patients', 'Species', '9606', (245, 253))	('GSE30219', 'Var', (448, 456))	('survival', 'CPA', (233, 241))
12307	31402485	In the training dataset (Figure 3A), GSE37745 (Figure 3B), and GSE30219 (Figure 3C), patients with high expression of NHLRC2 and PLIN5 or low-risk scores had a higher probability of survival, and patients with high-risk scores or high-expressed AC087521.1 and GNAI3 had shorter survival time.	('higher', 'PosReg', (160, 166))	('survival time', 'CPA', (278, 291))	('GSE37745', 'Var', (37, 45))	('high', 'Var', (99, 103))	('PLIN5', 'Gene', '440503', (129, 134))	('patients', 'Species', '9606', (196, 204))	('survival', 'CPA', (182, 190))	('GNAI3', 'Gene', (260, 265))	('PLIN5', 'Gene', (129, 134))	('GSE30219', 'Var', (63, 71))	('patients', 'Species', '9606', (85, 93))	('NHLRC2', 'Gene', '374354', (118, 124))	('NHLRC2', 'Gene', (118, 124))	('shorter', 'NegReg', (270, 277))	('GNAI3', 'Gene', '2773', (260, 265))
12313	31402485	Since GSE30219 without pathological stage information, we performed ROC analysis in two datasets (GSE31210/GSE37745, n = 226/106) to compare the survival prediction efficiency of pathological stage and the PCG-lncRNA signature.	('GSE31210/GSE37745', 'Var', (98, 115))	('ncRNA', 'Gene', (211, 216))	('ncRNA', 'Gene', '54719', (211, 216))	('GSE30219', 'Var', (6, 14))
12326	31402485	We found high expression of GNAI3, AC087521.1 was associated with a short survival time (HR > 1, P < .05) and NHLRC2, PLIN5 was associated with a long survival time (HR < 1, P < .05).	('GNAI3', 'Gene', '2773', (28, 33))	('short survival time', 'CPA', (68, 87))	('AC087521.1', 'Var', (35, 45))	('PLIN5', 'Gene', (118, 123))	('PLIN5', 'Gene', '440503', (118, 123))	('NHLRC2', 'Gene', '374354', (110, 116))	('NHLRC2', 'Gene', (110, 116))	('GNAI3', 'Gene', (28, 33))
12327	31402485	There was a study demonstrated that expression of GNAI3 shared a tight relationship with the prognosis of patients with hepatocellular carcinoma,26 but few research reported the function of AC087521.1, NHLRC2, and PLIN5 in cancer.	('hepatocellular carcinoma', 'Disease', (120, 144))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('PLIN5', 'Gene', '440503', (214, 219))	('AC087521.1', 'Var', (190, 200))	('NHLRC2', 'Gene', '374354', (202, 208))	('NHLRC2', 'Gene', (202, 208))	('GNAI3', 'Gene', (50, 55))	('PLIN5', 'Gene', (214, 219))	('GNAI3', 'Gene', '2773', (50, 55))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))
12331	31402485	In conclusion, using bioinformatics analysis, we identified a PCG-lncRNA signature composed of AC087521.1, GNAI3, NHLRC2, and PLIN5 that accurately predicted the overall survival of patients with LUAD based on three LUAD independent datasets.	('GNAI3', 'Gene', (107, 112))	('LUAD', 'Disease', (216, 220))	('LUAD', 'Disease', 'MESH:C538231', (196, 200))	('LUAD', 'Disease', 'MESH:C538231', (216, 220))	('ncRNA', 'Gene', (67, 72))	('predicted', 'Reg', (148, 157))	('GNAI3', 'Gene', '2773', (107, 112))	('AC087521.1', 'Var', (95, 105))	('ncRNA', 'Gene', '54719', (67, 72))	('PLIN5', 'Gene', '440503', (126, 131))	('patients', 'Species', '9606', (182, 190))	('NHLRC2', 'Gene', '374354', (114, 120))	('NHLRC2', 'Gene', (114, 120))	('PLIN5', 'Gene', (126, 131))	('LUAD', 'Disease', (196, 200))
12339	31637001	Ectopic expression of dominant-negative AMPKalpha partially mitigated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly by activating AMPK.	('mTORC1', 'cellular_component', 'GO:0031931', ('103', '109'))	('AMP', 'Chemical', 'MESH:D000249', (169, 172))	('activating', 'PosReg', (158, 168))	('mTORC1', 'Gene', '382056', (103, 109))	('AMPK', 'MPA', (169, 173))	('inhibitory effect', 'MPA', (74, 91))	('mTORC1', 'Gene', '382056', (141, 147))	('AMP', 'Chemical', 'MESH:D000249', (40, 43))	('inhibits', 'NegReg', (132, 140))	('AMPK', 'molecular_function', 'GO:0050405', ('169', '173'))	('AMPK', 'molecular_function', 'GO:0004691', ('169', '173'))	('mTORC1', 'cellular_component', 'GO:0031931', ('141', '147'))	('AMPKalpha', 'Gene', (40, 49))	('AMPK', 'molecular_function', 'GO:0047322', ('169', '173'))	('mTORC1', 'Gene', (103, 109))	('dominant-negative', 'Var', (22, 39))	('mitigated', 'NegReg', (60, 69))	('mTORC1', 'Gene', (141, 147))
12346	31637001	Studies have reported the various molecular mechanisms underlying these actions, including downregulation of c-myc, cyclin D1/E/B1, cyclin-dependent kinases (CDKs),  survivin, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2/9 (MMP-2/9); upregulation of CDK inhibitors (p21Cip1 and p27Kip1); inhibition of focal adhesion kinase (FAK), small GTPases, nuclear factor kappa B (NF-kappaB), protein kinase C (PKC), and Akt; and activation of p38 and c-Jun N-terminal kinase (JNK).	('NF-kappaB', 'Gene', (399, 408))	('cyclin-dependent kinases', 'Enzyme', (132, 156))	('E/B1', 'Var', (126, 130))	('p38', 'Enzyme', (462, 465))	('focal adhesion', 'cellular_component', 'GO:0005925', ('331', '345'))	('activation', 'PosReg', (448, 458))	('cyclin', 'molecular_function', 'GO:0016538', ('132', '138'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('176', '210'))	('upregulation', 'PosReg', (263, 275))	('CDK', 'molecular_function', 'GO:0004693', ('279', '282'))	('NF-kappaB', 'Gene', '4790', (399, 408))	('FAK', 'Gene', '5747', (354, 357))	('PKC', 'molecular_function', 'GO:0004697', ('429', '432'))	('p21Cip1', 'Var', (295, 302))	('inhibition', 'NegReg', (317, 327))	('cyclin', 'Enzyme', (116, 122))	('N', 'Chemical', 'MESH:D009584', (496, 497))	('protein', 'cellular_component', 'GO:0003675', ('411', '418'))	('MMP-2', 'molecular_function', 'GO:0004228', ('253', '258'))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('survivin', 'Gene', (166, 174))	('Akt', 'Gene', (439, 442))	('CDK inhibitors', 'Enzyme', (279, 293))	('downregulation', 'NegReg', (91, 105))	('N', 'Chemical', 'MESH:D009584', (399, 400))	('c-myc', 'Gene', (109, 114))	('small GTPases', 'Enzyme', (360, 373))	('GTP', 'Chemical', 'MESH:D006160', (366, 369))	('Akt', 'Gene', '207', (439, 442))	('p27Kip1', 'Var', (307, 314))	('FAK', 'molecular_function', 'GO:0004717', ('354', '357'))	('nuclear', 'Enzyme', (375, 382))	('VEGF', 'Gene', '7422', (212, 216))	('N', 'Chemical', 'MESH:D009584', (476, 477))	('JNK', 'molecular_function', 'GO:0004705', ('495', '498'))	('c-Jun', 'Enzyme', (470, 475))	('focal adhesion', 'Pathway', (331, 345))	('E/B1', 'SUBSTITUTION', 'None', (126, 130))	('VEGF', 'Gene', (212, 216))	('FAK', 'Gene', (354, 357))	('c-myc', 'Gene', '4609', (109, 114))
12349	31637001	Deregulated mTOR signaling has been frequently observed in various types of tumors, so mTOR is regarded as a promising target for cancer therapy.	('mTOR', 'Gene', '2475', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mTOR', 'Gene', '2475', (12, 16))	('observed', 'Reg', (47, 55))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('mTOR', 'Gene', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('mTOR', 'Gene', (87, 91))
12356	31637001	In addition, activated AMPK can also phosphorylate regulatory-associated protein of mTOR (raptor) on S792, leading to inhibition of mTORC1.	('mTORC1', 'Gene', (132, 138))	('mTOR', 'Gene', '2475', (132, 136))	('mTOR', 'Gene', (132, 136))	('inhibition', 'NegReg', (118, 128))	('AMPK', 'molecular_function', 'GO:0050405', ('23', '27'))	('mTOR', 'Gene', '2475', (84, 88))	('AMPK', 'molecular_function', 'GO:0004691', ('23', '27'))	('mTOR', 'Gene', (84, 88))	('AMP', 'Chemical', 'MESH:D000249', (23, 26))	('S792', 'Var', (101, 105))	('mTORC1', 'Gene', '382056', (132, 138))	('AMPK', 'molecular_function', 'GO:0047322', ('23', '27'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('mTORC1', 'cellular_component', 'GO:0031931', ('132', '138'))
12357	31637001	While S6K1 (p70 S6 kinase 1) and 4E-BP1 (eukaryotic initiation factor 4E binding protein 1) are two well-known substrates of mTORC1, Akt (S473) is the best-characterized substrate of mTORC2.	('mTORC2', 'cellular_component', 'GO:0031932', ('183', '189'))	('mTORC2', 'Gene', '74343', (183, 189))	('S473', 'Var', (138, 142))	('mTORC1', 'cellular_component', 'GO:0031931', ('125', '131'))	('Akt', 'Gene', '207', (133, 136))	('eukaryotic initiation factor 4E binding', 'molecular_function', 'GO:0008190', ('41', '80'))	('mTORC1', 'Gene', '382056', (125, 131))	('S473', 'Chemical', 'MESH:C015765', (138, 142))	('Akt', 'Gene', (133, 136))	('mTORC1', 'Gene', (125, 131))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('mTORC2', 'Gene', (183, 189))
12358	31637001	Although the biological functions of mTORC1/2 remain to be further determined, evidence indicates that mTOR can control the expression/activity of c-myc, cyclin D1, cyclin-dependent kinases (CDKs), the CDK inhibitor p27Kip1, VEGF, survivin, JNK, NF-kappaB, and MMP-2.	('mTORC1/2', 'Gene', (37, 45))	('p27Kip1', 'Var', (216, 223))	('expression/activity', 'MPA', (124, 143))	('cyclin', 'molecular_function', 'GO:0016538', ('165', '171'))	('mTOR', 'Gene', '2475', (37, 41))	('VEGF', 'Gene', '7422', (225, 229))	('c-myc', 'Gene', '4609', (147, 152))	('NF-kappaB', 'Gene', (246, 255))	('VEGF', 'Gene', (225, 229))	('N', 'Chemical', 'MESH:D009584', (242, 243))	('cyclin', 'molecular_function', 'GO:0016538', ('154', '160'))	('cyclin-dependent', 'MPA', (165, 181))	('NF-kappaB', 'Gene', '4790', (246, 255))	('mTOR', 'Gene', (103, 107))	('mTORC1', 'cellular_component', 'GO:0031931', ('37', '43'))	('mTORC1/2', 'Gene', '74343;382056', (37, 45))	('mTOR', 'Gene', '2475', (103, 107))	('N', 'Chemical', 'MESH:D009584', (246, 247))	('c-myc', 'Gene', (147, 152))	('JNK', 'molecular_function', 'GO:0004705', ('241', '244'))	('MMP-2', 'molecular_function', 'GO:0004228', ('261', '266'))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('202', '215'))	('mTOR', 'Gene', (37, 41))
12359	31637001	Interestingly, of the signaling molecules mediated by mTOR, many of them, e.g., c-myc, cyclin D1, CDKs, p27Kip1, survivin, NF-kappaB, JNK, FAK, small GTPases, MMP-2, and VEGF, are also targeted by G. lucidum extracts.	('CDKs', 'Gene', (98, 102))	('NF-kappaB', 'Gene', '4790', (123, 132))	('p27Kip1', 'Var', (104, 111))	('cyclin', 'molecular_function', 'GO:0016538', ('87', '93'))	('G. lucidum', 'Species', '5315', (197, 207))	('FAK', 'molecular_function', 'GO:0004717', ('139', '142'))	('c-myc', 'Gene', (80, 85))	('VEGF', 'Gene', '7422', (170, 174))	('FAK', 'Gene', (139, 142))	('VEGF', 'Gene', (170, 174))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('MMP-2', 'molecular_function', 'GO:0004228', ('159', '164'))	('GTP', 'Chemical', 'MESH:D006160', (150, 153))	('small GTPases', 'Protein', (144, 157))	('FAK', 'Gene', '5747', (139, 142))	('c-myc', 'Gene', '4609', (80, 85))	('mTOR', 'Gene', (54, 58))	('survivin', 'Protein', (113, 121))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('JNK', 'molecular_function', 'GO:0004705', ('134', '137'))	('mTOR', 'Gene', '2475', (54, 58))	('NF-kappaB', 'Gene', (123, 132))
12392	31637001	In addition, treatment with GLPT for 24 h also dose-dependently decreased the phosphorylation of Akt (S473) (Fig.	('phosphorylation', 'MPA', (78, 93))	('S473', 'Chemical', 'MESH:C015765', (102, 106))	('Akt', 'Gene', (97, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('S473', 'Var', (102, 106))	('Akt', 'Gene', '207', (97, 100))	('decreased', 'NegReg', (64, 73))
12396	31637001	4c); another control, AZD8055, an ATP-competitive and selective inhibitor of mTOR, inhibited both mTORC1 and mTORC2 (Fig.	('mTORC1', 'Gene', '382056', (98, 104))	('mTORC2', 'Gene', (109, 115))	('mTORC2', 'cellular_component', 'GO:0031932', ('109', '115'))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('mTORC2', 'Gene', '74343', (109, 115))	('mTOR', 'Gene', '2475', (109, 113))	('mTORC1', 'cellular_component', 'GO:0031931', ('98', '104'))	('inhibited', 'NegReg', (83, 92))	('mTOR', 'Gene', '2475', (77, 81))	('mTOR', 'Gene', (109, 113))	('mTORC1', 'Gene', (98, 104))	('mTOR', 'Gene', (77, 81))	('AZD8055', 'Chemical', 'MESH:C546624', (22, 29))	('mTOR', 'Gene', '2475', (98, 102))	('mTOR', 'Gene', (98, 102))	('AZD8055', 'Var', (22, 29))
12399	31637001	As predicted, treatment with GLPT for 24 h dose-dependently reduced the levels of p-IGFRbeta, p-PI3K (p85), and p-PDK1 in A549 cells (Fig.	('Rb', 'Disease', 'MESH:D058495', (87, 89))	('p-PDK1', 'Var', (112, 118))	('PDK1', 'molecular_function', 'GO:0004740', ('114', '118'))	('p-PI3K', 'Var', (94, 100))	('reduced', 'NegReg', (60, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('96', '100'))
12405	31637001	In addition, GLPT treatment also activated the AMPK network, as evidenced by increased phosphorylation of AMPKalpha (T172) and the two substrates of AMPK, TSC2 (S1387) and raptor (S792), in A549 cells (Fig.	('AMP', 'Chemical', 'MESH:D000249', (149, 152))	('activated', 'PosReg', (33, 42))	('increased', 'PosReg', (77, 86))	('AMPK', 'molecular_function', 'GO:0050405', ('47', '51'))	('AMPK', 'molecular_function', 'GO:0004691', ('47', '51'))	('AMPK', 'molecular_function', 'GO:0004691', ('149', '153'))	('AMPK', 'molecular_function', 'GO:0050405', ('149', '153'))	('S792', 'Var', (180, 184))	('T172', 'Gene', (117, 121))	('phosphorylation', 'MPA', (87, 102))	('AMPK', 'molecular_function', 'GO:0047322', ('47', '51'))	('AMP', 'Chemical', 'MESH:D000249', (47, 50))	('AMPKalpha', 'Gene', (106, 115))	('AMPK network', 'Pathway', (47, 59))	('AMP', 'Chemical', 'MESH:D000249', (106, 109))	('S1387', 'Chemical', 'MESH:C517209', (161, 166))	('AMPK', 'molecular_function', 'GO:0047322', ('149', '153'))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
12406	31637001	Interestingly, ectopic expression of dominant-negative AMPKalpha (AMPKalpha-dn) by infection with Ad-AMPKalpha-dn partially prevented GLPT from inhibiting mTORC1-mediated S6K1 and 4E-BP1 phosphorylation (Fig.	('AMP', 'Chemical', 'MESH:D000249', (55, 58))	('inhibiting', 'NegReg', (144, 154))	('infection', 'Disease', (83, 92))	('4E-BP1', 'Enzyme', (180, 186))	('AMP', 'Chemical', 'MESH:D000249', (101, 104))	('mTORC1', 'Gene', '382056', (155, 161))	('infection', 'Disease', 'MESH:D007239', (83, 92))	('AMPKalpha', 'Gene', (55, 64))	('mTORC1', 'cellular_component', 'GO:0031931', ('155', '161'))	('phosphorylation', 'biological_process', 'GO:0016310', ('187', '202'))	('Ad-AMPKalpha', 'Chemical', 'MESH:C432591', (98, 110))	('prevented', 'NegReg', (124, 133))	('Ad-AMPKalpha-dn', 'Var', (98, 113))	('GLPT', 'MPA', (134, 138))	('AMP', 'Chemical', 'MESH:D000249', (66, 69))	('mTORC1', 'Gene', (155, 161))	('dominant-negative', 'Var', (37, 54))
12417	31637001	This arrest was achieved through reductions in the levels of G1/S proteins, e.g., CDK4, CDK6, cyclin D1, and Cdc25A, and increases in the levels of p27Kip1 and p21Cip1 (CDK inhibitors), resulting in hypophosphorylation of Rb (Fig.	('Cdc25A', 'MPA', (109, 115))	('cyclin D1', 'MPA', (94, 103))	('levels', 'MPA', (51, 57))	('G1/S proteins', 'Protein', (61, 74))	('increases', 'PosReg', (121, 130))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('reductions', 'NegReg', (33, 43))	('hypophosphorylation', 'MPA', (199, 218))	('CDK6', 'MPA', (88, 92))	('p27Kip1', 'Var', (148, 155))	('arrest', 'Disease', 'MESH:D006323', (5, 11))	('Rb', 'Disease', 'MESH:D058495', (222, 224))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('CDK', 'molecular_function', 'GO:0004693', ('169', '172'))	('cyclin', 'molecular_function', 'GO:0016538', ('94', '100'))	('p21Cip1', 'Var', (160, 167))	('CDK4', 'MPA', (82, 86))	('arrest', 'Disease', (5, 11))
12420	31637001	It has been demonstrated that mTOR mediates the expression/activity of c-myc, cyclin D1, CDKs, p27Kip1, VEGF, survivin, JNK, MMP-2, and NF-kappaB.	('MMP-2', 'molecular_function', 'GO:0004228', ('125', '130'))	('survivin', 'Protein', (110, 118))	('NF-kappaB', 'Gene', (136, 145))	('mTOR', 'Gene', '2475', (30, 34))	('p27Kip1', 'Var', (95, 102))	('c-myc', 'Gene', (71, 76))	('NF-kappaB', 'Gene', '4790', (136, 145))	('JNK', 'molecular_function', 'GO:0004705', ('120', '123'))	('VEGF', 'Gene', '7422', (104, 108))	('CDKs', 'Gene', (89, 93))	('MMP-2', 'Gene', (125, 130))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('VEGF', 'Gene', (104, 108))	('cyclin', 'molecular_function', 'GO:0016538', ('78', '84'))	('expression/activity', 'MPA', (48, 67))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('c-myc', 'Gene', '4609', (71, 76))	('cyclin D1', 'Protein', (78, 87))	('mTOR', 'Gene', (30, 34))
12426	31637001	Expression of dn-AMPKalpha partially lessened the inhibitory effect of GLPT on mTORC1 (Fig.	('dn-AMPKalpha', 'Var', (14, 26))	('inhibitory effect', 'MPA', (50, 67))	('lessened', 'NegReg', (37, 45))	('mTORC1', 'Gene', '382056', (79, 85))	('mTORC1', 'cellular_component', 'GO:0031931', ('79', '85'))	('AMP', 'Chemical', 'MESH:D000249', (17, 20))	('mTORC1', 'Gene', (79, 85))
12435	31637001	In conclusion, we have demonstrated that GLPT (G. lucidum extracts) inhibited cell proliferation by decreasing the protein levels of CDK4/6, cyclin D1, and Cdc25A; increasing the protein levels of p27Kip1 and p21Cip1; inducing apoptosis by downregulating Bcl-xL, survivin and Bcl-2; and upregulating DR4 and DR5 in human lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (321, 332))	('apoptosis', 'biological_process', 'GO:0006915', ('227', '236'))	('CDK4/6', 'MPA', (133, 139))	('Bcl-2', 'molecular_function', 'GO:0015283', ('276', '281'))	('inducing', 'PosReg', (218, 226))	('decreasing', 'NegReg', (100, 110))	('cyclin D1', 'MPA', (141, 150))	('DR4', 'Gene', (300, 303))	('inhibited', 'NegReg', (68, 77))	('increasing', 'PosReg', (164, 174))	('p27Kip1', 'Var', (197, 204))	('apoptosis', 'CPA', (227, 236))	('protein levels', 'MPA', (179, 193))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('upregulating', 'PosReg', (287, 299))	('Bcl-2', 'Protein', (276, 281))	('Cdc25A', 'MPA', (156, 162))	('protein levels', 'MPA', (115, 129))	('lung cancer', 'Disease', (321, 332))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('cyclin', 'molecular_function', 'GO:0016538', ('141', '147'))	('DR5', 'Gene', (308, 311))	('p21Cip1', 'Var', (209, 216))	('CDK', 'molecular_function', 'GO:0004693', ('133', '136'))	('cell proliferation', 'CPA', (78, 96))	('human', 'Species', '9606', (315, 320))	('downregulating', 'NegReg', (240, 254))	('lung cancer', 'Disease', 'MESH:D008175', (321, 332))	('survivin', 'Protein', (263, 271))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('G. lucidum', 'Species', '5315', (47, 57))	('Bcl-xL', 'Protein', (255, 261))	('apoptosis', 'biological_process', 'GO:0097194', ('227', '236'))
12446	31637001	The antibodies used in the study included CDK1, cyclin E, TNFR1, FasL, TRAIL, DR4, DR5, TRADD, FADD, RIP1, RIP3, PI3K p85alpha/beta/gamma, p-IGFRbeta (Tyr1161), IGFRbeta (Santa Cruz Biotechnology, Santa Cruz, CA, USA), beta-tubulin (Sigma, St Louis, MO, USA), cleaved PARP, cleaved caspase 8, cleaved caspase 3, p-S6K1 (T389), S6K1, p-4E-BP1 (T70), 4E-BP1, p-Akt (S473), p-Akt (T308), Akt, p-PDK1 (S241), PDK1, p-AMPKalpha (Thr172), p-raptor (S792), p-TSC2 (S1387), p-PTEN (Ser380/Thr382/383), PTEN, p-PI3K p85 (Tyr458)/p55 (Tyr199), Rheb, and GAPDH (Cell Signaling, Danvers, MA, USA) antibodies.	('N', 'Chemical', 'MESH:D009584', (497, 498))	('Tyr1161', 'Chemical', 'MESH:D014196', (151, 158))	('Akt', 'Gene', '207', (373, 376))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('GAPDH', 'Gene', (544, 549))	('Rb', 'Disease', 'MESH:D058495', (144, 146))	('PDK1', 'molecular_function', 'GO:0004740', ('392', '396'))	('PDK1', 'molecular_function', 'GO:0004740', ('405', '409'))	('PI3K', 'molecular_function', 'GO:0016303', ('113', '117'))	('cyclin', 'molecular_function', 'GO:0016538', ('48', '54'))	('N', 'Chemical', 'MESH:D009584', (471, 472))	('Akt', 'Gene', (385, 388))	('Signaling', 'biological_process', 'GO:0023052', ('556', '565'))	('Ser', 'cellular_component', 'GO:0005790', ('474', '477'))	('Ser', 'Chemical', 'MESH:C530429', (474, 477))	('p-raptor', 'Species', '126213', (433, 441))	('Akt', 'Gene', '207', (385, 388))	('PTEN', 'Gene', (494, 498))	('Rb', 'Disease', 'MESH:D058495', (164, 166))	('Ser380/Thr382/383', 'Var', (474, 491))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('AMP', 'Chemical', 'MESH:D000249', (413, 416))	('Akt', 'Gene', (359, 362))	('PDK1', 'Gene', (405, 409))	('S473', 'Chemical', 'MESH:C015765', (364, 368))	('Thr172', 'Chemical', 'MESH:C055175', (424, 430))	('PI3K', 'molecular_function', 'GO:0016303', ('502', '506'))	('S1387', 'Chemical', 'MESH:C517209', (458, 463))	('Akt', 'Gene', (373, 376))	('Akt', 'Gene', '207', (359, 362))
12459	31368625	Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively.	('tumor', 'Disease', (64, 69))	('programmed cell death-1 ligand-1', 'Gene', (104, 136))	('ligand', 'molecular_function', 'GO:0005488', ('196', '202'))	('D7U8C', 'Var', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('programmed cell death-1 ligand-1', 'Gene', '29126', (104, 136))	('programmed cell death', 'biological_process', 'GO:0012501', ('104', '125'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('ligand', 'molecular_function', 'GO:0005488', ('128', '134'))
12461	31368625	The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14).	('CD8', 'Gene', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('CD8', 'Gene', '925', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('high/low', 'Var', (227, 235))	('high/high', 'Var', (168, 177))
12462	31368625	The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.	('CD8', 'Gene', (95, 98))	('CD8', 'Gene', '925', (95, 98))	('PD-L1', 'Gene', (85, 90))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('high', 'Var', (80, 84))	('EGFR', 'Gene', (16, 20))
12464	31368625	Mutations in the EGFR gene are one of the most common driver oncogenes in NSCLC.2, 3 Epidermal growth factor receptor-TKIs provide dramatic antitumor activity in advanced NSCLC patients with activating EGFR mutations.	('EGFR', 'Gene', (202, 206))	('Epidermal growth factor receptor', 'Gene', '1956', (85, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('202', '206'))	('activating', 'PosReg', (191, 201))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('EGFR', 'Gene', (17, 21))	('mutations', 'Var', (207, 216))	('NSCLC', 'Disease', (171, 176))	('EGFR', 'Gene', '1956', (202, 206))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('tumor', 'Disease', (144, 149))	('Epidermal growth factor receptor', 'Gene', (85, 117))	('NSCLC', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('EGFR', 'Gene', '1956', (17, 21))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('85', '108'))	('patients', 'Species', '9606', (177, 185))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
12465	31368625	Clinical studies have confirmed EGFR-activating mutations in exon 19 and exon 21 as the main predictor of clinical outcomes with TKI therapy for NSCLC; this has led to a paradigm shift on the use of TKI as a standard first-line treatment for NSCLC patients with EGFR-activating mutations.4, 5, 6, 7, 8  Following molecular-targeted therapy, immunotherapy led a second paradigm shift for the treatment of NSCLC.	('EGFR', 'Gene', '1956', (262, 266))	('NSCLC', 'Disease', (145, 150))	('EGFR', 'Gene', (262, 266))	('EGFR', 'Gene', '1956', (32, 36))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('NSCLC', 'Disease', (404, 409))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('NSCLC', 'Disease', (242, 247))	('NSCLC', 'Disease', 'MESH:D002289', (404, 409))	('patients', 'Species', '9606', (248, 256))	('NSCLC', 'Disease', 'MESH:D002289', (242, 247))	('mutations', 'Var', (48, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('262', '266'))
12466	31368625	Compared with conventional chemotherapy, immune checkpoint inhibitors that target PD-1 or its ligand PD-L1 have shown promising antitumor efficacy in patients with advanced NSCLC; in fact, nivolumab, pembrolizumab, and atezolizumab have been approved for the treatment of advanced NSCLC.9, 10, 11, 12 Recently, the first-line treatment of patients with advanced NSCLC has been further developed; pembrolizumab monotherapy for a PD-L1 TPS of 1% or higher and combination therapies with platinum doublet and pembrolizumab or atezolizumab, regardless of PD-L1 expression, have become standard first-line treatment options.13, 14, 15, 16, 17  However, patients with EGFR mutations from the KEYNOTE-024, KEYNOTE-042, and KEYNOTE-189 trials and TKI-naive EGFR-mutant patients from the IMpower150 trial were excluded.13, 14, 15, 17 In fact, the preferential use of EGFR-TKIs or immunotherapy as first-line treatment for patients with EGFR-activating mutations had not been strictly clear, because there had been no clinical trials that directly compared these therapies.	('EGFR', 'Gene', (662, 666))	('EGFR', 'Gene', '1956', (858, 862))	('pembrolizumab or atezolizumab', 'Disease', 'None', (506, 535))	('EGFR', 'Gene', (749, 753))	('patients', 'Species', '9606', (150, 158))	('tumor', 'Disease', (132, 137))	('patients', 'Species', '9606', (761, 769))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('KEYNOTE-189', 'Chemical', 'MESH:C045142', (716, 727))	('EGFR', 'molecular_function', 'GO:0005006', ('927', '931'))	('platinum', 'Chemical', 'MESH:D010984', (485, 493))	('EGFR', 'Gene', '1956', (927, 931))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('KEYNOTE-042', 'Chemical', 'MESH:C572522', (699, 710))	('patients', 'Species', '9606', (648, 656))	('mutations', 'Var', (943, 952))	('NSCLC', 'Disease', (173, 178))	('patients', 'Species', '9606', (339, 347))	('NSCLC', 'Disease', 'MESH:D002289', (362, 367))	('EGFR', 'Gene', '1956', (662, 666))	('EGFR', 'Gene', '1956', (749, 753))	('NSCLC', 'Disease', 'MESH:D002289', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EGFR', 'Gene', (858, 862))	('NSCLC', 'Disease', (362, 367))	('EGFR', 'molecular_function', 'GO:0005006', ('858', '862'))	('NSCLC', 'Disease', (281, 286))	('ligand', 'molecular_function', 'GO:0005488', ('94', '100'))	('EGFR', 'Gene', (927, 931))	('EGFR', 'molecular_function', 'GO:0005006', ('662', '666'))	('pembrolizumab or atezolizumab', 'Disease', (506, 535))	('EGFR', 'molecular_function', 'GO:0005006', ('749', '753'))	('patients', 'Species', '9606', (913, 921))
12467	31368625	Therefore, the correlation of EGFR mutation positivity and PD-L1 expression and its impact on anti-PD-1/PD-L1 therapies had been intensively investigated.	('EGFR', 'Gene', (30, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('PD-L1', 'Gene', (59, 64))	('mutation', 'Var', (35, 43))	('EGFR', 'Gene', '1956', (30, 34))
12468	31368625	A retrospective study that investigated the frequencies of each PD-L1 expression level in NSCLC harboring driver oncogenes revealed the existence of a subset of EGFR-mutated NSCLC patients with high PD-L1 expression,18 suggesting that the relationship between EGFR mutation positivity and PD-L1 expression might not be mutually exclusive.	('EGFR', 'Gene', (260, 264))	('high', 'Var', (194, 198))	('EGFR', 'Gene', (161, 165))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('260', '264'))	('PD-L1', 'Gene', (199, 204))	('EGFR', 'Gene', '1956', (260, 264))	('EGFR', 'Gene', '1956', (161, 165))	('patients', 'Species', '9606', (180, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))	('NSCLC', 'Disease', (174, 179))
12469	31368625	However, subgroup analyses of the clinical trials and a meta-analysis suggested that immune checkpoint inhibitors were less effective in patients with EGFR-mutant NSCLC than in those with EGFR WT NSCLC.10, 11, 19 Another retrospective study found that NSCLC harboring EGFR mutations was associated with low overall response rate to PD-1/PD-L1 inhibitors and that low expression of both PD-L1 and CD8+ TILs within the TME might underlie this unfavorable clinical response.20 In other words, the prediction of PD-1/PD-L1 inhibitor efficacy for NSCLC patients harboring EGFR mutations might need the assessment of both PD-L1 expression in tumor cells and the TME, including CD8+ TILs.	('EGFR', 'Gene', (567, 571))	('mutations', 'Var', (572, 581))	('EGFR', 'Gene', '1956', (188, 192))	('WT NSCLC', 'Disease', 'MESH:C536751', (193, 201))	('WT NSCLC', 'Disease', (193, 201))	('NSCLC', 'Disease', 'MESH:D002289', (252, 257))	('CD8', 'Gene', '925', (396, 399))	('EGFR', 'Gene', '1956', (268, 272))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('tumor', 'Disease', (636, 641))	('NSCLC', 'Disease', (252, 257))	('NSCLC', 'Disease', 'MESH:D002289', (542, 547))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('CD8', 'Gene', '925', (671, 674))	('EGFR', 'molecular_function', 'GO:0005006', ('268', '272'))	('EGFR', 'molecular_function', 'GO:0005006', ('567', '571'))	('NSCLC', 'Disease', (196, 201))	('EGFR', 'Gene', '1956', (567, 571))	('EGFR', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (636, 641))	('NSCLC', 'Disease', (163, 168))	('patients', 'Species', '9606', (137, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('NSCLC', 'Disease', (542, 547))	('CD8', 'Gene', (396, 399))	('EGFR', 'Gene', (188, 192))	('patients', 'Species', '9606', (548, 556))	('tumor', 'Phenotype', 'HP:0002664', (636, 641))	('EGFR', 'Gene', (268, 272))	('CD8', 'Gene', (671, 674))	('EGFR', 'Gene', '1956', (151, 155))
12474	31368625	We had previously reported the association between PFS after first-line conventional EGFR-TKIs and the abundance of preT790M in EGFR-TKI-naive EGFR-mutated NSCLC specimens that were assessed by droplet digital PCR.21 In the present retrospective study, the cohort used in that previous study was analyzed.	('EGFR', 'Gene', (143, 147))	('EGFR', 'Gene', (85, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('preT790M', 'Var', (116, 124))	('T790M', 'Mutation', 'p.T790M', (119, 124))	('NSCLC', 'Disease', (156, 161))	('EGFR', 'Gene', '1956', (143, 147))	('EGFR', 'Gene', '1956', (85, 89))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))	('PFS', 'Disease', (51, 54))
12475	31368625	The eligible patients who were screened comprised those with newly histologically proven locally advanced or metastatic lung adenocarcinoma, those with documented EGFR-activating mutation (exon 19 deletion or L858R mutation), and those treated with first-line EGFR-TKIs at the Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017.	('EGFR', 'Gene', (260, 264))	('L858R mutation', 'Var', (209, 223))	('exon', 'Var', (189, 193))	('locally', 'Disease', (89, 96))	('patients', 'Species', '9606', (13, 21))	('EGFR', 'Gene', '1956', (163, 167))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('260', '264'))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (120, 139))	('EGFR', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('EGFR', 'Gene', '1956', (260, 264))	('L858R', 'Mutation', 'p.L858R', (209, 214))	('lung adenocarcinoma', 'Disease', (120, 139))
12482	31368625	Positivity for PD-L1 was defined as membranous staining of tumor cells at any intensity.	('tumor', 'Disease', (59, 64))	('PD-L1', 'Gene', (15, 20))	('Positivity', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
12489	31368625	Each score was defined on the basis of the fraction of tumor cells that contained CD8+ TILs on top: score 0, none or rare; score 1, less than 5%; score 2, 5% or more and less than 25%; and score 3, 25% or more, based on a previous study (Figure S3).20  We defined PD-L1 expression with TPS 50% or more as PD-L1 high and that with TPS less than 50% as low.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CD8', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD8', 'Gene', '925', (82, 85))	('tumor', 'Disease', (55, 60))	('TPS 50', 'Var', (286, 292))	('PD-L1', 'Gene', (264, 269))
12498	31368625	Among the TME subtypes, there were no significant differences in age, gender, smoking status, stage, performance status, or EGFR status, but there was variability in the preT790M detection rate.	('EGFR', 'Gene', '1956', (124, 128))	('preT790M', 'Var', (170, 178))	('T790M', 'Mutation', 'p.T790M', (173, 178))	('EGFR', 'Gene', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))
12501	31368625	The PFS after first-line EGFR-TKIs was significantly shorter in patients with high PD-L1 expression than in those with low PD-L1 expression (median, 5.9 vs 13.2 months, P = .0059) (Figure 3A).	('high', 'Var', (78, 82))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (64, 72))	('PFS', 'MPA', (4, 7))	('PD-L1', 'Gene', (83, 88))	('shorter', 'NegReg', (53, 60))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
12504	31368625	In a CD8+ TIL high setting, PFS was significantly shorter in patients with high PD-L1 (type 1) than in those with low PD-L1 (type 4) (P = .00000056).	('CD8', 'Gene', (5, 8))	('PD-L1', 'Gene', (80, 85))	('CD8', 'Gene', '925', (5, 8))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (61, 69))	('PFS', 'MPA', (28, 31))	('shorter', 'NegReg', (50, 57))
12505	31368625	In a CD8+ TIL low setting, there was no significant difference in the PFS between PD-L1 high (type 3) and PD-L1 low (type 2) patients (P = .77) (Figure S6).	('high', 'Var', (88, 92))	('CD8', 'Gene', (5, 8))	('CD8', 'Gene', '925', (5, 8))	('PD-L1', 'Gene', (82, 87))	('PFS', 'MPA', (70, 73))	('patients', 'Species', '9606', (125, 133))
12506	31368625	Of the current study cohort, 26 patients underwent rebiopsy to confirm the emergence of T790M after acquired resistance to EGFR-TKIs.	('EGFR', 'Gene', (123, 127))	('patients', 'Species', '9606', (32, 40))	('T790M', 'Var', (88, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('T790M', 'Mutation', 'p.T790M', (88, 93))	('EGFR', 'Gene', '1956', (123, 127))
12510	31368625	A 75-year-old male never-smoker patient with stage IV lung adenocarcinoma harboring EGFR L858R mutation was given erlotinib as first-line treatment, which confirmed partial response after 1.6 months.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('L858R mutation', 'Var', (89, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (54, 73))	('erlotinib', 'Chemical', 'MESH:C400278', (114, 123))	('EGFR', 'Gene', '1956', (84, 88))	('lung adenocarcinoma', 'Disease', (54, 73))	('EGFR', 'Gene', (84, 88))	('patient', 'Species', '9606', (32, 39))	('L858R', 'Mutation', 'p.L858R', (89, 94))
12512	31368625	After disease progression, rebiopsy revealed EGFR T790M mutation, and the TME changed to type 1 (PD-L1 TPS of 100% and CD8+ TIL of score 3), with positive PD-L2 expression (80%).	('T790M mutation', 'Var', (50, 64))	('EGFR', 'Gene', (45, 49))	('CD8', 'Gene', (119, 122))	('CD8', 'Gene', '925', (119, 122))	('T790M', 'Mutation', 'p.T790M', (50, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))
12515	31368625	Our results suggested that differences in the TME could potentially impact treatment, and even the efficacy of EGFR-TKIs.	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('differences', 'Var', (27, 38))	('EGFR', 'Gene', '1956', (111, 115))	('treatment', 'CPA', (75, 84))	('EGFR', 'Gene', (111, 115))	('impact', 'Reg', (68, 74))
12527	31368625	These results, including our representative case, suggested that tumors with high expression of both PD-L1 and CD8+ TIL, despite harboring EGFR mutations, are likely to benefit less from EGFR-TKI therapies.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('less', 'NegReg', (177, 181))	('EGFR', 'Gene', '1956', (187, 191))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('EGFR', 'Gene', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('EGFR', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('CD8', 'Gene', (111, 114))	('CD8', 'Gene', '925', (111, 114))	('PD-L1', 'Gene', (101, 106))
12529	31368625	Progression-free survival was significantly shorter in patients with high PD-L1 expression than in those with low PD-L1 expression.	('PD-L1', 'Gene', (74, 79))	('high', 'Var', (69, 73))	('Progression-free survival', 'CPA', (0, 25))	('patients', 'Species', '9606', (55, 63))	('shorter', 'NegReg', (44, 51))
12543	31368625	According to the study by Su et al,35 any specific relationship between the TME of cases that showed de novo resistance to EGFR-TKIs and genetic profiles, such as EGFR T790M, MET amplification, ALK rearrangement, BIM deletion, and mutations of KRAS, PTEN, PIK3CA, HER2, were not observed.	('EGFR', 'Gene', (123, 127))	('MET amplification', 'Var', (175, 192))	('PIK3CA', 'Gene', '5290', (256, 262))	('EGFR', 'Gene', (163, 167))	('ALK', 'Gene', '238', (194, 197))	('PTEN', 'Gene', (250, 254))	('EGFR', 'Gene', '1956', (123, 127))	('PIK3CA', 'Gene', (256, 262))	('KRAS', 'Gene', (244, 248))	('HER2', 'Gene', (264, 268))	('ALK', 'Gene', (194, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('EGFR', 'Gene', '1956', (163, 167))	('PTEN', 'Gene', '5728', (250, 254))	('T790M', 'Mutation', 'p.T790M', (168, 173))	('KRAS', 'Gene', '3845', (244, 248))	('T790M', 'Var', (168, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('HER2', 'Gene', '2064', (264, 268))	('Su', 'Chemical', 'MESH:C035067', (26, 28))
12544	31368625	Further investigation is needed to reveal the association between a TME of high PD-L1 and high CD8+ TILs itself and the undiscovered resistance mechanisms to EGFR-TKI.	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))	('EGFR', 'Gene', (158, 162))	('CD8', 'Gene', '925', (95, 98))	('high', 'Var', (75, 79))	('EGFR', 'Gene', '1956', (158, 162))	('CD8', 'Gene', (95, 98))
12556	31481087	Meanwhile, knockdown of SPP1 rescued the YBX1/G3BP1-mediated activation of NF-kappaB signaling pathway, and RCC cell migration and invasion.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('RCC', 'Disease', (108, 111))	('invasion', 'CPA', (131, 139))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('61', '84'))	('NF-kappaB', 'Gene', (75, 84))	('SPP1', 'Gene', (24, 28))	('activation', 'PosReg', (61, 71))	('NF-kappaB', 'Gene', '4790', (75, 84))	('cell migration', 'biological_process', 'GO:0016477', ('112', '126'))	('SPP', 'molecular_function', 'GO:0042499', ('24', '27'))	('knockdown', 'Var', (11, 20))	('YBX1/G3BP1-mediated', 'Gene', (41, 60))
12574	31481087	However, it remains poorly understood whether G3BP1 interacts with key oncoproteins such as YBX1 to modulate RCC progression and metastasis.	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('metastasis', 'CPA', (129, 139))	('G3BP1', 'Var', (46, 51))	('modulate', 'Reg', (100, 108))
12582	31481087	In order to generate YBX1 and G3BP1 knockdown or overexpression stable clones, 293 T cells were transfected with lentiviral vectors, including pLKO.1-Scr, pLKO.1-shYBX1, pLKO.1-shG3BP1, pWPI-Vec, and pWPI-YBX1, together with lentivirus packaging plasmids (psAX2 and pMD2G) for 48 h using Lipofectamine 2000 (Invitrogen, USA).	('pLKO.1-shG3BP1', 'Var', (170, 184))	('G3BP1', 'Gene', (30, 35))	('pLKO.1-Scr', 'Var', (143, 153))	('293 T', 'CellLine', 'CVCL:0063', (79, 84))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (288, 306))	('expression', 'Species', '29278', (53, 63))	('pLKO.1-shYBX1', 'Var', (155, 168))	('YBX1', 'Gene', (21, 25))
12585	31481087	To generate G3BP1 overexpression cells, ACHN were then transfected with the pEGFP-C1 and pEGFP-G3BP1 constructs at 90% confluence using Lipofectamine 2000 (Invitrogen).	('pEGFP-G3BP1', 'Var', (89, 100))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (136, 154))	('ACHN', 'Gene', (40, 44))	('expression', 'Species', '29278', (22, 32))	('pEGFP-C1', 'Gene', (76, 84))	('ACHN', 'Gene', '55323', (40, 44))
12600	31481087	The RCC cell lines (786-0) and their corresponding YBX1 knockdown cells were sent to Jingtai Biotech company (Shanghai, China) for mRNA isolation, quality control, chip hybridization, and microarray data analysis, as previously described.	('knockdown', 'Var', (56, 65))	('YBX1', 'Gene', (51, 55))	('RCC', 'Disease', (4, 7))	('RCC', 'Phenotype', 'HP:0005584', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (4, 7))
12642	31481087	Further cell adhesion assay showed that depletion of YBX1 significantly inhibited RCC cell adhesion to fibronectin (Additional file 1: Figure S1A and S1B).	('cell adhesion', 'biological_process', 'GO:0007155', ('8', '21'))	('depletion', 'Var', (40, 49))	('cell adhesion', 'biological_process', 'GO:0007155', ('86', '99'))	('fibronectin', 'Gene', (103, 114))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('YBX1', 'Gene', (53, 57))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('inhibited', 'NegReg', (72, 81))	('fibronectin', 'Gene', '2335', (103, 114))
12643	31481087	Together, these findings suggested that aberrant expression of YBX1 was involved in metastatic phenotypes of RCC cells.	('aberrant expression', 'Var', (40, 59))	('YBX1', 'Gene', (63, 67))	('expression', 'Species', '29278', (49, 59))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('involved', 'Reg', (72, 80))
12649	31481087	ACHN cells were transfected with GFP-YBX1 or each of the GFP-YBX1 mutants.	('mutants', 'Var', (66, 73))	('GFP-YBX1', 'Gene', '4904', (33, 41))	('GFP-YBX1', 'Gene', '4904', (57, 65))	('ACHN', 'Gene', '55323', (0, 4))	('ACHN', 'Gene', (0, 4))	('GFP-YBX1', 'Gene', (33, 41))	('GFP-YBX1', 'Gene', (57, 65))
12652	31481087	Indeed, the analysis revealed that genes encoding molecules involved in enriched pathways such as cell adhesion, ECM-receptor interaction and sphingolipid metabolism were significantly down-regulated after YBX1 knockdown (Additional file 2: Figure S2A).	('YBX1', 'Gene', (206, 210))	('ECM', 'Gene', (113, 116))	('down-regulated', 'NegReg', (185, 199))	('knockdown', 'Var', (211, 220))	('sphingolipid', 'Chemical', 'MESH:D013107', (142, 154))	('sphingolipid metabolism', 'MPA', (142, 165))	('sphingolipid metabolism', 'biological_process', 'GO:0006665', ('142', '165'))	('ECM', 'Gene', '22915', (113, 116))	('cell adhesion', 'biological_process', 'GO:0007155', ('98', '111'))	('cell adhesion', 'CPA', (98, 111))
12653	31481087	Among these, ITGB8, RELN, and SPP1 were the top tumor-promoting candidates significantly downregulated (FDR < 0.05) by YBX1 knockdown in the ECM-receptor interaction pathway (Table 3).	('knockdown', 'Var', (124, 133))	('RELN', 'Gene', '5649', (20, 24))	('RELN', 'Gene', (20, 24))	('tumor', 'Disease', (48, 53))	('ECM', 'Gene', '22915', (141, 144))	('downregulated', 'NegReg', (89, 102))	('SPP', 'molecular_function', 'GO:0042499', ('30', '33'))	('ITGB8', 'Gene', '3696', (13, 18))	('ECM', 'Gene', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('YBX1', 'Gene', (119, 123))	('ITGB8', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
12655	31481087	Because SPP1 is frequently overexpressed in multiple cancers, is associated with defective apoptosis and invasion in RCC cells, and was dramatically downregulated after YBX1 knockdown, we prioritized SPP1 for further investigation.	('SPP1', 'Gene', (8, 12))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('YBX1', 'Gene', (169, 173))	('multiple cancers', 'Disease', (44, 60))	('invasion', 'CPA', (105, 113))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('overexpressed', 'PosReg', (27, 40))	('defective', 'NegReg', (81, 90))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('SPP', 'molecular_function', 'GO:0042499', ('200', '203'))	('apoptosis', 'CPA', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('downregulated', 'NegReg', (149, 162))	('SPP', 'molecular_function', 'GO:0042499', ('8', '11'))	('multiple cancers', 'Disease', 'MESH:D009369', (44, 60))	('knockdown', 'Var', (174, 183))
12656	31481087	Consistent with the microarray data, YBX1 knockdown decreased the expression of the SPP1 mRNA (Fig.	('SPP1', 'Gene', (84, 88))	('expression', 'Species', '29278', (66, 76))	('decreased', 'NegReg', (52, 61))	('expression', 'MPA', (66, 76))	('YBX1', 'Gene', (37, 41))	('SPP', 'molecular_function', 'GO:0042499', ('84', '87'))	('knockdown', 'Var', (42, 51))
12658	31481087	Our data showed that the expression of SPP1 in both mRNA and protein levels were down-regulated in G3BP1 knockdown RCC cells, suggesting a functional role of the YBX1/G3BP1 complex in the regulation of SPP1 (Fig.	('G3BP1', 'Gene', (99, 104))	('down-regulated', 'NegReg', (81, 95))	('SPP1', 'Gene', (39, 43))	('expression', 'Species', '29278', (25, 35))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('expression', 'MPA', (25, 35))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('knockdown', 'Var', (105, 114))	('SPP', 'molecular_function', 'GO:0042499', ('39', '42'))	('SPP', 'molecular_function', 'GO:0042499', ('202', '205'))	('regulation', 'biological_process', 'GO:0065007', ('188', '198'))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
12661	31481087	3c, YBX1 knockdown inhibited the phosphorylation of NF-kappaB subunit p65 (Ser536) together with the total amount of p65 protein levels in RCC cells.	('phosphorylation', 'MPA', (33, 48))	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('inhibited', 'NegReg', (19, 28))	('knockdown', 'Var', (9, 18))	('Ser536', 'Chemical', '-', (75, 81))	('p65', 'Gene', '5970', (117, 120))	('p65', 'Gene', '5970', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('NF-kappaB', 'Gene', '4790', (52, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('NF-kappaB', 'Gene', (52, 61))	('YBX1', 'Gene', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('p65', 'Gene', (117, 120))	('p65', 'Gene', (70, 73))
12664	31481087	The results indicated that NF-kappaB reporter activity was not only significantly decreased by YBX1 knockdown but also G3BP1 depletion (Fig.	('knockdown', 'Var', (100, 109))	('G3BP1', 'Var', (119, 124))	('NF-kappaB', 'Gene', '4790', (27, 36))	('depletion', 'NegReg', (125, 134))	('NF-kappaB', 'Gene', (27, 36))	('YBX1', 'Gene', (95, 99))	('decreased', 'NegReg', (82, 91))
12665	31481087	In order to determine whether YBX1/G3BP1 complex could regulate downstream NF-kappaB signaling pathway via SPP1 in RCC cells, we first selected the most effective siRNAs against SPP1 (si-SPP1-1, si-SPP1-2, si-SPP1-3) in ACHN cells (Fig.	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('si-SPP1-3', 'Var', (206, 215))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('si-SPP1-2', 'Var', (195, 204))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('NF-kappaB', 'Gene', (75, 84))	('RCC', 'Disease', (115, 118))	('SPP', 'molecular_function', 'GO:0042499', ('107', '110'))	('ACHN', 'Gene', '55323', (220, 224))	('SPP', 'molecular_function', 'GO:0042499', ('209', '212'))	('regulate', 'Reg', (55, 63))	('SPP', 'molecular_function', 'GO:0042499', ('178', '181'))	('SPP', 'molecular_function', 'GO:0042499', ('187', '190'))	('SPP', 'molecular_function', 'GO:0042499', ('198', '201'))	('ACHN', 'Gene', (220, 224))	('NF-kappaB', 'Gene', '4790', (75, 84))
12666	31481087	Then, the ACHN cells were transfected with pWPI+si-NC, pWPI-YBX1 + si-NC, pWPI-YBX1 + si-SPP1; pEGFP-C1 + si-NC, GFP-G3BP1 + si-NC, GFP-G3BP1 + si-SPP1.	('pEGFP-C1 + si-NC', 'Var', (95, 111))	('SPP', 'molecular_function', 'GO:0042499', ('89', '92'))	('GFP-G3BP1 + si-SPP1', 'Var', (132, 151))	('ACHN', 'Gene', '55323', (10, 14))	('SPP', 'molecular_function', 'GO:0042499', ('147', '150'))	('GFP-G3BP1 + si-NC', 'Var', (113, 130))	('ACHN', 'Gene', (10, 14))
12671	31481087	4a and b) and invasion in RCC ACHN cells, while SPP1 depletion strongly attenuated the effect of YBX1 or G3BP1 induced RCC cells migration and invasion (Fig.	('depletion', 'Var', (53, 62))	('attenuated', 'NegReg', (72, 82))	('invasion', 'CPA', (143, 151))	('RCC', 'Disease', (26, 29))	('YBX1', 'Gene', (97, 101))	('ACHN', 'Gene', '55323', (30, 34))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('ACHN', 'Gene', (30, 34))	('SPP', 'molecular_function', 'GO:0042499', ('48', '51'))	('G3BP1', 'Gene', (105, 110))
12684	31481087	In addition, immunohistochemistry staining of the xenograft renal tissues confirmed that YBX1 expression remained unchanged in the G3BP1 knockdown tumors compared to the control tumors, while the expression of SPP1 was significantly decreased in the G3BP1 knockdown tumors when compared to the control tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('decreased', 'NegReg', (233, 242))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('expression', 'Species', '29278', (94, 104))	('tumors', 'Disease', (302, 308))	('YBX1', 'Gene', (89, 93))	('expression', 'Species', '29278', (196, 206))	('knockdown', 'Var', (137, 146))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('expression', 'MPA', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (266, 272))	('G3BP1', 'Var', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('G3BP1 knockdown', 'Var', (131, 146))	('tumors', 'Disease', (147, 153))	('tumors', 'Disease', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('expression', 'MPA', (196, 206))	('SPP', 'molecular_function', 'GO:0042499', ('210', '213'))	('tumors', 'Disease', 'MESH:D009369', (266, 272))
12685	31481087	Collectively, the results from the in vivo tumor xenograft models indicated that silencing of G3BP1 suppresses RCC tumor cell metastasis through YBX1/G3BP1-SPP1 signaling pathway.	('RCC tumor', 'Disease', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('RCC tumor', 'Disease', 'MESH:C538614', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('SPP', 'molecular_function', 'GO:0042499', ('156', '159'))	('silencing', 'Var', (81, 90))	('suppresses', 'NegReg', (100, 110))	('G3BP1', 'Gene', (94, 99))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('signaling pathway', 'biological_process', 'GO:0007165', ('161', '178'))
12689	31481087	Consistently, our in vivo orthotopic tumor xenografts results confirmed that knockdown of G3BP1 suppressed RCC tumor metastasis in mice.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('RCC tumor metastasis', 'Disease', (107, 127))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('knockdown', 'Var', (77, 86))	('RCC tumor metastasis', 'Disease', 'MESH:C538614', (107, 127))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('suppressed', 'NegReg', (96, 106))	('G3BP1', 'Gene', (90, 95))	('mice', 'Species', '10090', (131, 135))
12695	31481087	YBX1 knockdown has been shown to inhibit lung adenocarcinoma cells growth.	('YBX1', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', (41, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (41, 60))	('knockdown', 'Var', (5, 14))	('inhibit', 'NegReg', (33, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (41, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
12696	31481087	reported that YBX1 knockdown was associated with decreased malignant pleural mesothelioma (MPM) cell proliferation, colony formation, migration, and invasion.	('YBX1', 'Gene', (14, 18))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (59, 89))	('knockdown', 'Var', (19, 28))	('malignant pleural mesothelioma', 'Disease', (59, 89))	('colony formation', 'CPA', (116, 132))	('decreased', 'NegReg', (49, 58))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))	('migration', 'CPA', (134, 143))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (69, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('invasion', 'CPA', (149, 157))
12700	31481087	Consistently, we demonstrated that knockdown of YBX1 significantly inhibited the adhesion, migration and invasion abilities of RCC cells in this present study, indicating that YBX1 promotes RCC progression.	('YBX1', 'Gene', (48, 52))	('knockdown', 'Var', (35, 44))	('inhibited', 'NegReg', (67, 76))	('YBX1', 'Gene', (176, 180))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('promotes', 'PosReg', (181, 189))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('adhesion', 'CPA', (81, 89))
12703	31481087	Moreover, the knockdown of G3BP1 inhibited RCC cell proliferation, migration, and invasion in vitro and in vivo.	('G3BP1', 'Gene', (27, 32))	('invasion', 'CPA', (82, 90))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('migration', 'CPA', (67, 76))	('knockdown', 'Var', (14, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('inhibited', 'NegReg', (33, 42))
12712	31481087	This notion was further supported by detecting the expression of YBX1, G3BP1, and SPP1 in clinical RCC tissue samples, which revealed the positive correlations of YBX1, G3BP1, and SPP1.	('YBX1', 'Gene', (65, 69))	('clinical', 'Species', '191496', (90, 98))	('SPP1', 'Gene', (82, 86))	('SPP', 'molecular_function', 'GO:0042499', ('180', '183'))	('YBX1', 'Gene', (163, 167))	('expression', 'Species', '29278', (51, 61))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('correlations', 'Interaction', (147, 159))	('RCC', 'Disease', (99, 102))	('SPP', 'molecular_function', 'GO:0042499', ('82', '85'))	('G3BP1', 'Var', (169, 174))	('SPP1', 'Gene', (180, 184))	('G3BP1', 'Gene', (71, 76))
12714	31481087	Functionally, our results demonstrated that SPP1 depletion strongly attenuated the effect of YBX1 or G3BP1 induced RCC cells migration and invasion.	('attenuated', 'NegReg', (68, 78))	('invasion', 'CPA', (139, 147))	('SPP1', 'Gene', (44, 48))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('YBX1', 'Gene', (93, 97))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('SPP', 'molecular_function', 'GO:0042499', ('44', '47'))	('RCC', 'Disease', (115, 118))	('G3BP1', 'Gene', (101, 106))	('depletion', 'Var', (49, 58))
12719	31481087	found that inhibition of NF-kappaB pathway attenuates cell migration ability in ccRCC cells.	('cell migration ability in', 'CPA', (54, 79))	('NF-kappaB', 'Gene', '4790', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('inhibition', 'Var', (11, 21))	('attenuates', 'NegReg', (43, 53))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('NF-kappaB', 'Gene', (25, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('cell migration', 'biological_process', 'GO:0016477', ('54', '68'))
12723	31481087	Our results showed that knockdown YBX1 significantly inhibited phosphorylation of p65 (Ser536) together with the total amount of p65 protein levels in RCC cells.	('YBX1', 'Gene', (34, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('inhibited', 'NegReg', (53, 62))	('p65', 'Gene', (129, 132))	('p65', 'Gene', (82, 85))	('phosphorylation', 'MPA', (63, 78))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('p65', 'Gene', '5970', (129, 132))	('p65', 'Gene', '5970', (82, 85))	('RCC', 'Disease', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('knockdown', 'Var', (24, 33))	('Ser536', 'Chemical', '-', (87, 93))	('Ser', 'cellular_component', 'GO:0005790', ('87', '90'))
12726	31481087	Further, ccRCCs are characterized by inactivation of the von Hippel-Lindau tumor suppressor (VHL), which is lost in up to 90% of ccRCCs.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('VHL', 'Gene', '7428', (93, 96))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (57, 80))	('von Hippel-Lindau tumor', 'Disease', (57, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('VHL', 'Gene', (93, 96))	('inactivation', 'Var', (37, 49))	('RCC', 'Disease', (11, 14))
12728	31481087	Thus, we examined the effects of YBX1 and G3BP1 in regulating RCC progression using both the VHL mutant (A498) and VHL wild-type (ACHN) RCC cell lines.	('VHL', 'Gene', (115, 118))	('ACHN', 'Gene', '55323', (130, 134))	('VHL', 'Gene', '7428', (115, 118))	('VHL', 'Gene', '7428', (93, 96))	('G3BP1', 'Gene', (42, 47))	('mutant', 'Var', (97, 103))	('YBX1', 'Gene', (33, 37))	('ACHN', 'Gene', (130, 134))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('VHL', 'Gene', (93, 96))	('RCC', 'Disease', (136, 139))
12939	30319415	Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers.	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('14', '23'))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('proteasome', 'molecular_function', 'GO:0004299', ('132', '142'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('122', '131'))	('Dysfunction', 'Var', (86, 97))	('proteasome', 'cellular_component', 'GO:0000502', ('132', '142'))	('multiple cancers', 'Disease', (215, 231))	('related', 'Reg', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('multiple cancers', 'Disease', 'MESH:D009369', (215, 231))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('dysregulation', 'Var', (101, 114))
12941	30319415	The aberrant expression or function of DUBs generally leads to the occurrence and progression of a series of disorders, including malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('malignant tumors', 'Disease', (130, 146))	('function', 'MPA', (27, 35))	('progression', 'CPA', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('aberrant expression', 'Var', (4, 23))	('malignant tumors', 'Disease', 'MESH:D018198', (130, 146))	('leads to', 'Reg', (54, 62))	('DUBs', 'Gene', (39, 43))
12946	30319415	Ubiquitin contains seven Lys-residues, including Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63, all of which can covalently attach to other ubiquitin molecules.	('Lys', 'Chemical', 'MESH:D008239', (83, 86))	('Lys', 'Chemical', 'MESH:D008239', (76, 79))	('Lys29', 'Var', (69, 74))	('Lys6', 'Chemical', '-', (94, 98))	('Lys6', 'Var', (49, 53))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('0', '9'))	('Lys63', 'Chemical', '-', (94, 99))	('ubiquitin', 'molecular_function', 'GO:0031386', ('145', '154'))	('Lys', 'Chemical', 'MESH:D008239', (25, 28))	('Lys', 'Chemical', 'MESH:D008239', (49, 52))	('Lys27', 'Chemical', '-', (62, 67))	('Lys48', 'Chemical', '-', (83, 88))	('Lys', 'Chemical', 'MESH:D008239', (62, 65))	('Lys', 'Chemical', 'MESH:D008239', (55, 58))	('Lys11', 'Var', (55, 60))	('Lys', 'Chemical', 'MESH:D008239', (94, 97))	('Lys6', 'Chemical', '-', (49, 53))	('Lys11', 'Chemical', '-', (55, 60))	('Lys48', 'Var', (83, 88))	('Lys33', 'Var', (76, 81))	('Lys33', 'Chemical', '-', (76, 81))	('Lys27', 'Var', (62, 67))	('Lys', 'Chemical', 'MESH:D008239', (69, 72))	('Lys29', 'Chemical', '-', (69, 74))	('Lys63', 'Var', (94, 99))	('attach', 'Interaction', (129, 135))
12947	30319415	Generally, proteins labeled with Lys48-linked poly-ubiquitin chains are bound for degradation, whereas proteins tagged with Lys63-linked chains are more typically associated with non-proteasomal roles, including DNA replication, signal transduction and DNA repair, of course, Lys63-ubiquitination can also lead to the substrates to be degraded via autophagy-lysome pathway (ALP) (McKeon et al.,).	('DNA replication', 'biological_process', 'GO:0006260', ('212', '227'))	('degraded', 'NegReg', (335, 343))	('autophagy-lysome pathway', 'CPA', (348, 372))	('autophagy', 'biological_process', 'GO:0006914', ('348', '357'))	('ALP', 'Disease', 'MESH:D050197', (374, 377))	('lead to', 'Reg', (306, 313))	('Lys63', 'Chemical', '-', (124, 129))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('DNA repair', 'biological_process', 'GO:0006281', ('253', '263'))	('signal transduction', 'biological_process', 'GO:0007165', ('229', '248'))	('Lys63-ubiquitination', 'Var', (276, 296))	('DNA', 'cellular_component', 'GO:0005574', ('253', '256'))	('ALP', 'Disease', (374, 377))	('degradation', 'biological_process', 'GO:0009056', ('82', '93'))	('substrates', 'MPA', (318, 328))	('Lys48', 'Chemical', '-', (33, 38))	('ubiquitin', 'molecular_function', 'GO:0031386', ('51', '60'))	('Lys63', 'Chemical', '-', (276, 281))	('autophagy', 'biological_process', 'GO:0016236', ('348', '357'))
12955	30319415	The overall evaluation of gene mutations and aberrant expression of USPs in various cancers makes USPs as potential anticancer targets, and there is increasing interest in developing USP-specific inhibitors as candidates for anticancer therapeutic agents (Anupama and Nicholas,).	('USPs', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (31, 40))	('Anupama', 'Disease', 'None', (256, 263))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (229, 235))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Disease', (120, 126))	('cancers', 'Disease', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('USP', 'molecular_function', 'GO:0051748', ('183', '186'))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Anupama', 'Disease', (256, 263))	('Nicholas', 'Disease', (268, 276))
12960	30319415	USP14 is specific to Lys-48-linked ubiquitin chains (Hu et al.,; Komander et al.,).	('ubiquitin', 'molecular_function', 'GO:0031386', ('35', '44'))	('USP14', 'Gene', '9097', (0, 5))	('Lys-48-linked', 'Var', (21, 34))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('USP14', 'Gene', (0, 5))	('Lys', 'Chemical', 'MESH:D008239', (21, 24))
12966	30319415	Dysfunction of the Fanconi anemia pathway can cause multiple abnormalities that lead to cancer, which are correlated with deregulation of USP1.	('lead to', 'Reg', (80, 87))	('cancer', 'Disease', (88, 94))	('Fanconi anemia', 'Disease', (19, 33))	('Dysfunction', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('multiple abnormalities', 'Disease', 'MESH:D000015', (52, 74))	('USP1', 'Gene', '7398', (138, 142))	('anemia', 'Phenotype', 'HP:0001903', (27, 33))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (19, 33))	('Fanconi anemia', 'Disease', 'MESH:D005199', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cause', 'Reg', (46, 51))	('multiple abnormalities', 'Disease', (52, 74))	('USP', 'molecular_function', 'GO:0051748', ('138', '141'))	('USP1', 'Gene', (138, 142))
12976	30319415	USP2a is known to deubiquitinate and stabilize MDM2 and MDMX, and unlike USP7/HAUSP, USP2a does not interact with p53; over-expression of USP2a was shown to increase the level of MDM2/MDMX protein and to reduce p53 stability (Sacco et al.,; D'Arcy et al.,).	('USP2', 'Gene', '9099', (0, 4))	('MDM2', 'Gene', '4193', (47, 51))	('MDM2', 'Gene', (179, 183))	('HAUSP', 'Gene', '7874', (78, 83))	('MDMX', 'Gene', (184, 188))	('level', 'MPA', (170, 175))	('increase', 'PosReg', (157, 165))	('reduce', 'NegReg', (204, 210))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('MDMX', 'Gene', '4194', (184, 188))	('USP', 'molecular_function', 'GO:0051748', ('73', '76'))	('MDMX', 'Gene', (56, 60))	('MDM2', 'Gene', '4193', (179, 183))	('USP2', 'Gene', (85, 89))	('USP2', 'Gene', (138, 142))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('USP2', 'Gene', '9099', (85, 89))	('p53 stability', 'MPA', (211, 224))	('MDMX', 'Gene', '4194', (56, 60))	('USP2', 'Gene', '9099', (138, 142))	('over-expression', 'Var', (119, 134))	('HAUSP', 'Gene', (78, 83))	('USP', 'molecular_function', 'GO:0051748', ('85', '88'))	('USP', 'molecular_function', 'GO:0051748', ('138', '141'))	('MDM2', 'Gene', (47, 51))	('USP2', 'Gene', (0, 4))
12978	30319415	There is evidence that USP2a functions as an oncogene in bladder cancer, the aberrant expression of USP2a results in an increase in proliferation, migration, invasion and resistance to multiple chemotherapeutic agents when compared to control cells (Kim et al.,).	('resistance', 'CPA', (171, 181))	('USP', 'molecular_function', 'GO:0051748', ('100', '103'))	('migration', 'CPA', (147, 156))	('USP2', 'Gene', '9099', (100, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('proliferation', 'CPA', (132, 145))	('USP2', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('USP', 'molecular_function', 'GO:0051748', ('23', '26'))	('invasion', 'CPA', (158, 166))	('USP2', 'Gene', (100, 104))	('USP2', 'Gene', '9099', (23, 27))	('increase', 'PosReg', (120, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('aberrant', 'Var', (77, 85))
12985	30319415	Increased USP7 expression is also observed in multiple myeloma tumors; patients with high USP7 levels showed a poorer overall survival rate when compared to patients with lower USP7 levels (Chauhan et al.,).	('multiple myeloma tumors', 'Disease', 'MESH:D009101', (46, 69))	('USP', 'molecular_function', 'GO:0051748', ('177', '180'))	('USP', 'molecular_function', 'GO:0051748', ('10', '13'))	('overall survival', 'CPA', (118, 134))	('patients', 'Species', '9606', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('high', 'Var', (85, 89))	('patients', 'Species', '9606', (157, 165))	('poorer', 'NegReg', (111, 117))	('multiple myeloma', 'Phenotype', 'HP:0006775', (46, 62))	('multiple myeloma tumors', 'Disease', (46, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('USP', 'molecular_function', 'GO:0051748', ('90', '93'))	('USP7', 'Gene', (90, 94))
12986	30319415	Similarly, USP7 expression is strongly correlated with disease severity and lower overall patient survival in gliomas (Cheng et al.,) and epithelial ovarian cancer (Ma and Yu,) as well as in non-small cell lung cancer (Zhao et al.,).	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('patient survival', 'CPA', (90, 106))	('lower', 'NegReg', (76, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('USP7', 'Gene', (11, 15))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (191, 217))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (138, 163))	('correlated', 'Reg', (39, 49))	('non-small cell lung cancer', 'Disease', (191, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('USP', 'molecular_function', 'GO:0051748', ('11', '14'))	('gliomas', 'Disease', (110, 117))	('epithelial ovarian cancer', 'Disease', (138, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('expression', 'Var', (16, 26))	('patient', 'Species', '9606', (90, 97))	('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))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (138, 163))
12987	30319415	Over-expression of USP7 promotes cell invasiveness, whereas USP7 knock-down inhibits cell viability in ovarian cancer cells (Ma and Yu,; Tavana and Gu,).	('USP7', 'Gene', (19, 23))	('cell viability', 'CPA', (85, 99))	('USP7', 'Gene', (60, 64))	('Tavana', 'Disease', 'None', (137, 143))	('USP', 'molecular_function', 'GO:0051748', ('60', '63'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('inhibits', 'NegReg', (76, 84))	('knock-down', 'Var', (65, 75))	('USP', 'molecular_function', 'GO:0051748', ('19', '22'))	('promotes', 'PosReg', (24, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('Tavana', 'Disease', (137, 143))	('ovarian cancer', 'Disease', (103, 117))	('cell invasiveness', 'CPA', (33, 50))
12993	30319415	Over-expression of USP9X is closely related to an increase in MCL1 protein, whereas aberrant expression of MCL1 stimulates chemoresistance and disease relapse (Opferman and Green,; Schwickart et al.,; D'Arcy et al.,).	('aberrant expression', 'Var', (84, 103))	('stimulates', 'PosReg', (112, 122))	('USP9X', 'Gene', '8239', (19, 24))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('disease relapse', 'CPA', (143, 158))	('chemoresistance', 'CPA', (123, 138))	('increase', 'PosReg', (50, 58))	('MCL1', 'Gene', '4170', (62, 66))	('MCL1', 'Gene', '4170', (107, 111))	('USP', 'molecular_function', 'GO:0051748', ('19', '22'))	('MCL1', 'Gene', (62, 66))	('MCL1', 'Gene', (107, 111))	('USP9X', 'Gene', (19, 24))
13002	30319415	Treatment with USP10 inhibitors promotes proteasome-mediated FLT3 degradation, leading to a decrease in FLT3 protein levels (Weisberg et al.,).	('USP10', 'Gene', (15, 20))	('proteasome', 'molecular_function', 'GO:0004299', ('41', '51'))	('FLT3', 'Gene', (104, 108))	('decrease', 'NegReg', (92, 100))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('degradation', 'biological_process', 'GO:0009056', ('66', '77'))	('inhibitors', 'Var', (21, 31))	('FLT3', 'Gene', '2322', (61, 65))	('USP10', 'Gene', '9100', (15, 20))	('FLT3', 'Gene', '2322', (104, 108))	('promotes', 'PosReg', (32, 40))	('FLT3', 'Gene', (61, 65))	('proteasome', 'cellular_component', 'GO:0000502', ('41', '51'))	('USP', 'molecular_function', 'GO:0051748', ('15', '18'))
13005	30319415	demonstrated that USP10 inhibits cancer cell proliferation in wild-type p53 cells, but promotes tumorigenesis in a mutant p53 background (Yuan et al.,).	('USP10', 'Gene', '9100', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('USP', 'molecular_function', 'GO:0051748', ('18', '21'))	('inhibits', 'NegReg', (24, 32))	('mutant', 'Var', (115, 121))	('tumor', 'Disease', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('USP10', 'Gene', (18, 23))	('promotes', 'PosReg', (87, 95))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('p53', 'Gene', (122, 125))
13010	30319415	All of these studies showed that USP10 can function as an oncogene or tumor suppressor, so intervention in USP10 may be a candidate anti-cancer strategy.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('USP10', 'Gene', (33, 38))	('USP10', 'Gene', '9100', (107, 112))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('USP10', 'Gene', '9100', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('USP', 'molecular_function', 'GO:0051748', ('107', '110'))	('USP', 'molecular_function', 'GO:0051748', ('33', '36'))	('cancer', 'Disease', (137, 143))	('USP10', 'Gene', (107, 112))	('intervention', 'Var', (91, 103))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
13019	30319415	Treatment with USP13 inhibitors can significantly suppress ovarian tumor progression and enhance the sensitivity of tumor cells to PI3K/AKT inhibitors (Han et al.,).	('suppress', 'NegReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('AKT', 'Gene', '207', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ovarian tumor', 'Phenotype', 'HP:0100615', (59, 72))	('USP13', 'Gene', '8975', (15, 20))	('USP', 'molecular_function', 'GO:0051748', ('15', '18'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('inhibitors', 'Var', (21, 31))	('USP13', 'Gene', (15, 20))	('enhance', 'PosReg', (89, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('ovarian tumor', 'Disease', (59, 72))	('sensitivity', 'MPA', (101, 112))	('ovarian tumor', 'Disease', 'MESH:D010051', (59, 72))	('AKT', 'Gene', (136, 139))
13030	30319415	Recent research showed that P22077 could induce cell apoptosis and cell proliferation inhibition mediated by p53 in the orthotopic neuroblastoma mouse models of IMR-32, SH-SY5Y, and NGP; since USP7 is overexpressed in neuroblastoma patients, P22077 may be an anti-neuroblastoma agent (Fan et al.,; Lim et al.,).	('neuroblastoma', 'Disease', 'MESH:D009447', (218, 231))	('neuroblastoma', 'Phenotype', 'HP:0003006', (264, 277))	('neuroblastoma', 'Disease', 'MESH:D009447', (264, 277))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (169, 176))	('cell apoptosis', 'CPA', (48, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('neuroblastoma', 'Disease', (131, 144))	('patients', 'Species', '9606', (232, 240))	('mouse', 'Species', '10090', (145, 150))	('neuroblastoma', 'Disease', (218, 231))	('P22077', 'Var', (28, 34))	('neuroblastoma', 'Phenotype', 'HP:0003006', (131, 144))	('neuroblastoma', 'Phenotype', 'HP:0003006', (218, 231))	('cell proliferation', 'CPA', (67, 85))	('USP', 'molecular_function', 'GO:0051748', ('193', '196'))	('neuroblastoma', 'Disease', (264, 277))	('neuroblastoma', 'Disease', 'MESH:D009447', (131, 144))	('P22077', 'Var', (242, 248))
13031	30319415	As disclosed in US 20160090351, P5091 displays a preference for USPs (Hedstrom et al.,) and another study (Pal et al.,) demonstrated that P5091 is a novel small-molecule inhibitor targeting USP7 and USP47, as well as functions as an active anticancer agent in various tumor models, including MM.1S multiple myeloma cells and HCT-116 colon cancer cells (Chauhan et al.,; Pal et al.,).	('USP', 'molecular_function', 'GO:0051748', ('190', '193'))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('multiple myeloma', 'Phenotype', 'HP:0006775', (298, 314))	('Pal', 'molecular_function', 'GO:0004598', ('370', '373'))	('P5091', 'Var', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('colon cancer', 'Phenotype', 'HP:0003003', (333, 345))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('multiple myeloma', 'Disease', 'MESH:D009101', (298, 314))	('USP47', 'Gene', (199, 204))	('USP', 'molecular_function', 'GO:0051748', ('199', '202'))	('colon cancer', 'Disease', 'MESH:D015179', (333, 345))	('cancer', 'Disease', (339, 345))	('multiple myeloma', 'Disease', (298, 314))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('P5091', 'Var', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', (268, 273))	('Pal', 'molecular_function', 'GO:0004598', ('107', '110'))	('colon cancer', 'Disease', (333, 345))	('MM.1S', 'CellLine', 'CVCL:8792', (292, 297))	('USP47', 'Gene', '55031', (199, 204))	('HCT-116', 'CellLine', 'CVCL:0291', (325, 332))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
13032	30319415	Treatment with p-5091 can stabilize p53 protein levels and inhibit cell growth as well as induce the occurrence of apoptosis in multiple myeloma cells resistant to traditional chemotherapy agents.	('p-5091', 'Var', (15, 21))	('cell growth', 'CPA', (67, 78))	('stabilize p53 protein levels', 'MPA', (26, 54))	('multiple myeloma', 'Phenotype', 'HP:0006775', (128, 144))	('multiple myeloma', 'Disease', 'MESH:D009101', (128, 144))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('multiple myeloma', 'Disease', (128, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('induce', 'Reg', (90, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('inhibit', 'NegReg', (59, 66))	('apoptosis', 'CPA', (115, 124))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))
13034	30319415	The reported inhibitors of USP10 primarily include P22077, HBX19818, and Spautin-1.	('USP10', 'Gene', '9100', (27, 32))	('USP', 'molecular_function', 'GO:0051748', ('27', '30'))	('P22077', 'Var', (51, 57))	('USP10', 'Gene', (27, 32))
13035	30319415	However, a recent study (Weisberg et al.,) revealed that P22077 and HBX19818 may also inhibit the deubiquitinase activity of USP10 and induce the proliferation inhibition of mutant-FLT3 (FLT3-ITD)-positive cancer cells.	('FLT3', 'Gene', (181, 185))	('HBX19818', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('98', '121'))	('USP10', 'Gene', '9100', (125, 130))	('FLT3', 'Gene', (187, 191))	('FLT3', 'Gene', '2322', (181, 185))	('USP', 'molecular_function', 'GO:0051748', ('125', '128'))	('deubiquitinase activity', 'MPA', (98, 121))	('induce', 'PosReg', (135, 141))	('inhibit', 'NegReg', (86, 93))	('USP10', 'Gene', (125, 130))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('98', '121'))	('P22077', 'Var', (57, 63))	('proliferation inhibition', 'CPA', (146, 170))	('FLT3', 'Gene', '2322', (187, 191))
13038	30319415	In addtion, a recent study showed that spautin-1 can also trigger immunogenic cancer cell death in vivo and in vitro by causing mitochondrial oxidative injury rather than autophagy inhibition, also demonstrated that spautin-1 may stimulate an apoptotic pathway that results in immunogenic cancer cell death, in TFAM- and AGER-dependent fashion (Yang et al.,).	('cell death', 'biological_process', 'GO:0008219', ('296', '306'))	('immunogenic cancer', 'Disease', (277, 295))	('TFAM', 'Gene', (311, 315))	('stimulate', 'PosReg', (230, 239))	('AGER', 'Gene', '177', (321, 325))	('results in', 'Reg', (266, 276))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('spautin-1', 'Var', (216, 225))	('apoptotic', 'CPA', (243, 252))	('autophagy', 'biological_process', 'GO:0016236', ('171', '180'))	('immunogenic cancer', 'Disease', 'MESH:D009369', (277, 295))	('spautin-1', 'Var', (39, 48))	('immunogenic cancer', 'Disease', (66, 84))	('TFAM', 'Gene', '7019', (311, 315))	('autophagy', 'biological_process', 'GO:0006914', ('171', '180'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cell death', 'biological_process', 'GO:0008219', ('85', '95'))	('AGER', 'Gene', (321, 325))	('immunogenic cancer', 'Disease', 'MESH:D009369', (66, 84))
13040	30319415	Beyond this, b-AP15 can also effectively inhibit the dissemination of acute myeloid leukemia (AML) mouse model of C1498 leukemia, and inhibit the carcinogenesis process in multiple solid tumor mouse models, including Lewis lung carcinomas (LLCs) xenografts, HCT-116 colon carcinoma xenografts overexpressing BCL2, 4T1 breast carcinomas xenografts, etc.	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('inhibit', 'NegReg', (134, 141))	('tumor', 'Disease', (187, 192))	('Lewis lung carcinomas', 'Disease', (217, 238))	('acute myeloid leukemia', 'Disease', (70, 92))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('colon carcinoma', 'Disease', 'MESH:D015179', (266, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('C1498 leukemia', 'Disease', (114, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (325, 335))	('AML', 'Disease', 'MESH:D015470', (94, 97))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('HCT-116', 'CellLine', 'CVCL:0291', (258, 265))	('dissemination', 'CPA', (53, 66))	('carcinogenesis', 'Disease', (146, 160))	('AML', 'Disease', (94, 97))	('BCL2', 'molecular_function', 'GO:0015283', ('308', '312'))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (70, 92))	('AML', 'Phenotype', 'HP:0004808', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('breast carcinomas', 'Phenotype', 'HP:0003002', (318, 335))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (70, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('b-AP15', 'Var', (13, 19))	('colon carcinoma', 'Disease', (266, 281))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (76, 92))	('breast carcinomas xenografts', 'Disease', 'MESH:D001943', (318, 346))	('Lewis lung carcinomas', 'Disease', 'MESH:D018827', (217, 238))	('mouse', 'Species', '10090', (99, 104))	('BCL2', 'Gene', '12043', (308, 312))	('inhibit', 'NegReg', (41, 48))	('C1498 leukemia', 'Disease', 'MESH:D007938', (114, 128))	('breast carcinomas xenografts', 'Disease', (318, 346))	('mouse', 'Species', '10090', (193, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('BCL2', 'Gene', (308, 312))
13041	30319415	Recent research revealed that b-AP15 can block the degradation of protein substrates, indicating that USP14 inhibition weakens the function of the proteasome (D'Arcy et al.,).	('degradation of protein substrates', 'MPA', (51, 84))	('USP14', 'Gene', (102, 107))	('proteasome', 'cellular_component', 'GO:0000502', ('147', '157'))	('USP14', 'Gene', '9097', (102, 107))	('proteasome', 'molecular_function', 'GO:0004299', ('147', '157'))	('degradation', 'biological_process', 'GO:0009056', ('51', '62'))	('USP', 'molecular_function', 'GO:0051748', ('102', '105'))	('weakens', 'NegReg', (119, 126))	('function of the proteasome', 'MPA', (131, 157))	('inhibition', 'Var', (108, 118))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
13042	30319415	showed that b-AP15 can also produce its antitumor therapeutic effects to hepatocellular carcinoma cells by enhancing the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), as well as inhibiting Wnt/beta-catenin and Notch1 signaling pathways (Ding et al.,).	('beta-catenin', 'Gene', '1499', (222, 234))	('Notch1', 'Gene', '4851', (239, 245))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (73, 97))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('121', '142'))	('hepatocellular carcinoma', 'Disease', (73, 97))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (73, 97))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('b-AP15', 'Var', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('unfolded protein response', 'MPA', (163, 188))	('beta-catenin', 'Gene', (222, 234))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('enhancing', 'PosReg', (107, 116))	('signaling', 'biological_process', 'GO:0023052', ('246', '255'))	('Notch1', 'Gene', (239, 245))	('tumor', 'Disease', (44, 49))	('inhibiting', 'NegReg', (207, 217))
13043	30319415	IU1 As disclosed in US 20130045992, IU1 can enhance the activity of proteasomes and prevent proteinopathies through inhibition of the function of USP14 and promotion of degradation of the protein substrates (Finley et al.,).	('USP', 'molecular_function', 'GO:0051748', ('146', '149'))	('USP14', 'Gene', (146, 151))	('function', 'MPA', (134, 142))	('activity', 'MPA', (56, 64))	('proteinopathies', 'Disease', 'MESH:C563476', (92, 107))	('IU1', 'Var', (36, 39))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('promotion', 'PosReg', (156, 165))	('inhibition', 'NegReg', (116, 126))	('proteinopathies', 'Disease', (92, 107))	('degradation of the', 'MPA', (169, 187))	('degradation', 'biological_process', 'GO:0009056', ('169', '180'))	('proteasomes', 'Protein', (68, 79))	('enhance', 'PosReg', (44, 51))	('USP14', 'Gene', '9097', (146, 151))	('prevent', 'NegReg', (84, 91))	('protein', 'Protein', (188, 195))
13044	30319415	The mechanism of action of IU1 is different from bortezomib, which inhibits the activity of the entire proteasome, whereas IU1 binds specifically and inhibits USP14 (Lim et al.,).	('USP14', 'Gene', (159, 164))	('proteasome', 'molecular_function', 'GO:0004299', ('103', '113'))	('proteasome', 'cellular_component', 'GO:0000502', ('103', '113'))	('IU1', 'Var', (123, 126))	('activity', 'MPA', (80, 88))	('bortezomib', 'Chemical', 'MESH:D000069286', (49, 59))	('USP14', 'Gene', '9097', (159, 164))	('USP', 'molecular_function', 'GO:0051748', ('159', '162'))	('inhibits', 'NegReg', (67, 75))	('inhibits', 'NegReg', (150, 158))	('binds', 'Interaction', (127, 132))
13046	30319415	WP1130 As described in US 20160090351, small molecule inhibitor WP1130 is a potent DUBs inhibitor (Hedstrom et al.,) and can target and inhibit several deubiquitinases, including USP5, USP9X, USP14, and UCHL5 (no-USP subfamily), all of which can regulate stability of the protein substrates and the function of the proteasome (D'Arcy et al.,; Lim et al.,).	('regulate', 'Reg', (246, 254))	('protein', 'Protein', (272, 279))	('deubiquitinases', 'Enzyme', (152, 167))	('UCHL5', 'Gene', (203, 208))	('USP5', 'Gene', '8078', (179, 183))	('proteasome', 'cellular_component', 'GO:0000502', ('315', '325'))	('USP14', 'Gene', (192, 197))	('USP', 'molecular_function', 'GO:0051748', ('185', '188'))	('UCHL5', 'Gene', '51377', (203, 208))	('WP1130', 'Var', (64, 70))	('stability', 'MPA', (255, 264))	('function', 'MPA', (299, 307))	('USP14', 'Gene', '9097', (192, 197))	('USP', 'molecular_function', 'GO:0051748', ('192', '195'))	('USP9X', 'Gene', '8239', (185, 190))	('USP', 'molecular_function', 'GO:0051748', ('179', '182'))	('protein', 'cellular_component', 'GO:0003675', ('272', '279'))	('inhibit', 'NegReg', (136, 143))	('USP', 'molecular_function', 'GO:0051748', ('213', '216'))	('USP9X', 'Gene', (185, 190))	('USP5', 'Gene', (179, 183))	('proteasome', 'molecular_function', 'GO:0004299', ('315', '325'))
13048	30319415	WP1130 can also inhibit the deubiquitinase activity of USP9X, and treatment with WP1130 can promote apoptosis by decreasing the level of MCL-1 and increasing the sensitivity of cancer cells to traditional chemotherapy (Lim et al.,).	('MCL-1', 'Gene', '4170', (137, 142))	('inhibit', 'NegReg', (16, 23))	('cancer', 'Disease', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('USP9X', 'Gene', '8239', (55, 60))	('MCL-1', 'Gene', (137, 142))	('deubiquitinase activity', 'MPA', (28, 51))	('WP1130', 'Var', (81, 87))	('USP9X', 'Gene', (55, 60))	('apoptosis', 'CPA', (100, 109))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('28', '51'))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('decreasing', 'NegReg', (113, 123))	('increasing', 'PosReg', (147, 157))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('28', '51'))	('promote', 'PosReg', (92, 99))	('USP', 'molecular_function', 'GO:0051748', ('55', '58'))	('sensitivity', 'CPA', (162, 173))
13053	30319415	To sum up, many USPs are involved in regulation of various pathways relevant to cancer, targeting USPs may be a novel anticancer therapeutic therapy.	('targeting', 'Var', (88, 97))	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('involved', 'Reg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('USPs', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
13123	29977740	Results: The GE11/HA/TATp-irinotecan liposomes evidently increased the uptake of irinotecan and showed significant antitumor efficacy in the xenografted A549 cancer cells in nude mice by intravenous administration.	('GE11', 'Chemical', '-', (13, 17))	('tumor', 'Disease', (119, 124))	('irinotecan', 'Chemical', 'MESH:D000077146', (81, 91))	('irinotecan', 'Chemical', 'MESH:D000077146', (26, 36))	('uptake', 'MPA', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('uptake', 'biological_process', 'GO:0098657', ('71', '77'))	('irinotecan', 'MPA', (81, 91))	('HA', 'Chemical', 'MESH:D006820', (18, 20))	('uptake', 'biological_process', 'GO:0098739', ('71', '77'))	('cancer', 'Disease', (158, 164))	('nude mice', 'Species', '10090', (174, 183))	('A549', 'CellLine', 'CVCL:0023', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('increased', 'PosReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('GE11/HA/TATp-irinotecan', 'Var', (13, 36))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
13124	29977740	The mechanisms were defined to be two aspects: GE11 exhibits high affinity for EGFR binding and the degradation of the HA by HAase results in the long-chain PEG removal and exposure of the previously hidden surface-attached TATp to enhance the target cell internalization.	('degradation', 'biological_process', 'GO:0009056', ('100', '111'))	('EGFR', 'Protein', (79, 83))	('EGFR binding', 'molecular_function', 'GO:0005154', ('79', '91'))	('GE11', 'Chemical', '-', (47, 51))	('HA', 'Chemical', 'MESH:D006820', (119, 121))	('GE11', 'Var', (47, 51))	('HA', 'Chemical', 'MESH:D006820', (125, 127))	('degradation', 'Var', (100, 111))	('PEG removal', 'MPA', (157, 168))	('enhance', 'PosReg', (232, 239))	('binding', 'Interaction', (84, 91))	('PEG', 'Chemical', 'MESH:D011092', (157, 160))	('affinity', 'Interaction', (66, 74))
13232	29977740	As compared to irinotecan liposomes, TATp-irinotecan liposomes, GE11-irinotecan liposomes and GE11/HA/TATp-irinotecan liposomes, GE11/HA/TATp- irinotecan liposomes after HAase pre-treatment showed the strongest inhibitory effects at various dose levels.	('pre', 'molecular_function', 'GO:0003904', ('176', '179'))	('HA', 'Chemical', 'MESH:D006820', (134, 136))	('inhibitory', 'MPA', (211, 221))	('irinotecan', 'Chemical', 'MESH:D000077146', (42, 52))	('irinotecan', 'Chemical', 'MESH:D000077146', (107, 117))	('irinotecan', 'Chemical', 'MESH:D000077146', (143, 153))	('irinotecan', 'Chemical', 'MESH:D000077146', (69, 79))	('GE11', 'Chemical', '-', (94, 98))	('GE11-irinotecan', 'Chemical', '-', (64, 79))	('HA', 'Chemical', 'MESH:D006820', (170, 172))	('irinotecan', 'Chemical', 'MESH:D000077146', (15, 25))	('GE11/HA/TATp-', 'Var', (129, 142))	('HA', 'Chemical', 'MESH:D006820', (99, 101))	('GE11', 'Chemical', '-', (64, 68))	('GE11', 'Chemical', '-', (129, 133))
13235	29977740	It was clear that the cell endocytosis of GE11/HA/TATp-irinotecan liposomes after HAase pre-treatment was much higher than that of GE11/HA/TATp-irinotecan liposomes, TATp-irinotecan liposomes, GE11-irinotecan liposomes and irinotecan liposomes for cells.	('HA', 'Chemical', 'MESH:D006820', (82, 84))	('irinotecan', 'Chemical', 'MESH:D000077146', (198, 208))	('GE11/HA/TATp-irinotecan', 'Var', (42, 65))	('irinotecan', 'Chemical', 'MESH:D000077146', (171, 181))	('HA', 'Chemical', 'MESH:D006820', (136, 138))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('endocytosis', 'biological_process', 'GO:0006897', ('27', '38'))	('irinotecan', 'Chemical', 'MESH:D000077146', (144, 154))	('cell endocytosis', 'MPA', (22, 38))	('irinotecan', 'Chemical', 'MESH:D000077146', (223, 233))	('GE11', 'Chemical', '-', (42, 46))	('GE11-irinotecan', 'Chemical', '-', (193, 208))	('irinotecan', 'Chemical', 'MESH:D000077146', (55, 65))	('higher', 'PosReg', (111, 117))	('GE11', 'Chemical', '-', (131, 135))	('GE11', 'Chemical', '-', (193, 197))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
13236	29977740	Figure 4 shows the intracellular uptake of GE11/HA/TATp-irinotecan liposomes.	('GE11', 'Chemical', '-', (43, 47))	('uptake', 'biological_process', 'GO:0098739', ('33', '39'))	('HA', 'Chemical', 'MESH:D006820', (48, 50))	('uptake', 'biological_process', 'GO:0098657', ('33', '39'))	('intracellular', 'cellular_component', 'GO:0005622', ('19', '32'))	('intracellular uptake', 'MPA', (19, 39))	('irinotecan', 'Chemical', 'MESH:D000077146', (56, 66))	('GE11/HA/TATp-irinotecan', 'Var', (43, 66))
13240	29977740	Figure 5A shows the efficacy of GE11/HA/TATp-irinotecan liposomes in treating the A549 cells xenografts tumor model.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('HA', 'Chemical', 'MESH:D006820', (37, 39))	('GE11/HA/TATp-irinotecan', 'Var', (32, 55))	('irinotecan', 'Chemical', 'MESH:D000077146', (45, 55))	('GE11', 'Chemical', '-', (32, 36))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
13243	29977740	The rank of inhibitory effects was GE11/HA/TATp-irinotecan liposomes > GE11-irinotecan liposomes > TATp-irinotecan liposomes > irinotecan liposomes > free irinotecan > the blank control with tumor volume at day 25.	('GE11', 'Chemical', '-', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('HA', 'Chemical', 'MESH:D006820', (40, 42))	('GE11/HA/TATp-irinotecan', 'Var', (35, 58))	('irinotecan', 'Chemical', 'MESH:D000077146', (127, 137))	('irinotecan', 'Chemical', 'MESH:D000077146', (48, 58))	('GE11-irinotecan', 'Chemical', '-', (71, 86))	('tumor', 'Disease', (191, 196))	('GE11', 'Chemical', '-', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('irinotecan', 'Chemical', 'MESH:D000077146', (104, 114))	('irinotecan', 'Chemical', 'MESH:D000077146', (155, 165))	('irinotecan', 'Chemical', 'MESH:D000077146', (76, 86))
13246	29977740	After administration of GE11/HA/TATp-irinotecan liposomes, the levels of WBC, Hb, and PLT in blood specimens were slightly decreased, but without significant difference as compared to those in control group.	('decreased', 'NegReg', (123, 132))	('GE11/HA/TATp-irinotecan', 'Var', (24, 47))	('irinotecan', 'Chemical', 'MESH:D000077146', (37, 47))	('GE11', 'Chemical', '-', (24, 28))	('PLT', 'MPA', (86, 89))	('HA', 'Chemical', 'MESH:D006820', (29, 31))	('levels of WBC', 'MPA', (63, 76))
13247	29977740	After administration of TATp-irinotecan liposomes, GE11-irinotecan liposomes and irinotecan liposomes, the levels of WBC, Hb, and PLT in blood specimens were decreased.	('irinotecan', 'Chemical', 'MESH:D000077146', (29, 39))	('decreased', 'NegReg', (158, 167))	('GE11-irinotecan', 'Var', (51, 66))	('levels of WBC', 'MPA', (107, 120))	('irinotecan', 'Chemical', 'MESH:D000077146', (81, 91))	('GE11-irinotecan', 'Chemical', '-', (51, 66))	('PLT', 'MPA', (130, 133))	('irinotecan', 'Chemical', 'MESH:D000077146', (56, 66))
13250	29977740	While after administration of irinotecan liposomes, TATp-irinotecan liposomes, GE11-irinotecan liposomes and GE11/HA/TATp-irinotecan liposomes, the plasma irinotecan concentration decreased relatively slowly in the initial phase and remained at higher concentration levels in the terminal phase (Figure 7), resulting in longer blood exposure.	('GE11-irinotecan', 'Chemical', '-', (79, 94))	('GE11-irinotecan', 'Var', (79, 94))	('irinotecan', 'Chemical', 'MESH:D000077146', (57, 67))	('irinotecan', 'Chemical', 'MESH:D000077146', (30, 40))	('irinotecan', 'Chemical', 'MESH:D000077146', (122, 132))	('GE11', 'Chemical', '-', (79, 83))	('plasma irinotecan concentration', 'MPA', (148, 179))	('blood exposure', 'MPA', (327, 341))	('decreased', 'NegReg', (180, 189))	('HA', 'Chemical', 'MESH:D006820', (114, 116))	('GE11', 'Chemical', '-', (109, 113))	('longer', 'PosReg', (320, 326))	('irinotecan', 'Chemical', 'MESH:D000077146', (155, 165))	('irinotecan', 'Chemical', 'MESH:D000077146', (84, 94))
13259	29977740	Functionalization of liposomes for active targeting by chemically modifying their surface with targeting ligands show a strong specificity for antigens or receptors over-expressed on cancer cells.	('antigens', 'Protein', (143, 151))	('cancer', 'Disease', (183, 189))	('receptors', 'Protein', (155, 164))	('over-expressed', 'PosReg', (165, 179))	('chemically modifying', 'Var', (55, 75))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
13270	29977740	Results demonstrate that GE11/HA/TATp-irinotecan liposomes have the following physicochemical features: high encapsulation efficiency (Table 1), well-distributed particle size (Figure 2A), and delayed drug release (Figure 2B).	('GE11/HA/TATp-irinotecan', 'Var', (25, 48))	('encapsulation', 'MPA', (109, 122))	('GE11', 'Chemical', '-', (25, 29))	('irinotecan', 'Chemical', 'MESH:D000077146', (38, 48))	('delayed drug release', 'MPA', (193, 213))	('HA', 'Chemical', 'MESH:D006820', (30, 32))
13275	29977740	Cytotoxicity results demonstrate that the GE11/HA/TATp-irinotecan liposomes exhibit strong inhibitory effect to A549 lung cancer cells after HAase pre-treatment (Figure 2C).	('inhibitory', 'NegReg', (91, 101))	('Cytotoxicity', 'Disease', (0, 12))	('GE11/HA/TATp-irinotecan', 'Var', (42, 65))	('pre', 'molecular_function', 'GO:0003904', ('147', '150'))	('A549 lung cancer', 'Disease', (112, 128))	('HA', 'Chemical', 'MESH:D006820', (141, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('GE11', 'Chemical', '-', (42, 46))	('irinotecan', 'Chemical', 'MESH:D000077146', (55, 65))	('A549 lung cancer', 'Disease', 'MESH:D008175', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
13276	29977740	The enhanced inhibitory effects are explained by A549 lung cancer cells uptake study by fluorescence microscope in which the GE11/HA/TATp-irinotecan liposomes are the most strongly endocytosed by A549 lung cancer cells.	('uptake', 'biological_process', 'GO:0098739', ('72', '78'))	('GE11/HA/TATp-irinotecan', 'Var', (125, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('A549 lung cancer', 'Disease', 'MESH:D008175', (49, 65))	('uptake', 'biological_process', 'GO:0098657', ('72', '78'))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('A549 lung cancer', 'Disease', (196, 212))	('GE11', 'Chemical', '-', (125, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('A549 lung cancer', 'Disease', (49, 65))	('irinotecan', 'Chemical', 'MESH:D000077146', (138, 148))	('endocytosed', 'MPA', (181, 192))	('HA', 'Chemical', 'MESH:D006820', (130, 132))	('A549 lung cancer', 'Disease', 'MESH:D008175', (196, 212))
13277	29977740	In good agreement with our cytotoxicity studies, robust fluorescence signals of irinotecan were detected in cytoplasm of the A549 lung cancer cells incubated with GE11/HA/TATp-irinotecan liposomes after HAase pre-treatment, indicating the specificity of GE11/HA/TATp-irinotecan liposomes (Figure 3).	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('GE11', 'Chemical', '-', (254, 258))	('GE11/HA/TATp-irinotecan', 'Var', (163, 186))	('HA', 'Chemical', 'MESH:D006820', (259, 261))	('irinotecan', 'Chemical', 'MESH:D000077146', (176, 186))	('HA', 'Chemical', 'MESH:D006820', (203, 205))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('fluorescence', 'MPA', (56, 68))	('irinotecan', 'Chemical', 'MESH:D000077146', (80, 90))	('detected', 'Reg', (96, 104))	('cytoplasm', 'cellular_component', 'GO:0005737', ('108', '117'))	('A549 lung cancer', 'Disease', 'MESH:D008175', (125, 141))	('A549 lung cancer', 'Disease', (125, 141))	('GE11', 'Chemical', '-', (163, 167))	('pre', 'molecular_function', 'GO:0003904', ('209', '212'))	('irinotecan', 'Chemical', 'MESH:D000077146', (267, 277))	('HA', 'Chemical', 'MESH:D006820', (168, 170))	('cytotoxicity', 'Disease', (27, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (27, 39))
13278	29977740	The inhibitory effects on tumor volume in the A549 lung cancer cells xenografted female nude mice demonstrate that, by intravenous injection administration, the GE11/HA/TATp-irinotecan liposomes exhibit significantly higher antitumor activity as compared to TATp-irinotecan liposomes, GE11-irinotecan liposomes, irinotecan liposomes and free irinotecan (Figure 4A and C).	('irinotecan', 'Chemical', 'MESH:D000077146', (290, 300))	('nude mice', 'Species', '10090', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('GE11', 'Chemical', '-', (285, 289))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('HA', 'Chemical', 'MESH:D006820', (166, 168))	('irinotecan', 'Chemical', 'MESH:D000077146', (263, 273))	('irinotecan', 'Chemical', 'MESH:D000077146', (342, 352))	('irinotecan', 'Chemical', 'MESH:D000077146', (312, 322))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('A549 lung cancer', 'Disease', 'MESH:D008175', (46, 62))	('tumor', 'Disease', (26, 31))	('A549 lung cancer', 'Disease', (46, 62))	('GE11/HA/TATp-irinotecan', 'Var', (161, 184))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('irinotecan', 'Chemical', 'MESH:D000077146', (174, 184))	('higher', 'PosReg', (217, 223))	('GE11-irinotecan', 'Chemical', '-', (285, 300))	('GE11', 'Chemical', '-', (161, 165))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
13279	29977740	As compared to TATp-irinotecan liposomes, GE11-irinotecan liposomes, irinotecan liposomes and free irinotecan, GE11/HA/TATp-irinotecan liposomes do not cause an appreciable reduction in body weight (Figure 4B).	('irinotecan', 'Chemical', 'MESH:D000077146', (47, 57))	('reduction in body weight', 'Phenotype', 'HP:0004325', (173, 197))	('irinotecan', 'Chemical', 'MESH:D000077146', (99, 109))	('reduction', 'NegReg', (173, 182))	('irinotecan', 'Chemical', 'MESH:D000077146', (20, 30))	('HA', 'Chemical', 'MESH:D006820', (116, 118))	('GE11/HA/TATp-irinotecan', 'Var', (111, 134))	('GE11', 'Chemical', '-', (42, 46))	('irinotecan', 'Chemical', 'MESH:D000077146', (69, 79))	('GE11', 'Chemical', '-', (111, 115))	('irinotecan', 'Chemical', 'MESH:D000077146', (124, 134))	('GE11-irinotecan', 'Chemical', '-', (42, 57))	('body weight', 'CPA', (186, 197))
13280	29977740	After administering GE11/HA/TATp-irinotecan liposomes to the A549 lung cancer cells xenografted female nude mice, the bone marrow indicators (WBC, Hb, and PLT) are mildly decreased, suggesting that GE11/HA/TATp-irinotecan liposomes may have no significant influences on bone marrow (Figure 5).	('decreased', 'NegReg', (171, 180))	('irinotecan', 'Chemical', 'MESH:D000077146', (33, 43))	('irinotecan', 'Chemical', 'MESH:D000077146', (211, 221))	('HA', 'Chemical', 'MESH:D006820', (203, 205))	('GE11/HA/TATp-irinotecan', 'Var', (20, 43))	('A549 lung cancer', 'Disease', (61, 77))	('HA', 'Chemical', 'MESH:D006820', (25, 27))	('GE11', 'Chemical', '-', (20, 24))	('A549 lung cancer', 'Disease', 'MESH:D008175', (61, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('bone marrow indicators', 'CPA', (118, 140))	('nude mice', 'Species', '10090', (103, 112))	('GE11', 'Chemical', '-', (198, 202))
13284	29977740	Furthermore, GE11/HA/TATp-irinotecan liposomes demonstrate a robust anticancer activity against the tumor xenografted with A549 lung cancer cells.	('GE11', 'Chemical', '-', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('irinotecan', 'Chemical', 'MESH:D000077146', (26, 36))	('tumor', 'Disease', (100, 105))	('A549 lung cancer', 'Disease', (123, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HA', 'Chemical', 'MESH:D006820', (18, 20))	('cancer', 'Disease', (133, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('GE11/HA/TATp-irinotecan', 'Var', (13, 36))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('A549 lung cancer', 'Disease', 'MESH:D008175', (123, 139))	('cancer', 'Disease', (72, 78))
13294	29515166	We identify the key Ser314 phosphorylation site on GAC that is regulated by the NF-kappaB-PKCepsilon axis.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('GAC', 'Gene', '2744', (51, 54))	('Ser314', 'Var', (20, 26))	('NF-kappaB', 'Gene', '4790', (80, 89))	('GAC', 'Gene', (51, 54))	('Ser314', 'Chemical', '-', (20, 26))	('Ser', 'cellular_component', 'GO:0005790', ('20', '23'))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('90', '100'))	('NF-kappaB', 'Gene', (80, 89))
13295	29515166	Blocking Ser314 phosphorylation by the S314A mutation in lung cancer cells inhibits the glutaminase activity, triggers genetic reprogramming, and alleviates tumor malignancy.	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('glutaminase', 'Gene', (88, 99))	('Ser314', 'Var', (9, 15))	('genetic reprogramming', 'CPA', (119, 140))	('tumor malignancy', 'Disease', 'MESH:D018198', (157, 173))	('Ser', 'cellular_component', 'GO:0005790', ('9', '12'))	('alleviates', 'NegReg', (146, 156))	('S314A', 'Var', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('88', '108'))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('triggers', 'Reg', (110, 118))	('lung cancer', 'Disease', (57, 68))	('inhibits', 'NegReg', (75, 83))	('Ser314', 'Chemical', '-', (9, 15))	('S314A', 'Mutation', 'p.S314A', (39, 44))	('tumor malignancy', 'Disease', (157, 173))	('glutaminase', 'Gene', '2744', (88, 99))
13297	29515166	These findings highlight a previously unappreciated mechanism for activation of GAC by phosphorylation and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.	('GAC', 'Gene', (80, 83))	('oncogenic transformation', 'CPA', (167, 191))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('134', '154'))	('glutaminase', 'Gene', (134, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('GAC', 'Gene', '2744', (80, 83))	('glutaminase', 'Gene', '2744', (134, 145))	('phosphorylation', 'MPA', (87, 102))	('targeting', 'Var', (124, 133))	('inhibit', 'NegReg', (159, 166))	('activation', 'PosReg', (66, 76))
13299	29515166	A hallmark of these alterations is the increased utilization of glucose and secretion of lactate even in the presence of oxygen and is known as the Warburg effect.	('alterations', 'Var', (20, 31))	('lactate', 'Chemical', 'MESH:D019344', (89, 96))	('utilization of glucose', 'MPA', (49, 71))	('secretion of lactate', 'MPA', (76, 96))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('oxygen', 'Chemical', 'MESH:D010100', (121, 127))	('increased', 'PosReg', (39, 48))	('secretion', 'biological_process', 'GO:0046903', ('76', '85'))
13326	29515166	We found that highly phosphorylated GAC closely correlates with poor patient survival.	('GAC', 'Gene', (36, 39))	('GAC', 'Gene', '2744', (36, 39))	('patient', 'Species', '9606', (69, 76))	('highly phosphorylated', 'Var', (14, 35))
13336	29515166	We found that by rescuing the expression of GAC, we could recover the reduced growth of H1299 cells resulting from GAC knockdown (Figure S1D).	('GAC', 'Gene', (44, 47))	('reduced', 'NegReg', (70, 77))	('growth', 'MPA', (78, 84))	('GAC', 'Gene', '2744', (115, 118))	('H1299', 'CellLine', 'CVCL:0060', (88, 93))	('GAC', 'Gene', '2744', (44, 47))	('knockdown', 'Var', (119, 128))	('GAC', 'Gene', (115, 118))
13357	29515166	We just focused on the phosphorylation sites which differed in H1299 cells from those in HBE cells, namely, Thr112, Thr188, Ser274, Thr278, Ser314, Ser511, and Ser576 (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('Ser', 'cellular_component', 'GO:0005790', ('124', '127'))	('Ser314', 'Var', (140, 146))	('Ser', 'cellular_component', 'GO:0005790', ('140', '143'))	('H1299', 'Var', (63, 68))	('Thr188', 'Var', (116, 122))	('Thr188', 'Chemical', '-', (116, 122))	('Ser511', 'Var', (148, 154))	('Ser576', 'Chemical', '-', (160, 166))	('Thr278', 'Chemical', '-', (132, 138))	('Ser314', 'Chemical', '-', (140, 146))	('Ser511', 'Chemical', '-', (148, 154))	('Ser274', 'Chemical', '-', (124, 130))	('Ser274', 'Var', (124, 130))	('Ser576', 'Var', (160, 166))	('Thr112', 'Var', (108, 114))	('Ser', 'cellular_component', 'GO:0005790', ('148', '151'))	('Thr112', 'Chemical', '-', (108, 114))	('Thr278', 'Var', (132, 138))	('Ser', 'cellular_component', 'GO:0005790', ('160', '163'))	('HBE', 'CellLine', 'CVCL:0287', (89, 92))	('H1299', 'CellLine', 'CVCL:0060', (63, 68))
13358	29515166	We mutated each of these residues into alanines, transfected the mutants into H1299 cells, and assessed glutaminase activity.	('glutaminase', 'Gene', '2744', (104, 115))	('H1299', 'CellLine', 'CVCL:0060', (78, 83))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('104', '124'))	('alanines', 'Chemical', 'MESH:D000409', (39, 47))	('glutaminase', 'Gene', (104, 115))	('assessed', 'Reg', (95, 103))	('mutated', 'Var', (3, 10))
13359	29515166	Mutation of serine 314 to alanine (S314A) but not the other phosphorylation sites drastically reduced glutaminase activity (Fig.	('reduced', 'NegReg', (94, 101))	('S314A', 'Mutation', 'p.S314A', (35, 40))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('102', '122'))	('glutaminase', 'Gene', (102, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('glutaminase', 'Gene', '2744', (102, 113))	('serine 314 to alanine', 'Mutation', 'p.S314A', (12, 33))	('S314A', 'Var', (35, 40))
13360	29515166	In contrast, GAC mutant with Ser314 changed to aspartic acid (S314D) showed higher activity than the wild-type GAC (Fig.	('activity', 'MPA', (83, 91))	('GAC', 'Gene', (13, 16))	('GAC', 'Gene', '2744', (111, 114))	('Ser314 changed to aspartic acid', 'Mutation', 'p.S314D', (29, 60))	('S314D', 'Var', (62, 67))	('S314D', 'Mutation', 'p.S314D', (62, 67))	('Ser314 changed', 'Var', (29, 43))	('GAC', 'Gene', '2744', (13, 16))	('higher', 'PosReg', (76, 82))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('GAC', 'Gene', (111, 114))
13363	29515166	Whereas the signal was almost undetectable in HBE cells, the extent of phosphorylation of GAC at Ser314 in A549, SPC-A1, H1299, and H292 cells was quite obvious (Fig.	('phosphorylation', 'MPA', (71, 86))	('H1299', 'CellLine', 'CVCL:0060', (121, 126))	('Ser314', 'Chemical', '-', (97, 103))	('SPC', 'molecular_function', 'GO:0009004', ('113', '116'))	('HBE', 'CellLine', 'CVCL:0287', (46, 49))	('GAC', 'Gene', '2744', (90, 93))	('H292', 'CellLine', 'CVCL:0455', (132, 136))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('SPC-A1', 'Gene', (113, 119))	('SPC-A1', 'Gene', '27032', (113, 119))	('Ser', 'cellular_component', 'GO:0005790', ('97', '100'))	('GAC', 'Gene', (90, 93))	('Ser314', 'Var', (97, 103))
13366	29515166	In addition, the phosphorylation level of GAC at Ser314 was also downregulated (Supplementary information, Figure S3C-H).	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('Ser314', 'Chemical', '-', (49, 55))	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('GAC', 'Gene', '2744', (42, 45))	('downregulated', 'NegReg', (65, 78))	('phosphorylation level', 'MPA', (17, 38))	('Ser314', 'Var', (49, 55))	('GAC', 'Gene', (42, 45))
13374	29515166	We found that inhibition of PKC, but none of the other kinases largely abrogated GAC activity and the phosphorylation of GAC at Ser314 (Fig.	('GAC', 'Gene', (81, 84))	('Ser314', 'Chemical', '-', (128, 134))	('phosphorylation', 'MPA', (102, 117))	('PKC', 'Gene', (28, 31))	('GAC', 'Gene', '2744', (121, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('abrogated', 'NegReg', (71, 80))	('PKC', 'Gene', '5578;5580;5581;18754;5582;5590', (28, 31))	('GAC', 'Gene', '2744', (81, 84))	('Ser314', 'Var', (128, 134))	('GAC', 'Gene', (121, 124))	('activity', 'MPA', (85, 93))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))	('Ser', 'cellular_component', 'GO:0005790', ('128', '131'))	('inhibition', 'NegReg', (14, 24))
13376	29515166	These results indicate that PKC is the major kinase responsible for GAC phosphorylation at Ser314 and that this is a general phenomenon in many tumor types and not just NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('tumor', 'Disease', (144, 149))	('Ser314', 'Var', (91, 97))	('PKC', 'Gene', (28, 31))	('NSCLC', 'Disease', (169, 174))	('GAC', 'Gene', (68, 71))	('Ser314', 'Chemical', '-', (91, 97))	('PKC', 'Gene', '5578;5580;5581;18754;5582;5590', (28, 31))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))	('GAC', 'Gene', '2744', (68, 71))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))
13383	29515166	Only the knockdown of PKCepsilon significantly inhibited GAC activity and reduced levels of GAC-pS314 (Fig.	('inhibited', 'NegReg', (47, 56))	('knockdown', 'Var', (9, 18))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('22', '32'))	('GAC', 'Gene', (92, 95))	('GAC', 'Gene', (57, 60))	('PKCepsilon', 'Gene', (22, 32))	('GAC-pS314', 'Gene', '2744', (92, 101))	('GAC-pS314', 'Gene', (92, 101))	('reduced', 'NegReg', (74, 81))	('GAC', 'Gene', '2744', (92, 95))	('GAC', 'Gene', '2744', (57, 60))
13386	29515166	HBE cells were transfected separately with plasmids expressing HA-PKCepsilon-WT, HA-PKCepsilon-(K437R), V5-GAC-WT, and V5-GAC-S314A, the individual proteins were immunoprecipitated from cell extracts, and in vitro kinase assays were performed (Fig.	('GAC', 'Gene', '2744', (122, 125))	('HA-PKCepsilon-(K437R', 'Var', (81, 101))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('66', '76'))	('GAC', 'Gene', '2744', (107, 110))	('GAC', 'Gene', (122, 125))	('K437R', 'Mutation', 'p.K437R', (96, 101))	('HA-PKCepsilon-WT', 'Var', (63, 79))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('84', '94'))	('GAC', 'Gene', (107, 110))	('HBE', 'CellLine', 'CVCL:0287', (0, 3))	('S314A', 'Mutation', 'p.S314A', (126, 131))
13387	29515166	PKCepsilon induced a significantly shifted band above the primary band of GAC, indicating the phosphorylation of GAC by PKCepsilon.	('PKCepsilon', 'molecular_function', 'GO:0004697', ('120', '130'))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('PKCepsilon', 'Var', (0, 10))	('GAC', 'Gene', (74, 77))	('shifted', 'Reg', (35, 42))	('GAC', 'Gene', (113, 116))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('0', '10'))	('GAC', 'Gene', '2744', (113, 116))	('band', 'MPA', (43, 47))	('GAC', 'Gene', '2744', (74, 77))
13389	29515166	Moreover, the phosphorylation of GAC by PKCepsilon was abolished by mutating serine 314 to alanine.	('GAC', 'Gene', (33, 36))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('40', '50'))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('phosphorylation', 'MPA', (14, 29))	('serine 314 to alanine', 'MPA', (77, 98))	('abolished', 'NegReg', (55, 64))	('GAC', 'Gene', '2744', (33, 36))	('mutating', 'Var', (68, 76))	('PKCepsilon', 'Gene', (40, 50))	('serine 314 to alanine', 'Mutation', 'p.S314A', (77, 98))
13392	29515166	This result is consistent with the observation of differential phosphorylation of GAC at S314 in NSCLC and HBE cells (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('HBE', 'CellLine', 'CVCL:0287', (107, 110))	('NSCLC', 'Disease', (97, 102))	('GAC', 'Gene', (82, 85))	('phosphorylation', 'MPA', (63, 78))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('GAC', 'Gene', '2744', (82, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('at S314', 'Var', (86, 93))
13396	29515166	To validate this hypothesis, we measured glutaminase activity and found that the enzymatic activity was reduced significantly when cells were treated with the NF-kappaB inhibitor, Bay117082 (Fig.	('glutaminase', 'Gene', '2744', (41, 52))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('159', '178'))	('Bay117082', 'Chemical', 'MESH:C434003', (180, 189))	('reduced', 'NegReg', (104, 111))	('Bay117082', 'Var', (180, 189))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('41', '61'))	('NF-kappaB', 'Gene', '4790', (159, 168))	('glutaminase', 'Gene', (41, 52))	('NF-kappaB', 'Gene', (159, 168))
13398	29515166	Reduction of glutaminase activity and the phosphorylation level of GAC at Ser314 were also observed when p65 was knocked down in H1299 and A549 cells (Fig.	('knocked down', 'Var', (113, 125))	('p65', 'Gene', (105, 108))	('p65', 'Gene', '5970', (105, 108))	('glutaminase', 'Gene', (13, 24))	('GAC', 'Gene', '2744', (67, 70))	('H1299', 'CellLine', 'CVCL:0060', (129, 134))	('Ser314', 'Chemical', '-', (74, 80))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('phosphorylation level', 'MPA', (42, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('Reduction', 'NegReg', (0, 9))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('13', '33'))	('glutaminase', 'Gene', '2744', (13, 24))	('GAC', 'Gene', (67, 70))	('activity', 'MPA', (25, 33))
13399	29515166	However, mutant GAC (S314D) was resistant to the inhibitory effects of either Bay117082 treatment or knockdown of p65 (Supplementary information, Figure S7B, C).	('GAC', 'Gene', (16, 19))	('p65', 'Gene', '5970', (114, 117))	('S314D', 'Var', (21, 26))	('mutant', 'Var', (9, 15))	('Bay117082', 'Chemical', 'MESH:C434003', (78, 87))	('GAC', 'Gene', '2744', (16, 19))	('S314D', 'Mutation', 'p.S314D', (21, 26))	('p65', 'Gene', (114, 117))
13402	29515166	We found that p65 knockdown reduced both GAC activity and the extent of phosphorylation of GAC at Ser314, whereas overexpression of PKCepsilon rescued the expression of GAC-pS314 and GAC activity resulting from p65 knockdown (Fig.	('p65', 'Gene', (211, 214))	('reduced', 'NegReg', (28, 35))	('Ser', 'cellular_component', 'GO:0005790', ('98', '101'))	('GAC', 'Gene', '2744', (169, 172))	('phosphorylation', 'MPA', (72, 87))	('GAC', 'Gene', '2744', (41, 44))	('GAC', 'Gene', (91, 94))	('p65', 'Gene', '5970', (14, 17))	('p65', 'Gene', '5970', (211, 214))	('GAC', 'Gene', '2744', (183, 186))	('GAC-pS314', 'Gene', '2744', (169, 178))	('GAC-pS314', 'Gene', (169, 178))	('GAC', 'Gene', (169, 172))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('knockdown', 'Var', (18, 27))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('132', '142'))	('activity', 'MPA', (187, 195))	('GAC', 'Gene', (41, 44))	('GAC', 'Gene', (183, 186))	('expression', 'MPA', (155, 165))	('knockdown', 'Var', (215, 224))	('GAC', 'Gene', '2744', (91, 94))	('Ser314', 'Chemical', '-', (98, 104))	('p65', 'Gene', (14, 17))
13403	29515166	However, the overexpression of p65 could not restore reduced GAC-pS314 and GAC activity caused by PKCepsilon knockdown (Fig.	('p65', 'Gene', '5970', (31, 34))	('GAC', 'Gene', (75, 78))	('GAC', 'Gene', (61, 64))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('98', '108'))	('knockdown', 'Var', (109, 118))	('GAC-pS314', 'Gene', (61, 70))	('PKCepsilon', 'Gene', (98, 108))	('GAC', 'Gene', '2744', (75, 78))	('p65', 'Gene', (31, 34))	('GAC-pS314', 'Gene', '2744', (61, 70))	('GAC', 'Gene', '2744', (61, 64))
13414	29515166	When we mutated the p65 binding motif in the PKCepsilon promoter (GTTAGATGTT), the luciferase activity did not change irrespective of whether NF-kappaB (p65) was overexpressed or depleted (Fig.	('p65', 'Gene', (153, 156))	('luciferase activity', 'molecular_function', 'GO:0047077', ('83', '102'))	('mutated', 'Var', (8, 15))	('p65', 'Gene', '5970', (153, 156))	('luciferase activity', 'molecular_function', 'GO:0045289', ('83', '102'))	('p65', 'Gene', (20, 23))	('luciferase activity', 'molecular_function', 'GO:0047712', ('83', '102'))	('activity', 'MPA', (94, 102))	('luciferase activity', 'molecular_function', 'GO:0050248', ('83', '102'))	('NF-kappaB', 'Gene', '4790', (142, 151))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('83', '102'))	('NF-kappaB', 'Gene', (142, 151))	('p65', 'Gene', '5970', (20, 23))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('45', '55'))	('luciferase', 'Enzyme', (83, 93))
13419	29515166	Treatment with Bay117082 significantly reduced the proliferation of H1299 cells (Supplementary information, Figure S9A).	('Bay117082', 'Chemical', 'MESH:C434003', (15, 24))	('Bay117082', 'Var', (15, 24))	('proliferation', 'CPA', (51, 64))	('H1299', 'CellLine', 'CVCL:0060', (68, 73))	('reduced', 'NegReg', (39, 46))
13420	29515166	Knocking down p65 using specific siRNAs also drastically inhibited the proliferation rate of NSCLC cells (Supplementary information, Figure S9B, C).	('p65', 'Gene', '5970', (14, 17))	('Knocking down', 'Var', (0, 13))	('NSCLC', 'Disease', (93, 98))	('inhibited', 'NegReg', (57, 66))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('p65', 'Gene', (14, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))
13422	29515166	We then investigated the effects of p65 on glutamine metabolism and found that knockdown of p65 significantly reduced the production of glutamate in H1299 cells (Supplementary information, Figure S9E).	('p65', 'Gene', (36, 39))	('reduced', 'NegReg', (110, 117))	('p65', 'Gene', (92, 95))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('43', '63'))	('H1299', 'CellLine', 'CVCL:0060', (149, 154))	('p65', 'Gene', '5970', (36, 39))	('glutamine', 'Chemical', 'MESH:D005973', (43, 52))	('production of glutamate', 'MPA', (122, 145))	('p65', 'Gene', '5970', (92, 95))	('knockdown', 'Var', (79, 88))	('glutamate', 'Chemical', 'MESH:D018698', (136, 145))
13424	29515166	In accord with this idea, we found that the proliferation and ability of NSCLC cells to form foci were inhibited following PKCepsilon knockdown (Supplementary information, Figure S10A-E).	('S10A', 'Var', (179, 183))	('ability', 'CPA', (62, 69))	('knockdown', 'Var', (134, 143))	('inhibited', 'NegReg', (103, 112))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('S10A', 'SUBSTITUTION', 'None', (179, 183))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('123', '133'))	('PKCepsilon knockdown', 'Var', (123, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('proliferation', 'CPA', (44, 57))
13426	29515166	This revealed that glutamine accumulated while the glutamate production was reduced in H1299 cells following PKCepsilon knockdown (Supplementary information, Figure S10F, G).	('H1299', 'CellLine', 'CVCL:0060', (87, 92))	('S10F', 'Mutation', 'p.S10F', (165, 169))	('accumulated', 'PosReg', (29, 40))	('glutamate production', 'MPA', (51, 71))	('glutamate', 'Chemical', 'MESH:D018698', (51, 60))	('glutamine', 'Chemical', 'MESH:D005973', (19, 28))	('knockdown', 'Var', (120, 129))	('reduced', 'NegReg', (76, 83))	('glutamine', 'MPA', (19, 28))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('109', '119'))	('PKCepsilon', 'Gene', (109, 119))
13428	29515166	We next wished to assess the effects of mutating Ser314 of the endogenous GLS gene to an alanine residue and so generated such a mutation by CRISPR/Cas9 mutagenesis of A549 cells, A549-GAC (S314A) (Supplementary information, Figure S11A).	('Ser314', 'Chemical', '-', (49, 55))	('GLS', 'Gene', '2744', (74, 77))	('GAC', 'Gene', '2744', (185, 188))	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('mutagenesis', 'Var', (153, 164))	('A549', 'CellLine', 'CVCL:0023', (168, 172))	('S11A', 'SUBSTITUTION', 'None', (232, 236))	('GLS', 'Gene', (74, 77))	('A549', 'CellLine', 'CVCL:0023', (180, 184))	('mutating Ser314', 'Var', (40, 55))	('S314A', 'Mutation', 'p.S314A', (190, 195))	('GAC', 'Gene', (185, 188))	('mutagenesis', 'biological_process', 'GO:0006280', ('153', '164'))	('Ser314', 'Var', (49, 55))	('Cas', 'cellular_component', 'GO:0005650', ('148', '151'))	('alanine', 'Chemical', 'MESH:D000409', (89, 96))	('S11A', 'Var', (232, 236))
13432	29515166	We found that in contrast to the transformed phenotypes of the parental A549 cells, the A549-GAC (S314A) cells were unable to form colonies in soft agar (Supplementary information, Figure S11B) and showed slower cell proliferation rates (Supplementary information, Figure S11C).	('S11C', 'Var', (272, 276))	('S11B', 'Var', (188, 192))	('S11B', 'SUBSTITUTION', 'None', (188, 192))	('slower', 'NegReg', (205, 211))	('GAC', 'Gene', '2744', (93, 96))	('S11C', 'SUBSTITUTION', 'None', (272, 276))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('S314A', 'Mutation', 'p.S314A', (98, 103))	('cell proliferation rates', 'CPA', (212, 236))	('unable', 'NegReg', (116, 122))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('GAC', 'Gene', (93, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('212', '230'))
13433	29515166	Moreover, the A549-GAC (S314A) cells were more susceptible to 968 treatment than A549-WT cells (Supplementary information, Figure S11D).	('susceptible', 'MPA', (47, 58))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('GAC', 'Gene', (19, 22))	('S11D', 'Var', (130, 134))	('S11D', 'SUBSTITUTION', 'None', (130, 134))	('GAC', 'Gene', '2744', (19, 22))	('S314A', 'Mutation', 'p.S314A', (24, 29))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
13443	29515166	The tumors formed by A549-WT cells were TTF1-negative, whereas TTF1-positive cells were observed in tumors formed by A549-GAC (S314A) cells (Fig.	('GAC', 'Gene', '2744', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('A549', 'CellLine', 'CVCL:0023', (21, 25))	('TTF1', 'Gene', (40, 44))	('TTF1', 'Gene', '7270', (40, 44))	('TTF1', 'Gene', (63, 67))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('tumors', 'Disease', (100, 106))	('GAC', 'Gene', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('TTF1', 'Gene', '7270', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('A549-WT', 'Var', (21, 28))	('S314A', 'Mutation', 'p.S314A', (127, 132))
13477	29515166	Taken together, these results indicate that blocking glutamine metabolism promotes lung cancer cell differentiation and significantly inhibits lung cancer initiation and progression.	('promotes', 'PosReg', (74, 82))	('inhibits', 'NegReg', (134, 142))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('lung cancer initiation', 'Disease', 'MESH:D008175', (143, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('glutamine', 'Protein', (53, 62))	('glutamine', 'Chemical', 'MESH:D005973', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancer initiation', 'Disease', (143, 165))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('53', '73'))	('blocking', 'Var', (44, 52))	('cell differentiation', 'biological_process', 'GO:0030154', ('95', '115'))
13485	29515166	8d, patients with low levels of phosphorylated GAC exhibited better survival than patients with high levels of phosphorylated GAC (P = 0.0207).	('better', 'PosReg', (61, 67))	('GAC', 'Gene', '2744', (126, 129))	('survival', 'CPA', (68, 76))	('GAC', 'Gene', (47, 50))	('patients', 'Species', '9606', (82, 90))	('GAC', 'Gene', (126, 129))	('patients', 'Species', '9606', (4, 12))	('GAC', 'Gene', '2744', (47, 50))	('phosphorylated', 'Var', (32, 46))
13486	29515166	These results indicate that the phosphorylation of GAC at Ser314 is closely related to NSCLC progression and patient survival.	('GAC', 'Gene', '2744', (51, 54))	('NSCLC', 'Disease', (87, 92))	('patient', 'Species', '9606', (109, 116))	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Ser314', 'Var', (58, 64))	('GAC', 'Gene', (51, 54))	('Ser314', 'Chemical', '-', (58, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('phosphorylation', 'MPA', (32, 47))	('related', 'Reg', (76, 83))
13504	29515166	We have identified Ser314 as the key phosphorylation site in GAC and found that this site is very important for GAC activity.	('Ser314', 'Var', (19, 25))	('phosphorylation', 'MPA', (37, 52))	('GAC', 'Gene', (61, 64))	('GAC', 'Gene', (112, 115))	('Ser314', 'Chemical', '-', (19, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('Ser', 'cellular_component', 'GO:0005790', ('19', '22'))	('GAC', 'Gene', '2744', (61, 64))	('GAC', 'Gene', '2744', (112, 115))
13505	29515166	reported that the residue Ser314 was located in the glutaminase domain and this residue together with others formed a loop region (Glu312-Pro329) in the crystal structure of KGA.	('Ser314', 'Var', (26, 32))	('glutaminase', 'Gene', '2744', (52, 63))	('Glu312', 'Chemical', '-', (131, 137))	('Ser314', 'Chemical', '-', (26, 32))	('KGA', 'Gene', (174, 177))	('Pro329', 'Chemical', '-', (138, 144))	('KGA', 'Gene', '2744', (174, 177))	('Glu312-Pro329', 'Var', (131, 144))	('glutaminase', 'Gene', (52, 63))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))
13506	29515166	Specifically, Phe318 makes hydrophobic interactions with Tyr466 and the side chain of the Asn319 makes hydrogen-bonding contact with the backbone of Asn335.	('hydrophobic interactions', 'MPA', (27, 51))	('Tyr466', 'Var', (57, 63))	('Asn335', 'Chemical', '-', (149, 155))	('Asn319', 'Chemical', '-', (90, 96))	('Phe318', 'Var', (14, 20))	('Tyr466', 'Chemical', '-', (57, 63))	('Phe318', 'Chemical', '-', (14, 20))	('hydrogen-bonding contact', 'MPA', (103, 127))	('hydrogen', 'Chemical', 'MESH:D006859', (103, 111))	('Asn319', 'Var', (90, 96))
13507	29515166	The residues Tyr466 and Asn335 in the active site are involved in binding to L-glutamine and in catalysis.	('L-glutamine', 'Chemical', 'MESH:D005973', (77, 88))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('binding', 'Interaction', (66, 73))	('Tyr466', 'Var', (13, 19))	('Tyr466', 'Chemical', '-', (13, 19))	('catalysis', 'MPA', (96, 105))	('Asn335', 'Var', (24, 30))	('L-glutamine', 'Protein', (77, 88))	('Asn335', 'Chemical', '-', (24, 30))	('involved', 'Reg', (54, 62))
13509	29515166	Thus, we propose that phosphorylation of GAC on Ser314 might lead to elevated negative charge at the Glu312 to Pro329 loop and subsequent increase in the flexibility of the active site, allowing L-glutamine to enter into the active site to be catalyzed.	('increase', 'PosReg', (138, 146))	('flexibility of the active site', 'MPA', (154, 184))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('L-glutamine', 'Chemical', 'MESH:D005973', (195, 206))	('Ser314', 'Chemical', '-', (48, 54))	('Pro329', 'Chemical', '-', (111, 117))	('phosphorylation', 'Var', (22, 37))	('Ser314', 'Var', (48, 54))	('GAC', 'Gene', (41, 44))	('negative charge', 'MPA', (78, 93))	('enter', 'MPA', (210, 215))	('Glu312', 'Chemical', '-', (101, 107))	('L-glutamine', 'MPA', (195, 206))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('elevated', 'PosReg', (69, 77))	('GAC', 'Gene', '2744', (41, 44))
13511	29515166	Furthermore, we found that the phosphorylation of GAC could be directly regulated by PKCepsilon.	('GAC', 'Gene', (50, 53))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('85', '95'))	('phosphorylation', 'MPA', (31, 46))	('GAC', 'Gene', '2744', (50, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('PKCepsilon', 'Var', (85, 95))	('regulated', 'Reg', (72, 81))
13513	29515166	In NSCLC cells, PKCepsilon is upregulated and knockdown of PKCepsilon impairs tumor growth.	('NSCLC', 'Disease', (3, 8))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('59', '69'))	('knockdown', 'Var', (46, 55))	('upregulated', 'PosReg', (30, 41))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('PKCepsilon', 'Enzyme', (16, 26))	('PKCepsilon impairs tumor', 'Disease', 'MESH:D015417', (59, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PKCepsilon impairs tumor', 'Disease', (59, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('16', '26'))
13515	29515166	We have shown that PKCepsilon can affect the proliferation of NSCLC cells by regulating glutamine metabolism.	('NSCLC', 'Disease', (62, 67))	('regulating', 'Reg', (77, 87))	('proliferation', 'CPA', (45, 58))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('88', '108'))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('glutamine', 'Chemical', 'MESH:D005973', (88, 97))	('glutamine metabolism', 'MPA', (88, 108))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('19', '29'))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('PKCepsilon', 'Var', (19, 29))	('affect', 'Reg', (34, 40))
13519	29515166	Another important finding of our study is that blocking glutamine metabolism leads to tumor cell differentiation.	('cell differentiation', 'biological_process', 'GO:0030154', ('92', '112'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('glutamine', 'Chemical', 'MESH:D005973', (56, 65))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('56', '76'))	('glutamine metabolism', 'MPA', (56, 76))	('blocking', 'Var', (47, 55))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('leads to', 'Reg', (77, 85))
13522	29515166	In contrast, tumors formed by A549-expressing mutant GAC (S314A) were Ki67-negative indicative of a very low proliferation rate.	('GAC', 'Gene', (53, 56))	('A549', 'CellLine', 'CVCL:0023', (30, 34))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutant', 'Var', (46, 52))	('GAC', 'Gene', '2744', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('S314A', 'Mutation', 'p.S314A', (58, 63))
13523	29515166	Previous studies demonstrated that absence of TTF-1 was pathognomonic of high-grade, poorly differentiated tumors.	('high-grade', 'Disease', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('TTF-1', 'Gene', (46, 51))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('absence', 'Var', (35, 42))
13525	29515166	Another study showed that patients with adenocarcinomas with low or high TTF-1 expression had a significantly better outcome than those in which TTF-1 expression was absent.	('adenocarcinomas', 'Disease', (40, 55))	('high', 'Var', (68, 72))	('low', 'NegReg', (61, 64))	('TTF-1', 'Gene', (73, 78))	('patients', 'Species', '9606', (26, 34))	('adenocarcinomas', 'Disease', 'MESH:D000230', (40, 55))
13528	29515166	These findings suggest that inhibition of glutamine metabolism leads lung adenocarcinomas to differentiate from high-grade poorly differentiated tumors to well-differentiated tumors.	('lung adenocarcinomas', 'Disease', (69, 89))	('tumors', 'Disease', (175, 181))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (69, 89))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('glutamine metabolism', 'MPA', (42, 62))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('inhibition', 'Var', (28, 38))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('42', '62'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('glutamine', 'Chemical', 'MESH:D005973', (42, 51))
13536	29515166	Taken together, these metabolomic and human genome oligo microarray analyses demonstrated that blocking glutamine metabolism led to genetic reprogramming and subsequent metabolic reprogramming with the consequence of reduced proliferation rate and tumorigenesis of NSCLC cells.	('blocking', 'Var', (95, 103))	('glutamine', 'Protein', (104, 113))	('glutamine', 'Chemical', 'MESH:D005973', (104, 113))	('tumor', 'Disease', (248, 253))	('human', 'Species', '9606', (38, 43))	('NSCLC', 'Disease', (265, 270))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('104', '124'))	('NSCLC', 'Disease', 'MESH:D002289', (265, 270))	('proliferation rate', 'CPA', (225, 243))	('genetic reprogramming', 'CPA', (132, 153))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('reduced', 'NegReg', (217, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (265, 270))	('metabolic reprogramming', 'CPA', (169, 192))
13547	29515166	A549 cells in which the endogenous GAC carried the mutation S314A were produced by CRISPR/Cas9 mutagenesis by Beijing Biocytogen Co. Ltd.	('GAC', 'Gene', '2744', (35, 38))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('mutagenesis', 'biological_process', 'GO:0006280', ('95', '106'))	('S314A', 'Var', (60, 65))	('mutagenesis', 'Var', (95, 106))	('GAC', 'Gene', (35, 38))	('S314A', 'Mutation', 'p.S314A', (60, 65))	('Cas', 'cellular_component', 'GO:0005650', ('90', '93'))
13553	29515166	For cell growth assays following knockdown of GAC or with overexpression of wild-type or mutant (S314A) GAC, cells were transiently transfected with GAC siRNAs or related plasmids and seeded in 24-well plates at 3000 cells per well in 0.5 ml medium containing 10% FBS.	('S314A', 'Var', (97, 102))	('GAC', 'Gene', (46, 49))	('FBS', 'Disease', (264, 267))	('GAC', 'Gene', '2744', (104, 107))	('GAC', 'Gene', '2744', (149, 152))	('S314A', 'Mutation', 'p.S314A', (97, 102))	('GAC', 'Gene', '2744', (46, 49))	('FBS', 'Disease', 'MESH:D005198', (264, 267))	('cell growth', 'biological_process', 'GO:0016049', ('4', '15'))	('GAC', 'Gene', (104, 107))	('GAC', 'Gene', (149, 152))	('cell growth', 'CPA', (4, 15))	('mutant (S314A', 'Var', (89, 102))
13565	29515166	For the glutaminase activity assay upon GAC-WT and GAC mutants, the indicated plasmids were transiently transfected into H1299 cells and the tagged proteins were immunoprecipitated from cell extracts using an anti-V5 antibody.	('activity', 'MPA', (20, 28))	('antibody', 'cellular_component', 'GO:0042571', ('217', '225'))	('H1299', 'CellLine', 'CVCL:0060', (121, 126))	('GAC', 'Gene', '2744', (51, 54))	('antibody', 'cellular_component', 'GO:0019815', ('217', '225'))	('GAC', 'Gene', (40, 43))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('8', '28'))	('mutants', 'Var', (55, 62))	('antibody', 'cellular_component', 'GO:0019814', ('217', '225'))	('glutaminase', 'Gene', '2744', (8, 19))	('GAC', 'Gene', (51, 54))	('antibody', 'molecular_function', 'GO:0003823', ('217', '225'))	('GAC', 'Gene', '2744', (40, 43))	('glutaminase', 'Gene', (8, 19))
13569	29515166	pCDNA3.1-V5-GAC was used as a template to generate mutations of glutaminase phosphorylation sites.	('mutations', 'Var', (51, 60))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('glutaminase', 'Gene', (64, 75))	('GAC', 'Gene', '2744', (12, 15))	('glutaminase', 'Gene', '2744', (64, 75))	('GAC', 'Gene', (12, 15))
13576	29515166	Cells were fixed with 1% formaldehyde for 15 min at room temperature to cross-link DNA with associated proteins.	('proteins', 'Protein', (103, 111))	('DNA', 'Gene', (83, 86))	('formaldehyde', 'Chemical', 'MESH:D005557', (25, 37))	('cross-link', 'Var', (72, 82))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))
13588	29515166	The sequence of the probe for the WT NF-kappaB binding site is (underlined): Sense: 5'-CGAGCCCGCGCGGATGTGAGATTCCGGGCTCCTGGCGCCT-3' Antisense: 5'-AGGCGCCAGGAGCCCGGAATCTCACATCCGCGCGGGCTCG-3' The sequence of the probe for the mutant of the NF-kappaB binding site is (underlined): Sense: 5'-CGAGCCCGCGCGGATGTTAGATGTTGGGCTCCTGGCGCCT-3' Antisense: 5'-AGGCGCCAGGAGCCCAACATCTAACATCCGCGCGGGCTCG-3' Protein extracts were prepared using NP-40 lysis buffer containing phosphatase and protease inhibitors and the cell lysates were then subjected to Laemmli SDS-PAGE followed by immunoblot using indicated antibodies.	('mutant', 'Var', (223, 229))	('NF-kappaB', 'Gene', (37, 46))	('NF-kappaB binding', 'molecular_function', 'GO:0051059', ('237', '254'))	('NP-40', 'Chemical', 'MESH:C010615', (426, 431))	('lysis', 'biological_process', 'GO:0019835', ('432', '437'))	('NF-kappaB', 'Gene', '4790', (237, 246))	('phosphatase', 'molecular_function', 'GO:0016791', ('456', '467'))	('NF-kappaB binding', 'molecular_function', 'GO:0051059', ('37', '54'))	('NF-kappaB', 'Gene', (237, 246))	('Laemmli SDS', 'Chemical', '-', (536, 547))	("5'-AGGCGCCAGGAGCCCAACATCTAACATCCGCGCGGGCTCG-3", 'Chemical', '-', (342, 387))	('NF-kappaB', 'Gene', '4790', (37, 46))	('TCA', 'Chemical', 'MESH:D014238', (166, 169))
13600	29515166	The Phos-tag SDS-PAGE was performed on 8% (w/v) acrylamide gels containing 50 muM Phos-tag acrylamide and 100 muM MnCl2.	('muM', 'Gene', (78, 81))	('Phos-tag', 'Var', (82, 90))	('Phos', 'Chemical', 'MESH:C005448', (4, 8))	('muM', 'Gene', '56925', (110, 113))	('SDS', 'Chemical', 'MESH:D012967', (13, 16))	('acrylamide', 'Chemical', 'MESH:D020106', (91, 101))	('muM', 'Gene', (110, 113))	('acrylamide', 'Chemical', 'MESH:D020106', (48, 58))	('muM', 'Gene', '56925', (78, 81))	('Phos', 'Chemical', 'MESH:C005448', (82, 86))	('MnCl2', 'Chemical', 'MESH:C025340', (114, 119))
13641	29683843	Largely based on the results of NLST, the Centers for Medicare & Medicaid Services (CMS) initiated coverage of lung cancer screening in high-risk current and former smokers (age 55-77, 30 pack-years of smoking, current smoker or quit within 15 years).	('smokers', 'Var', (165, 172))	('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))
13697	29683843	Average screening LDCT exams per person screened and overdiagnosis were both lower for patients with 80% adherence rate compared with 100%.	('lower', 'NegReg', (77, 82))	('screening', 'CPA', (8, 17))	('adherence rate', 'Var', (105, 119))	('person', 'Species', '9606', (33, 39))	('patients', 'Species', '9606', (87, 95))
13740	29683843	Author contribution: All authors for this study meet the following four criteria specified by the ICMJE: Source of funding: This report is based on research conducted through support from the National Cancer Institute (R01CA173754 to C.Y.K., D.F.S., J.P.W., K.C., R.S.B.	('C.Y.K.', 'Var', (234, 240))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('K.C.', 'Var', (258, 262))	('R01CA173754 to C.Y.K.', 'Var', (219, 240))	('D.F.S.', 'Var', (242, 248))	('J.P.W.', 'Var', (250, 256))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('Cancer', 'Disease', (201, 207))
13798	29390473	Borghesi et al evaluated patients who underwent secondary surgery for stage IEC with intermediate and advanced recurrence risk, including the risk of lymph vascular space invasion (LVSI).Thus, LVSI is an independent factor for overall survival and progression-free survival, HR 7.2, 95% CI 3.1-17, P < .001and HR 3.7, 95% CI 1.6-8.5, P < .003, respectively.	('overall survival', 'CPA', (227, 243))	('progression-free survival', 'CPA', (248, 273))	('patients', 'Species', '9606', (25, 33))	('LVSI', 'Var', (193, 197))	('EC', 'Phenotype', 'HP:0012114', (77, 79))
13809	29390473	In the present case, the patient with pathological immunohistochemical staining showed ER (++), PR (++), which can allow the patient to also choose hormone therapy instead of radiotherapy or chemotherapy.	('patient', 'Species', '9606', (25, 32))	('ER (++', 'Var', (87, 93))	('patient', 'Species', '9606', (125, 132))	('PR (++', 'Var', (96, 102))	('choose', 'Reg', (141, 147))
13824	28055219	This tool, available on the Global Natural Products Social Molecular Networking (GNPS at http://gnps.ucsd.edu) Web site, allows users to include their newly described and structurally annotated data sets into a publicly available database, thereby enabling future compound dereplication against authentic, structurally annotated MS/MS spectra.	('dereplication', 'Var', (273, 286))	('Pro', 'Chemical', 'MESH:D011392', (43, 46))	('compound', 'MPA', (264, 272))
13844	28055219	The molecular formula of 1 was determined to be C50H70N8O8 based on the protonated and sodiated pseudomolecular ion peaks in the HRESIMS at m/z 911.54187 (calcd for C50H71N8O8+, 911.53894) and 933.52322 (calcd for C50H70N8O8Na+, 933.52088), respectively.	('C50H70N8O8Na+', 'Var', (214, 227))	('C50H70N8O8', 'Chemical', '-', (214, 224))	('C50H70N8O8', 'Chemical', '-', (48, 58))	('C50H71N8O8', 'Chemical', '-', (165, 175))	('C50H70N8O8', 'Var', (48, 58))	('C50H71N8O8+', 'Var', (165, 176))	('933.52322', 'Var', (193, 202))	('C50H70N8O8Na', 'Chemical', '-', (214, 226))
13849	28055219	From the HSQC experiment, it was obvious that four resonances between deltaH 7.58 and 7.83 could be attributed to amide protons, as was a fifth at deltaH 5.81.	('amide', 'Chemical', 'MESH:D000577', (114, 119))	('amide protons', 'MPA', (114, 127))	('C', 'Chemical', 'MESH:D002244', (12, 13))	('deltaH', 'Chemical', '-', (147, 153))	('deltaH', 'Chemical', '-', (70, 76))	('deltaH 7.58', 'Var', (70, 81))
13854	28055219	Correlations in the HMBC spectrum from methylene groups at deltaH 3.64 and 3.25 ppm (CH2-14) to deltaC 129.3 (C-16 & 20) as well as deltaH 3.39 and 2.99 (CH2-34) to deltaC 128.9 (C-36 & 40) indicated that the two phenyl rings observed in the 1H NMR spectrum were each part of phenylalanine moieties.	('C', 'Chemical', 'MESH:D002244', (170, 171))	('deltaC', 'Var', (96, 102))	('deltaC', 'Chemical', '-', (165, 171))	('C', 'Chemical', 'MESH:D002244', (154, 155))	('deltaH', 'Var', (59, 65))	('phenylalanine', 'Chemical', 'MESH:D010649', (276, 289))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CH2', 'Chemical', '-', (85, 88))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('CH2-14', 'Disease', (85, 91))	('1H', 'Chemical', '-', (242, 244))	('deltaH', 'Chemical', '-', (132, 138))	('deltaC', 'Chemical', '-', (96, 102))	('CH2', 'Chemical', '-', (154, 157))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('CH2-14', 'Disease', 'OMIM:615513', (85, 91))	('deltaH', 'Chemical', '-', (59, 65))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('C', 'Chemical', 'MESH:D002244', (179, 180))
13858	28055219	Accordingly, the planar structure of 1 was resolved as cyclic Leu-Val-Phe(1)-Pro(1)-Ile-Phe(2)-Pro(2)-Pro(3) (cycLVFPIFPP); such a cyclic peptide is not present in any of the literature databases.	('Pro', 'Chemical', 'MESH:D011392', (77, 80))	('Pro', 'Chemical', 'MESH:D011392', (95, 98))	('Pro', 'Chemical', 'MESH:D011392', (102, 105))	('Leu-Val-Phe', 'Var', (62, 73))	('Pro(1)-Ile', 'Var', (77, 87))	('Pro(1)-Ile', 'SUBSTITUTION', 'None', (77, 87))	('cyclic Leu-Val-Phe', 'Chemical', '-', (55, 73))	('peptide', 'Chemical', 'MESH:D010455', (138, 145))
13868	28055219	Vildagliptin itself has been shown to prevent DPP4 from degrading glucagon-like peptide 1 (GLP-1), which in turn has a multitude of downstream effects including treatment of diabetes mellitus and osteoporosis.	('osteoporosis', 'Disease', 'MESH:D010024', (196, 208))	('diabetes mellitus', 'Disease', 'MESH:D003920', (174, 191))	('osteoporosis', 'Disease', (196, 208))	('GLP-1', 'Gene', (91, 96))	('glucagon-like peptide 1', 'Gene', '2641', (66, 89))	('osteoporosis', 'Phenotype', 'HP:0000939', (196, 208))	('glucagon-like peptide 1', 'Gene', (66, 89))	('Vildagliptin', 'Chemical', 'MESH:D000077597', (0, 12))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (174, 191))	('DPP4', 'Var', (46, 50))	('GLP-1', 'Gene', '2641', (91, 96))	('degrading', 'NegReg', (56, 65))	('diabetes mellitus', 'Disease', (174, 191))
13894	28055219	The sample yields from this chromatography were 2228A (51.7 mg), 2228B (163.7 mg), 2228C (88.5 mg), 2228D (24.9 mg), 2228E (11.9 mg), 2228F (7.8 mg), 2228G (11.1 mg), 2228H (23.0 mg), and 2228I (67.1 mg).	('C', 'Chemical', 'MESH:D002244', (87, 88))	('2228G', 'Var', (150, 155))	('2228B', 'Var', (65, 70))	('2228H', 'Chemical', '-', (167, 172))	('2228E', 'Var', (117, 122))	('2228D', 'Var', (100, 105))	('2228C', 'Var', (83, 88))	('2228F', 'Var', (134, 139))	('2228I', 'Var', (188, 193))
13895	28055219	Of these, fractions 2228E and 2228G demonstrated weak in vitro cytotoxicity to H-460 cells, 2228F was moderately cytotoxic, and 2228H was the most potently cytotoxic when tested at 1 and 10 mug/mL.	('2228G', 'Var', (30, 35))	('H-460', 'Chemical', '-', (79, 84))	('2228H', 'Chemical', '-', (128, 133))	('2228H', 'Var', (128, 133))	('cytotoxicity', 'Disease', (63, 75))	('mug', 'molecular_function', 'GO:0043739', ('190', '193'))	('2228F', 'Var', (92, 97))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))
13908	28055219	Amorphous light green solid; [alpha]D -146.9 (c 0.1, MeOH) and -178.9 (c 0.1, CHCl3); UV (MeOH) lambdamax (log epsilon) 214 (4.98), 284 (3.74), 421 (3.12), 676 (2.55) nm; IR (film) numax 3301, 2962, 2931, 2877, 1658, 1620, 1527, 1458, 1323, 1250, 1199, 1141, 756, 702 cm-1; 1H NMR and 13C NMR, see Table 1; HRESIMS m/z 911.54187 (calcd for C50H71N8O8+, 911.53894) and 933.52322 (calcd for C50H70N8O8Na+, 933.52088).	('1H', 'Chemical', '-', (274, 276))	('C50H70N8O8Na+', 'Var', (389, 402))	('13C', 'Chemical', '-', (285, 288))	('C50H71N8O8', 'Chemical', '-', (340, 350))	('933.52322', 'Var', (368, 377))	('C50H70N8O8Na', 'Chemical', '-', (389, 401))	('MeOH', 'Chemical', 'MESH:D000432', (90, 94))	('C50H71N8O8+', 'Var', (340, 351))	('MeOH', 'Chemical', 'MESH:D000432', (53, 57))
13915	28055219	The D-FDAA derivatized 1-hydrolysate peaks with the expected masses were observed at 43.38, 42.70, 38.47, 42.54, and 28.96 min, respectively, corresponding to L-Leu, L-Ile, L-Val, L-Phe, and L-Pro, respectively.	('L-Pro', 'Chemical', '-', (191, 196))	('L-Pro', 'Var', (191, 196))	('L-Ile', 'Var', (166, 171))	('L-Leu', 'Chemical', '-', (159, 164))	('L-Leu', 'Var', (159, 164))	('L-Phe', 'Var', (180, 185))	('L-Ile', 'Chemical', 'MESH:D007532', (166, 171))	('L-Val', 'Chemical', '-', (173, 178))	('1-hydrolysate', 'Chemical', '-', (23, 36))	('D-FDAA', 'Chemical', '-', (4, 10))	('L-Val', 'Var', (173, 178))	('L-Phe', 'Chemical', '-', (180, 185))
13940	28540288	During UPR, transmembrane proteins in the ER act as sensors to detect disturbances in protein handling (proteostasis) caused by misfolded/mutant proteins, or by alterations in signaling networks or in the ionic balance such as calcium in the cell.	('signaling networks', 'Pathway', (176, 194))	('protein handling', 'MPA', (86, 102))	('proteins', 'Protein', (145, 153))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('transmembrane', 'cellular_component', 'GO:0044214', ('12', '25'))	('misfolded/mutant', 'Var', (128, 144))	('transmembrane', 'cellular_component', 'GO:0016021', ('12', '25'))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('rat', 'Species', '10116', (165, 168))	('alterations', 'Reg', (161, 172))	('disturbances', 'Reg', (70, 82))	('calcium', 'Chemical', 'MESH:D002118', (227, 234))
13962	28540288	The lack of ATP6 decreased the levels of BiP and other chaperones reducing the folding and transport of EM proteins such as pro-collagen that interferes with early development (Ishikawa et al.,).	('levels', 'MPA', (31, 37))	('folding', 'MPA', (79, 86))	('decreased', 'NegReg', (17, 26))	('ATP6', 'Gene', (12, 16))	('collagen', 'molecular_function', 'GO:0005202', ('128', '136'))	('transport of EM proteins', 'MPA', (91, 115))	('BiP', 'Gene', (41, 44))	('reducing', 'NegReg', (66, 74))	('lack', 'Var', (4, 8))	('ATP6', 'Gene', '4508', (12, 16))	('BiP', 'Gene', '3309', (41, 44))	('transport', 'biological_process', 'GO:0006810', ('91', '100'))
13972	28540288	Wolframin (WFS1) is a transmembrane ER resident protein encoded by the WFS1 gene that in a mutant form causes Wolfram syndrome 1 (WS1), an autosomal recessive degenerative disease characterized by insulin-dependent diabetes mellitus, optic atrophy, deafness and various neurological symptoms (Hofmann et al.,).	('WFS1', 'Gene', (71, 75))	('insulin-dependent diabetes mellitus', 'Disease', 'MESH:D003922', (197, 232))	('causes', 'Reg', (103, 109))	('WS1', 'Gene', (130, 133))	('deafness', 'Phenotype', 'HP:0000365', (249, 257))	('deafness', 'Disease', (249, 257))	('Wolframin', 'Gene', (0, 9))	('transmembrane', 'cellular_component', 'GO:0016021', ('22', '35'))	('deafness', 'Disease', 'MESH:D003638', (249, 257))	('neurological symptoms', 'Disease', 'MESH:D009422', (270, 291))	('insulin', 'molecular_function', 'GO:0016088', ('197', '204'))	('optic atrophy', 'Disease', 'MESH:D009896', (234, 247))	('autosomal recessive degenerative disease', 'Disease', 'MESH:D020271', (139, 179))	('WS1', 'Gene', '5077', (130, 133))	('transmembrane', 'cellular_component', 'GO:0044214', ('22', '35'))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('insulin-dependent diabetes mellitus', 'Phenotype', 'HP:0100651', (197, 232))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (215, 232))	('degenerative disease', 'Phenotype', 'HP:0002180', (159, 179))	('neurological symptoms', 'Disease', (270, 291))	('insulin-dependent diabetes mellitus', 'Disease', (197, 232))	('Wolframin', 'Gene', '7466', (0, 9))	('autosomal recessive degenerative disease', 'Disease', (139, 179))	('optic atrophy', 'Disease', (234, 247))	('Wolfram syndrome 1', 'Gene', '5077', (110, 128))	('optic atrophy', 'Phenotype', 'HP:0000648', (234, 247))	('mutant', 'Var', (91, 97))	('Wolfram syndrome 1', 'Gene', (110, 128))
13973	28540288	The promoter region of WFS1 gene has ER stress response element (ERSE) like sequence and WFS1 expression is increased during ER stress by XBP1 and ATF6 (Kakiuchi et al.,; Odisho et al.,) WFS1 stabilizes the yeast E3 ubiquitin ligase HRD1 (SYVN1 in humans) involved in ERAD and enhances the proteasome-mediated degradation of ATF6alpha thereby reducing ER stress signaling (Fonseca et al.,).	('humans', 'Species', '9606', (248, 254))	('reducing', 'NegReg', (343, 351))	('WFS1', 'Gene', (23, 27))	('AD', 'Disease', (270, 272))	('AD', 'Phenotype', 'HP:0002511', (270, 272))	('ER stress response', 'biological_process', 'GO:0034976', ('37', '55'))	('stabilizes', 'PosReg', (192, 202))	('ubiquitin', 'molecular_function', 'GO:0031386', ('216', '225'))	('WFS1', 'Var', (187, 191))	('ER stress signaling', 'MPA', (352, 371))	('yeast', 'Species', '4932', (207, 212))	('AD', 'Disease', 'MESH:D000544', (270, 272))	('degradation', 'biological_process', 'GO:0009056', ('310', '321'))	('increased', 'PosReg', (108, 117))	('proteasome', 'molecular_function', 'GO:0004299', ('290', '300'))	('ATF6alpha', 'Protein', (325, 334))	('HRD1', 'Gene', (233, 237))	('signaling', 'biological_process', 'GO:0023052', ('362', '371'))	('proteasome', 'cellular_component', 'GO:0000502', ('290', '300'))	('enhances', 'PosReg', (277, 285))	('WFS1', 'Gene', (89, 93))	('HRD1', 'Gene', '854149', (233, 237))	('proteasome-mediated degradation', 'MPA', (290, 321))	('ERAD', 'biological_process', 'GO:0030433', ('268', '272'))
13974	28540288	Lack of functional WFS1 protein makes cells more vulnerable to different environmental insults (Koks et al.,), and pancreatic beta-cells degenerate in WFS1 gene deleted mice subsequent to ER-stress (Ishihara et al.,).	('WFS1', 'Gene', (19, 23))	('deleted', 'Var', (161, 168))	('pancreatic beta-cells', 'CPA', (115, 136))	('protein', 'Protein', (24, 31))	('Lack', 'NegReg', (0, 4))	('degenerate', 'NegReg', (137, 147))	('WFS1', 'Gene', (151, 155))	('rat', 'Species', '10116', (143, 146))	('mice', 'Species', '10090', (169, 173))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('vulnerable', 'MPA', (49, 59))
13975	28540288	Deregulated trafficking of cell surface proteins occurs in human diseases such as cystic fibrosis (CF) caused by mutations in CF transmembrane conductance regulator gene, CFTR (Schmidt et al.,).	('transmembrane', 'cellular_component', 'GO:0044214', ('129', '142'))	('transmembrane', 'cellular_component', 'GO:0016021', ('129', '142'))	('human', 'Species', '9606', (59, 64))	('Deregulated trafficking of cell surface proteins', 'MPA', (0, 48))	('cystic fibrosis', 'Disease', 'MESH:D003550', (82, 97))	('CFTR', 'Gene', (171, 175))	('cystic fibrosis', 'Disease', (82, 97))	('mutations', 'Var', (113, 122))	('CFTR', 'Gene', '1080', (171, 175))	('cell surface', 'cellular_component', 'GO:0009986', ('27', '39'))	('caused by', 'Reg', (103, 112))
13978	28540288	However, a lesson learned from studies of the yeast ATP-binding cassette transporter Yor1p, a homolog of mammalian CFTR, is that the interconnections between protein retention and ERAD of mutant proteins are complex and competing signals control protein trafficking in the ER (Pagant et al.,).	('control', 'Reg', (238, 245))	('Yor1p', 'Gene', (85, 90))	('CFTR', 'Gene', '1080', (115, 119))	('Yor1p', 'Gene', '853198', (85, 90))	('ERAD', 'biological_process', 'GO:0030433', ('180', '184'))	('ATP-binding cassette transporter', 'molecular_function', 'GO:0140359', ('52', '84'))	('protein retention', 'biological_process', 'GO:0045185', ('158', '175'))	('protein trafficking', 'MPA', (246, 265))	('AD', 'Phenotype', 'HP:0002511', (182, 184))	('mammalian', 'Species', '9606', (105, 114))	('AD', 'Disease', 'MESH:D000544', (182, 184))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))	('AD', 'Disease', (182, 184))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('CFTR', 'Gene', (115, 119))	('protein', 'cellular_component', 'GO:0003675', ('246', '253'))	('yeast', 'Species', '4932', (46, 51))	('mutant', 'Var', (188, 194))
13984	28540288	As shown for mutant transthyretin (TTR) protein, ATF6 signaling is able to counteract amyloid formation and cytotoxicity by reducing secretion of misfolded TTR (Chen J. J. et al.,).	('mutant', 'Var', (13, 19))	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('secretion', 'MPA', (133, 142))	('TTR', 'Gene', '7276', (35, 38))	('TTR', 'Gene', '7276', (156, 159))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('secretion', 'biological_process', 'GO:0046903', ('133', '142'))	('transthyretin', 'Gene', (20, 33))	('transthyretin', 'Gene', '7276', (20, 33))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('reducing', 'NegReg', (124, 132))	('TTR', 'Gene', (35, 38))	('cytotoxicity', 'Disease', (108, 120))	('TTR', 'Gene', (156, 159))
13993	28540288	Mutations in or loss of these protein lead to impaired mitochondria functions and can cause human diseases exemplified by spinocerebellar ataxia type 28 and hereditary spastic paraplegia type 7 (Casari et al.,; Di Bella et al.,).	('spinocerebellar ataxia type', 'Disease', (122, 149))	('hereditary spastic paraplegia type', 'Disease', 'MESH:D015419', (157, 191))	('impaired', 'NegReg', (46, 54))	('mitochondria', 'cellular_component', 'GO:0005739', ('55', '67'))	('hereditary spastic paraplegia type', 'Disease', (157, 191))	('spinocerebellar ataxia type', 'Disease', 'MESH:D017827', (122, 149))	('spastic paraplegia', 'Phenotype', 'HP:0001258', (168, 186))	('loss', 'NegReg', (16, 20))	('cause', 'Reg', (86, 91))	('ataxia', 'Phenotype', 'HP:0001251', (138, 144))	('Mutations in', 'Var', (0, 12))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('mitochondria functions', 'MPA', (55, 77))	('human', 'Species', '9606', (92, 97))	('paraplegia', 'Phenotype', 'HP:0010550', (176, 186))
13994	28540288	Alterations in mitochondria are also linked to pathogenesis of different diseases (Nunnari and Suomalainen,).	('mitochondria', 'MPA', (15, 27))	('Suomalainen', 'Disease', (95, 106))	('Alterations', 'Var', (0, 11))	('linked', 'Reg', (37, 43))	('rat', 'Species', '10116', (4, 7))	('mitochondria', 'cellular_component', 'GO:0005739', ('15', '27'))	('pathogenesis', 'biological_process', 'GO:0009405', ('47', '59'))
13999	28540288	Thus, it was shown that UPR(mt) is constitutively activated in a the heteroplasmic C. elegans strain that helps to maintain the high amount of mtDNA deletions present (Lin et al.,).	('mtDNA', 'Gene', (143, 148))	('C. elegans', 'Species', '6239', (83, 93))	('mtDNA', 'cellular_component', 'GO:0000262', ('143', '148'))	('deletions', 'Var', (149, 158))
14005	28540288	UPR has been shown to play a dual role in neurodegeneration as the lack of XBP1 increased survival in a ALS mouse model (Hetz et al.,).	('neurodegeneration', 'Disease', (42, 59))	('neurodegeneration', 'Disease', 'MESH:D019636', (42, 59))	('lack', 'Var', (67, 71))	('ALS', 'Phenotype', 'HP:0007354', (104, 107))	('increased', 'PosReg', (80, 89))	('mouse', 'Species', '10090', (108, 113))	('neurodegeneration', 'Phenotype', 'HP:0002180', (42, 59))	('survival', 'CPA', (90, 98))	('XBP1', 'Gene', (75, 79))
14006	28540288	Further data showed that XBP1 deficiency increased autophagy through the forkhead box 01 (FOXO1) transcription factor improving the degradation of mutant SOD1 protein (Hetz et al.,).	('mutant', 'Var', (147, 153))	('SOD1', 'molecular_function', 'GO:0004784', ('154', '158'))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('improving', 'PosReg', (118, 127))	('degradation', 'MPA', (132, 143))	('XBP1 deficiency increased autophagy', 'Disease', 'MESH:C564093', (25, 60))	('transcription factor', 'molecular_function', 'GO:0000981', ('97', '117'))	('protein', 'Protein', (159, 166))	('autophagy', 'biological_process', 'GO:0016236', ('51', '60'))	('degradation', 'biological_process', 'GO:0009056', ('132', '143'))	('FOXO1', 'Gene', '2308', (90, 95))	('XBP1 deficiency increased autophagy', 'Disease', (25, 60))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('SOD1', 'Gene', (154, 158))	('FOXO1', 'Gene', (90, 95))	('autophagy', 'biological_process', 'GO:0006914', ('51', '60'))
14007	28540288	In dopaminergic neurons degenerating in PD, XBP1 deletion produce different outcomes depending on the age of the animals and reflecting compensatory changes in UPR-regulated factors.	('dopamine', 'Chemical', 'MESH:D004298', (3, 11))	('PD', 'Disease', 'MESH:D010300', (40, 42))	('rat', 'Species', '10116', (30, 33))	('degenerating', 'NegReg', (24, 36))	('deletion', 'Var', (49, 57))	('XBP1', 'Gene', (44, 48))
14008	28540288	Thus, the lack of XBP1 during development induced a mild ER stress with protection of dopamine neurons against neurotoxicity of 6-hydroxydopamine, whilst silencing XBP1 in adulthood led to chronic ER stress and the loss of dopamine neurons (Valdes et al.,).	('XBP1', 'Gene', (164, 168))	('neurotoxicity', 'Disease', (111, 124))	('ER stress', 'MPA', (197, 206))	('dopamine', 'Chemical', 'MESH:D004298', (223, 231))	('loss', 'NegReg', (215, 219))	('dopamine', 'Chemical', 'MESH:D004298', (86, 94))	('XBP1', 'Gene', (18, 22))	('6-hydroxydopamine', 'Chemical', 'MESH:D016627', (128, 145))	('lack', 'Var', (10, 14))	('induced', 'Reg', (42, 49))	('neurotoxicity', 'Disease', 'MESH:D020258', (111, 124))	('dopamine neurons', 'MPA', (223, 239))	('silencing', 'Var', (154, 163))	('dopamine', 'Chemical', 'MESH:D004298', (137, 145))
14009	28540288	In transgenic mice expressing mutant alfasunyclein as a model for PD, the administration of salubrinal inhibiting the PPP1R15A/GADD34 phosphatase inducing phospho-eIF2alpha levels was found to be neuroprotective suggesting an involvement of the PERK pathway in dopamine neuron degeneration (Colla et al.,).	('PPP1R15A/GADD34', 'Gene', (118, 133))	('neuron degeneration', 'Disease', (270, 289))	('AD', 'Phenotype', 'HP:0002511', (128, 130))	('dopamine', 'Chemical', 'MESH:D004298', (261, 269))	('neuron degeneration', 'Disease', 'MESH:D009410', (270, 289))	('phosphatase', 'molecular_function', 'GO:0016791', ('134', '145'))	('rat', 'Species', '10116', (283, 286))	('inhibiting', 'NegReg', (103, 113))	('PD', 'Disease', 'MESH:D010300', (66, 68))	('involvement', 'Reg', (226, 237))	('rat', 'Species', '10116', (82, 85))	('transgenic mice', 'Species', '10090', (3, 18))	('eIF2', 'cellular_component', 'GO:0005850', ('163', '167'))	('mutant', 'Var', (30, 36))	('salubrinal', 'Chemical', 'MESH:C496827', (92, 102))
14016	28540288	Recent data have shown that ALS and frontotemporal dementia share a major genetic risk factor related to the presence of a hexanucleotide repeat expansion in the gene, C9orf72 (Renton et al.,).	('ALS', 'Phenotype', 'HP:0007354', (28, 31))	('dementia', 'Phenotype', 'HP:0000726', (51, 59))	('ALS', 'Disease', (28, 31))	('hexanucleotide repeat expansion', 'Var', (123, 154))	('presence', 'Var', (109, 117))	('C9orf72', 'Gene', '203228', (168, 175))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (36, 59))	('dementia', 'Disease', (51, 59))	('hexanucleotide', 'Chemical', '-', (123, 137))	('dementia', 'Disease', 'MESH:D003704', (51, 59))	('C9orf72', 'Gene', (168, 175))
14021	28540288	In vivo sephin1 was neuroprotective in the mutant SOD1-ALS mouse model, and improved behavior with no obvious adverse effects (Das et al.,).	('mouse', 'Species', '10090', (59, 64))	('ALS', 'Phenotype', 'HP:0007354', (55, 58))	('SOD1', 'molecular_function', 'GO:0004784', ('50', '54'))	('behavior', 'CPA', (85, 93))	('improved', 'PosReg', (76, 84))	('sephin1', 'Gene', (8, 15))	('mutant', 'Var', (43, 49))
14022	28540288	Sephin1 also prevented demyelination in Charcot-Marie-Tooth disease model caused by mutant myelin protein zero.	('Sephin1', 'Chemical', 'MESH:C000597020', (0, 7))	('demyelination', 'Disease', 'MESH:D003711', (23, 36))	('demyelination', 'Disease', (23, 36))	('prevented', 'NegReg', (13, 22))	('myelin protein zero', 'Protein', (91, 110))	('Charcot-Marie-Tooth disease', 'Disease', 'MESH:D000699', (40, 67))	('mutant', 'Var', (84, 90))	('Charcot-Marie-Tooth disease', 'Disease', (40, 67))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('demyelination', 'Phenotype', 'HP:0011096', (23, 36))
14024	28540288	Studies in models of HD have shown that the lack of XBP1 is neuroprotective by reducing the aggregation of mutant Huntingtin protein (Htt) and increasing cell survival (Vidal et al.,).	('cell survival', 'CPA', (154, 167))	('lack', 'Var', (44, 48))	('mutant', 'Var', (107, 113))	('Htt', 'Gene', '3064', (134, 137))	('aggregation', 'MPA', (92, 103))	('reducing', 'NegReg', (79, 87))	('Htt', 'Gene', (134, 137))	('increasing', 'PosReg', (143, 153))	('XBP1', 'Gene', (52, 56))	('Huntingtin', 'Gene', '3064', (114, 124))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('HD', 'Disease', 'MESH:D006816', (21, 23))	('Huntingtin', 'Gene', (114, 124))
14026	28540288	As shown recently, the ubiquitin-specific protease 14 (Usp14) plays a role in degradation of mutant Htt by binding IRE1alpha and by regulating the proteasome activity, adding a further degree of complexity to HD pathophysiology (Hyrskyluoto et al.,).	('Usp14', 'Gene', '9097', (55, 60))	('degradation', 'MPA', (78, 89))	('HD', 'Disease', 'MESH:D006816', (209, 211))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))	('Usp14', 'Gene', (55, 60))	('Htt', 'Gene', (100, 103))	('binding', 'Interaction', (107, 114))	('IRE1alpha', 'Protein', (115, 124))	('Usp', 'molecular_function', 'GO:0051748', ('55', '58'))	('regulating', 'Reg', (132, 142))	('Htt', 'Gene', '3064', (100, 103))	('proteasome', 'molecular_function', 'GO:0004299', ('147', '157'))	('IR', 'Phenotype', 'HP:0000855', (115, 117))	('ubiquitin', 'molecular_function', 'GO:0031386', ('23', '32'))	('ubiquitin-specific protease 14', 'Gene', (23, 53))	('proteasome activity', 'MPA', (147, 166))	('proteasome', 'cellular_component', 'GO:0000502', ('147', '157'))	('mutant', 'Var', (93, 99))	('degradation', 'biological_process', 'GO:0009056', ('78', '89'))	('ubiquitin-specific protease 14', 'Gene', '9097', (23, 53))
14027	28540288	The aggregation of mutant Htt may takes place in different neuronal compartments, such as in the nucleus and the cytosol.	('Htt', 'Gene', '3064', (26, 29))	('nucleus', 'cellular_component', 'GO:0005634', ('97', '104'))	('mutant', 'Var', (19, 25))	('cytosol', 'cellular_component', 'GO:0005829', ('113', '120'))	('Htt', 'Gene', (26, 29))
14044	28540288	Mutant and misfolded PrP aggregates in brain tissue as amyloid fibrils leading to spongiform changes and loss of brain cells over time.	('loss', 'NegReg', (105, 109))	('PrP', 'Gene', (21, 24))	('Mutant', 'Var', (0, 6))	('loss of brain cells', 'Phenotype', 'HP:0002529', (105, 124))	('spongiform changes', 'CPA', (82, 100))	('PrP', 'Gene', '5621', (21, 24))
14045	28540288	Mounting evidence has shown that the spreading of the disease (propagation) occurs from cell to cell during PrP replication by misfolded PrP causing an abnormal folding of the cellular PrP (Colby and Prusiner,).	('PrP', 'Gene', '5621', (185, 188))	('PrP', 'Gene', '5621', (108, 111))	('PrP', 'Gene', (137, 140))	('misfolded', 'Var', (127, 136))	('PrP', 'Gene', '5621', (137, 140))	('PrP', 'Gene', (185, 188))	('folding', 'MPA', (161, 168))	('PrP', 'Gene', (108, 111))
14048	28540288	Similar domains are also found in other proteins such as in mutant TDP-43 that causes cytoplasmic inclusions in ALS (Smethurst et al.,).	('TDP-43', 'Gene', '23435', (67, 73))	('TDP-43', 'Gene', (67, 73))	('cytoplasmic inclusions', 'MPA', (86, 108))	('causes', 'Reg', (79, 85))	('mutant', 'Var', (60, 66))	('ALS', 'Phenotype', 'HP:0007354', (112, 115))
14051	28540288	In prion-infected mice, UPR and the PERK pathway was specifically activated with a sustained increase in phospho-eIF2alpha reduced the synthesis and levels of synaptic proteins causing neuronal death (Moreno et al.,).	('neuronal death', 'Disease', (185, 199))	('PERK pathway', 'Pathway', (36, 48))	('phospho-eIF2alpha', 'Var', (105, 122))	('increase', 'PosReg', (93, 101))	('mice', 'Species', '10090', (18, 22))	('prion', 'Species', '36469', (3, 8))	('neuronal death', 'Disease', 'MESH:D009410', (185, 199))	('synthesis', 'biological_process', 'GO:0009058', ('135', '144'))	('eIF2', 'cellular_component', 'GO:0005850', ('113', '117'))	('reduced', 'NegReg', (123, 130))
14052	28540288	This lends credence to the view that the modulation of the PERK/p-eIF2alpha pathway may constitute a drug target for the development of novel therapeutics in prion diseases.	('modulation', 'Var', (41, 51))	('eIF2', 'cellular_component', 'GO:0005850', ('66', '70'))	('prion', 'Species', '36469', (158, 163))	('prion diseases', 'Disease', (158, 172))
14072	28540288	Human eye diseases affecting either the rods (responsible for night vision) or cones (responsible for day-light and color vision) are often caused by mutations in specific genes involved in phototransduction or in protein quality control (Chan et al.,).	('Human', 'Species', '9606', (0, 5))	('eye disease', 'Phenotype', 'HP:0000478', (6, 17))	('eye diseases', 'Phenotype', 'HP:0000478', (6, 18))	('vision', 'biological_process', 'GO:0007601', ('68', '74'))	('caused by', 'Reg', (140, 149))	('mutations', 'Var', (150, 159))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('vision', 'biological_process', 'GO:0007601', ('122', '128'))	('eye diseases', 'Disease', (6, 18))	('eye diseases', 'Disease', 'MESH:D005128', (6, 18))	('phototransduction', 'biological_process', 'GO:0007602', ('190', '207'))	('night vision', 'Phenotype', 'HP:0000662', (62, 74))
14074	28540288	Mutations in cyclic-nucleotide-gated ion channel proteins, governing phototransduction by cGMP, are common causes of congenital forms of achromatopsia.	('phototransduction', 'biological_process', 'GO:0007602', ('69', '86'))	('achromatopsia', 'Phenotype', 'HP:0011516', (137, 150))	('achromatopsia', 'Disease', (137, 150))	('cyclic-nucleotide', 'Chemical', 'MESH:D009712', (13, 30))	('causes', 'Reg', (107, 113))	('Mutations', 'Var', (0, 9))	('cGMP', 'Chemical', 'MESH:D006152', (90, 94))	('achromatopsia', 'Disease', 'MESH:D003117', (137, 150))	('cyclic-nucleotide-gated ion channel proteins', 'Protein', (13, 57))	('congenital', 'Disease', (117, 127))
14075	28540288	Recently, mutations in ATF6 were found in patients with autosomal recessive achromatopsia, showing that normal ATF6 signaling and BiP levels are crucial for correct protein folding in the photoreceptors (Kohl et al.,).	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('autosomal recessive achromatopsia', 'Disease', 'MESH:D003117', (56, 89))	('found', 'Reg', (33, 38))	('BiP', 'Gene', (130, 133))	('protein folding', 'biological_process', 'GO:0006457', ('165', '180'))	('ATF6', 'Gene', (23, 27))	('autosomal recessive achromatopsia', 'Disease', (56, 89))	('BiP', 'Gene', '3309', (130, 133))	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (42, 50))	('achromatopsia', 'Phenotype', 'HP:0011516', (76, 89))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
14078	28540288	Mutations in rhodopsin is a common cause of RF and induce an increase in UPR particularly in IRE1alpha/XBP1 signaling attempting to reduce the amount of mutant rhodopsin in the ER (Chiang et al.,).	('rhodopsin', 'Gene', '6010', (160, 169))	('rhodopsin', 'Gene', (13, 22))	('rhodopsin', 'Gene', (160, 169))	('Mutations', 'Var', (0, 9))	('IRE1alpha/XBP1 signaling', 'MPA', (93, 117))	('IR', 'Phenotype', 'HP:0000855', (93, 95))	('rhodopsin', 'Gene', '6010', (13, 22))	('UPR', 'MPA', (73, 76))	('increase', 'PosReg', (61, 69))	('cause', 'Reg', (35, 40))	('signaling', 'biological_process', 'GO:0023052', ('108', '117'))
14093	28540288	Recently, variations in the autophagy related 16 like-1 gene were found associated with psoriasis vulgaris and palmoplantar pustulosis (Douroudis et al.,).	('palmoplantar pustulosis', 'Phenotype', 'HP:0100847', (111, 134))	('autophagy related 16 like-1', 'Gene', (28, 55))	('psoriasis vulgaris and palmoplantar pustulosis', 'Disease', 'MESH:D011565', (88, 134))	('associated', 'Reg', (72, 82))	('autophagy related 16 like-1', 'Gene', '55054', (28, 55))	('psoriasis', 'Phenotype', 'HP:0003765', (88, 97))	('variations', 'Var', (10, 20))	('autophagy', 'biological_process', 'GO:0016236', ('28', '37'))	('autophagy', 'biological_process', 'GO:0006914', ('28', '37'))
14097	28540288	Deregulated metabolism may also influence the immune system, and high cholesterol was shown to impair immune cells causing autoimmune diseases (Ito et al.,).	('high cholesterol', 'Var', (65, 81))	('immune system', 'CPA', (46, 59))	('immune cells', 'CPA', (102, 114))	('Deregulated', 'Var', (0, 11))	('influence', 'Reg', (32, 41))	('metabolism', 'biological_process', 'GO:0008152', ('12', '22'))	('autoimmune diseases', 'Disease', (123, 142))	('metabolism', 'MPA', (12, 22))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (123, 142))	('high cholesterol', 'Phenotype', 'HP:0003124', (65, 81))	('cholesterol', 'Chemical', 'MESH:D002784', (70, 81))	('autoimmune diseases', 'Disease', 'MESH:D001327', (123, 142))	('impair', 'NegReg', (95, 101))
14101	28540288	Treatment with the compound 4mu8C inhibited IRE1alpha, reduced pro-inflammatory cytokine production and alleviated the joint inflammation in mice with experimental arthritis (Qiu et al.,).	('joint inflammation', 'Disease', (119, 137))	('4mu8C', 'Var', (28, 33))	('arthritis', 'Phenotype', 'HP:0001369', (164, 173))	('alleviated', 'NegReg', (104, 114))	('experimental arthritis', 'Disease', 'MESH:D001169', (151, 173))	('reduced', 'NegReg', (55, 62))	('inhibited', 'NegReg', (34, 43))	('pro-inflammatory cytokine production', 'MPA', (63, 99))	('IRE1alpha', 'Protein', (44, 53))	('experimental arthritis', 'Disease', (151, 173))	('cytokine production', 'biological_process', 'GO:0001816', ('80', '99'))	('inflammation', 'biological_process', 'GO:0006954', ('125', '137'))	('joint inflammation', 'Phenotype', 'HP:0001369', (119, 137))	('mice', 'Species', '10090', (141, 145))	('joint inflammation', 'Disease', 'MESH:D007249', (119, 137))	('IR', 'Phenotype', 'HP:0000855', (44, 46))
14116	28540288	Recently, the use of the specific IRE1alpha inhibitor, STF-083010 in mice was shown to reduce atherosclerotic plaque size, lipid-induced inflammation and cytokine production in vivo (Tufanli et al.,), suggesting that alleviation of ER stress may provide therapeutic benefits also in cardiovascular diseases.	('cytokine production', 'MPA', (154, 173))	('atherosclerotic', 'Disease', (94, 109))	('lipid', 'Chemical', 'MESH:D008055', (123, 128))	('inflammation', 'biological_process', 'GO:0006954', ('137', '149'))	('cytokine production', 'biological_process', 'GO:0001816', ('154', '173'))	('inflammation', 'Disease', 'MESH:D007249', (137, 149))	('mice', 'Species', '10090', (69, 73))	('atherosclerotic', 'Disease', 'MESH:D050197', (94, 109))	('STF-083010', 'Var', (55, 65))	('inflammation', 'Disease', (137, 149))	('cardiovascular diseases', 'Disease', (283, 306))	('reduce', 'NegReg', (87, 93))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (283, 306))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (283, 306))	('IR', 'Phenotype', 'HP:0000855', (34, 36))
14150	28540288	Modulation of UPR signaling pathways by different drugs and chemicals has also been used to successfully induce cell death of human lung cancer cells (Zhang et al.,; Yang et al.,).	('cell death', 'CPA', (112, 122))	('induce', 'PosReg', (105, 111))	('Modulation', 'Var', (0, 10))	('human', 'Species', '9606', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('UPR signaling pathways', 'Pathway', (14, 36))	('lung cancer', 'Disease', (132, 143))	('cell death', 'biological_process', 'GO:0008219', ('112', '122'))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
14152	28540288	In particular, podocytes are vulnerable cells and the injury or dysfunctions of these cells can lead to progressive defects in the globular filtration barriers, with proteinuria, and kidney failure as consequences (Maekawa and Inagi,).	('dysfunctions', 'Var', (64, 76))	('globular filtration barriers', 'MPA', (131, 159))	('proteinuria', 'Disease', (166, 177))	('injury', 'Var', (54, 60))	('kidney failure', 'Phenotype', 'HP:0000083', (183, 197))	('lead to', 'Reg', (96, 103))	('proteinuria', 'Phenotype', 'HP:0000093', (166, 177))	('kidney failure', 'Disease', (183, 197))	('defects', 'NegReg', (116, 123))	('kidney failure', 'Disease', 'MESH:D051437', (183, 197))	('proteinuria', 'Disease', 'MESH:D011507', (166, 177))	('rat', 'Species', '10116', (144, 147))
14155	28540288	It has recently been shown that tauroursdeoxycholic acid, inhibiting ER stress, counteracted podocyte and glomeruli injury, reduced proteinuria and improved kidney functions in a diabetic mouse model (Fan et al.,).	('mouse', 'Species', '10090', (188, 193))	('tauroursdeoxycholic acid', 'Var', (32, 56))	('reduced', 'NegReg', (124, 131))	('kidney functions', 'MPA', (157, 173))	('proteinuria', 'Disease', (132, 143))	('diabetic', 'Disease', 'MESH:D003920', (179, 187))	('proteinuria', 'Phenotype', 'HP:0000093', (132, 143))	('improved', 'PosReg', (148, 156))	('glomeruli injury', 'Disease', (106, 122))	('inhibiting', 'NegReg', (58, 68))	('proteinuria', 'Disease', 'MESH:D011507', (132, 143))	('glomeruli injury', 'Disease', 'MESH:D058186', (106, 122))	('diabetic', 'Disease', (179, 187))	('tauroursdeoxycholic acid', 'Chemical', '-', (32, 56))	('ER stress', 'MPA', (69, 78))
14160	28540288	Studies of aging and protein quality control in the yeast, Saccharomyces cerevisiae have shown that that damaged and aggregates proteins are segregated between mother and daughter cells so that potentially harmful proteins are eliminated from the progeny.	('Saccharomyces cerevisiae', 'Species', '4932', (59, 83))	('proteins', 'Protein', (128, 136))	('aging', 'biological_process', 'GO:0007568', ('11', '16'))	('proteins', 'Protein', (214, 222))	('yeast', 'Species', '4932', (52, 57))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('aggregates', 'Var', (117, 127))
14178	28540288	PERK can also affect the cell cycle and act in a tumor-suppressive manner inducing cell dormancy (Vandewynckel et al.,).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PERK', 'Var', (0, 4))	('cell cycle', 'CPA', (25, 35))	('affect', 'Reg', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cell dormancy', 'CPA', (83, 96))	('tumor', 'Disease', (49, 54))	('dormancy', 'biological_process', 'GO:0030431', ('88', '96'))	('cell cycle', 'biological_process', 'GO:0007049', ('25', '35'))	('inducing', 'Reg', (74, 82))
14183	28540288	Main issue with all these inhibitors are their side effects as for examples PERK inhibitors cause pancreatic beta-cell loss and diabetes (Oakes,).	('cause', 'Reg', (92, 97))	('PERK', 'Gene', (76, 80))	('pancreatic beta-cell loss and diabetes', 'Disease', 'MESH:C538111', (98, 136))	('inhibitors', 'Var', (81, 91))
14198	28293125	As predictive factors for unlikely chemotherapy, multivariate logistic analysis detected Eastern Cooperative Oncology Group (ECOG) performance status (PS) >=2, hemoglobin <13.2 g/dL, creatinine clearance (Ccr) <50.4 mL/min, and CRP >=0.53 mg/dL.	('CRP', 'Gene', (228, 231))	('Oncology', 'Phenotype', 'HP:0002664', (109, 117))	('Ccr', 'molecular_function', 'GO:0043880', ('205', '208'))	('CRP', 'Gene', '1401', (228, 231))	('>=2', 'Var', (155, 158))	('hemoglobin', 'MPA', (160, 170))	('creatinine clearance', 'MPA', (183, 203))	('creatinine', 'Chemical', 'MESH:D003404', (183, 193))	('<50.4', 'Var', (210, 215))
14207	28293125	Furthermore, adenocarcinoma has been divided into two subsets according to genetic information: adenocarcinoma harboring a driver mutation, either positive EGFR mutation or ALK rearrangement; and adenocarcinoma without these driver mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('EGFR', 'Gene', '1956', (156, 160))	('mutation', 'Var', (161, 169))	('positive', 'Var', (147, 155))	('adenocarcinoma', 'Disease', (13, 27))	('ALK', 'Gene', '238', (173, 176))	('adenocarcinoma', 'Disease', (196, 210))	('adenocarcinoma', 'Disease', (96, 110))	('EGFR', 'Gene', (156, 160))	('adenocarcinoma', 'Disease', 'MESH:D000230', (196, 210))	('adenocarcinoma', 'Disease', 'MESH:D000230', (13, 27))	('ALK', 'Gene', (173, 176))	('adenocarcinoma', 'Disease', 'MESH:D000230', (96, 110))
14216	28293125	Fluorescence in situ hybridization and immunohistochemistry for ALK gene rearrangement were approved in April 2012 and June 2014, respectively.	('ALK', 'Gene', '238', (64, 67))	('rearrangement', 'Var', (73, 86))	('ALK', 'Gene', (64, 67))
14239	28293125	As factors predicting OS from the start of first-, second-, and third-line chemotherapy, univariate Cox-hazard analysis detected that the variables female, ECOG PS >=2, neutrophil count, lymphocyte count, monocyte count, creatinine clearance, sodium concentration, and CRP in first-line therapy (Table 4); age >=75 years, male, ECOG PS >=2, neutrophil count, lymphocyte count, monocyte count, hemoglobin, red cell distribution width (RDW), platelet count, creatinine clearance, sodium concentration, LDH, ALP, CRP, and interval between first and second lines in second-line therapy (Table 5); and ECOG PS >=2, neutrophil count, lymphocyte count, monocyte count, sodium concentration, LDH, ALP, CRP, and interval between first and third lines in third-line therapy (Table 6).	('CRP', 'Gene', '1401', (269, 272))	('LDH', 'MPA', (684, 687))	('Cox', 'Gene', '1351', (100, 103))	('ALP', 'Gene', '250', (505, 508))	('ALP', 'Gene', (689, 692))	('CRP', 'Gene', (510, 513))	('CRP', 'Gene', '1401', (510, 513))	('CRP', 'Gene', '1401', (694, 697))	('Cox', 'Gene', (100, 103))	('creatinine', 'Chemical', 'MESH:D003404', (456, 466))	('ALP', 'Gene', '250', (689, 692))	('ECOG PS >=2', 'Var', (597, 608))	('sodium concentration', 'MPA', (662, 682))	('creatinine', 'Chemical', 'MESH:D003404', (221, 231))	('CRP', 'Gene', (269, 272))	('ALP', 'Gene', (505, 508))	('CRP', 'Gene', (694, 697))
14242	28293125	Our study revealed a flow of patients with adenocarcinoma with EGFR wild-type status.	('EGFR', 'Gene', '1956', (63, 67))	('patients', 'Species', '9606', (29, 37))	('adenocarcinoma', 'Disease', (43, 57))	('adenocarcinoma', 'Disease', 'MESH:D000230', (43, 57))	('EGFR', 'Gene', (63, 67))	('wild-type', 'Var', (68, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
14244	28293125	1) 76% of patients who had been diagnosed with adenocarcinoma with EGFR wild-type status received chemotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('EGFR', 'Gene', '1956', (67, 71))	('patients', 'Species', '9606', (10, 18))	('EGFR', 'Gene', (67, 71))	('wild-type status', 'Var', (72, 88))	('adenocarcinoma', 'Disease', (47, 61))
14259	28293125	Approximately 76% of patients with adenocarcinoma with EGFR wild-type status were treated with first-line chemotherapy.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('wild-type status', 'Var', (60, 76))	('EGFR', 'Gene', (55, 59))	('adenocarcinoma', 'Disease', (35, 49))	('patients', 'Species', '9606', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('adenocarcinoma', 'Disease', 'MESH:D000230', (35, 49))
14271	28076456	Modulation of miR-486 might contribute to the anti-tumor activity of propofol.	('Modulation', 'Var', (0, 10))	('miR-486', 'Gene', '619554', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('propofol', 'Chemical', 'MESH:D015742', (69, 77))	('tumor', 'Disease', (51, 56))	('contribute', 'Reg', (28, 38))	('miR-486', 'Gene', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
14277	28076456	An increasing number of studies have suggested that miRNAs are involved in the pathophysiology of cancers, and may provide a new insight into cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('involved', 'Reg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('men', 'Species', '9606', (154, 157))	('cancers', 'Disease', (98, 105))	('cancer', 'Disease', (98, 104))	('miRNAs', 'Var', (52, 58))	('cancer', 'Disease', (142, 148))
14278	28076456	Aberrant expression of miRNAs have been well described in lung cancer.	('Aberrant', 'Var', (0, 8))	('miRNAs', 'Protein', (23, 29))	('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))
14312	28076456	Further, the cell viability was dramatically higher by transfection with miR-486 compared to the propofol group or control group (P<0.05; Figure 2A and B).	('cell viability', 'CPA', (13, 27))	('miR-486', 'Gene', '619554', (73, 80))	('transfection', 'Var', (55, 67))	('propofol', 'Chemical', 'MESH:D015742', (97, 105))	('higher', 'PosReg', (45, 51))	('miR-486', 'Gene', (73, 80))
14355	28076456	A previous study showed that the expression of FOXO1 was a favorable prognostic factor in NSCLC.	('FOXO1', 'Gene', '2308', (47, 52))	('expression', 'Var', (33, 43))	('FOXO1', 'Gene', (47, 52))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
14356	28076456	In addition, inactivation of FOXO3a occurs frequently in carcinogen-induced lung adenocarcinoma  and FOXO3a could regulate the cytotoxic effects of cisplatin in lung cancer cells.	('FOXO3a', 'Gene', (101, 107))	('cytotoxic effects', 'CPA', (127, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('inactivation', 'Var', (13, 25))	('lung adenocarcinoma', 'Disease', (76, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('lung cancer', 'Disease', (161, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('FOXO3a', 'Gene', '2309', (29, 35))	('regulate', 'Reg', (114, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('FOXO3a', 'Gene', '2309', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('FOXO3a', 'Gene', (29, 35))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
14360	27734950	The Role of PIK3CA Mutations among Lung Adenocarcinoma Patients with Primary and Acquired Resistance to EGFR Tyrosine Kinase Inhibition To understand the impact of PIK3CA mutations on clinical characteristics and treatment response to epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) of lung adenocarcinoma, we examined PIK3CA and EGFR mutations in lung adenocarcinoma patients, and analyzed their clinical outcomes.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (301, 320))	('Mutations', 'Var', (19, 28))	('PIK3CA', 'Gene', (164, 170))	('EGFR', 'Gene', (345, 349))	('mutations', 'Var', (350, 359))	('PIK3CA', 'Gene', '5290', (334, 340))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (363, 382))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('PIK3CA', 'Gene', (12, 18))	('EGFR', 'Gene', (104, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (363, 382))	('EGFR', 'Gene', (287, 291))	('Patients', 'Species', '9606', (55, 63))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (40, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('287', '291'))	('PIK3CA', 'Gene', (334, 340))	('EGFR', 'Gene', '1956', (345, 349))	('lung adenocarcinoma', 'Disease', (301, 320))	('PIK3CA', 'Gene', '5290', (164, 170))	('EGFR', 'Gene', '1956', (104, 108))	('response to epidermal growth factor', 'biological_process', 'GO:0070849', ('223', '258'))	('EGFR', 'molecular_function', 'GO:0005006', ('345', '349'))	('PIK3CA', 'Gene', '5290', (12, 18))	('patients', 'Species', '9606', (383, 391))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('235', '258'))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (301, 320))	('EGFR', 'Gene', '1956', (287, 291))	('lung adenocarcinoma', 'Disease', (363, 382))	('Adenocarcinoma', 'Disease', (40, 54))
14362	27734950	PIK3CA and EGFR mutations were analyzed by RT-PCR and direct sequencing.	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))
14363	27734950	In EGFR TKI-nave specimens, PIK3CA mutation rate was 1.8% (14/760).	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'molecular_function', 'GO:0005006', ('3', '7'))	('EGFR', 'Gene', (3, 7))	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutation', 'Var', (35, 43))
14364	27734950	Twelve patients had coexisting PIK3CA and EGFR mutations.	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('patients', 'Species', '9606', (7, 15))
14365	27734950	Among the 344 EGFR TKI-treated EGFR mutant patients, there was no significant difference in treatment response (p = 0.476) and progression-free survival (p = 0.401) of EGFR TKI between PIK3CA mutation-positive and negative patients.	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('patients', 'Species', '9606', (43, 51))	('EGFR', 'Gene', (31, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('PIK3CA', 'Gene', (185, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('mutant', 'Var', (36, 42))	('PIK3CA', 'Gene', '5290', (185, 191))	('patients', 'Species', '9606', (223, 231))
14366	27734950	The PIK3CA mutation rate in lung adenocarcinoma with acquired resistance to EGFR TKI is not higher than that in EGFR TKI-naive tissue specimens (2.9% (6/207) vs. 1.8%; p = 0.344).	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('lung adenocarcinoma', 'Disease', (28, 47))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 47))	('PIK3CA', 'Gene', (4, 10))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('EGFR', 'Gene', (76, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('PIK3CA', 'Gene', '5290', (4, 10))	('EGFR', 'Gene', '1956', (112, 116))	('mutation', 'Var', (11, 19))
14367	27734950	Of the 74 patients with paired specimens (TKI-naive and acquired resistance to TKIs) only one patient (1.4%) developed acquired PIK3CA (E545K) mutation, and he also had acquired EGFR (T790M) mutation.	('PIK3CA', 'Gene', '5290', (128, 134))	('EGFR', 'Gene', '1956', (178, 182))	('E545K', 'Mutation', 'rs104886003', (136, 141))	('E545K', 'Var', (136, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('178', '182'))	('EGFR', 'Gene', (178, 182))	('patient', 'Species', '9606', (10, 17))	('PIK3CA', 'Gene', (128, 134))	('patient', 'Species', '9606', (94, 101))	('patients', 'Species', '9606', (10, 18))	('T790M', 'Mutation', 'rs121434569', (184, 189))
14368	27734950	In conclusion, PIK3CA mutation may not be associated with primary resistance to EGFR TKI among lung adenocarcinoma patients.	('patients', 'Species', '9606', (115, 123))	('mutation', 'Var', (22, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('PIK3CA', 'Gene', '5290', (15, 21))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('lung adenocarcinoma', 'Disease', (95, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))	('PIK3CA', 'Gene', (15, 21))
14369	27734950	Acquired PIK3CA mutation related to EGFR TKI treatment is rare.	('mutation', 'Var', (16, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('PIK3CA', 'Gene', (9, 15))	('EGFR', 'Gene', (36, 40))	('PIK3CA', 'Gene', '5290', (9, 15))
14371	27734950	For example, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often are highly effective in lung cancer patients with somatic EGFR mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('epidermal growth factor receptor', 'Gene', (13, 45))	('EGFR', 'Gene', '1956', (151, 155))	('EGFR', 'Gene', (151, 155))	('patients', 'Species', '9606', (129, 137))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('lung cancer', 'Disease', (117, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('EGFR', 'Gene', '1956', (47, 51))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('13', '36'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('EGFR', 'Gene', (47, 51))	('mutation', 'Var', (156, 164))
14373	27734950	PIK3CA signaling pathway alterations and the frequencies of PIK3CA mutations were varied in different types of non-small cell lung cancer (NSCLC) in different published studies.	('non-small cell lung cancer', 'Disease', (111, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('PIK3CA', 'Gene', (60, 66))	('signaling pathway', 'biological_process', 'GO:0007165', ('7', '24'))	('PIK3CA', 'Gene', '5290', (60, 66))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('NSCLC', 'Disease', (139, 144))	('mutations', 'Var', (67, 76))	('PIK3CA', 'Gene', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('PIK3CA', 'Gene', '5290', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (111, 137))	('alterations', 'Reg', (25, 36))
14374	27734950	PIK3 inhibitors also render preliminary antitumor activity in preclinical studies and early phase clinical trials.	('PIK3', 'Gene', (0, 4))	('PIK3', 'Gene', '5294', (0, 4))	('inhibitors', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
14377	27734950	PIK3CA mutation has been reported to have correlation with poor survival of NSCLC patients.	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', (76, 81))	('PIK3CA', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
14378	27734950	In a preclinical study, introduction of an activated PIK3CA c.1633G > A (p.E545K) mutation into the EGFR mutation positive cell line, HCC827, confers resistance to gefitinib.	('gefitinib', 'Chemical', 'MESH:D000077156', (164, 173))	('HCC827', 'CellLine', 'CVCL:2063', (134, 140))	('c.1633G > A', 'Var', (60, 71))	('EGFR', 'Gene', '1956', (100, 104))	('resistance to gefitinib', 'MPA', (150, 173))	('PIK3CA', 'Gene', '5290', (53, 59))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('c.1633G > A', 'Mutation', 'rs104886003', (60, 71))	('p.E545K', 'Mutation', 'rs104886003', (73, 80))	('PIK3CA', 'Gene', (53, 59))
14379	27734950	Prior studies also showed that PIK3CA mutation is a predictor for resistance to EGFR TKIs.	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('mutation', 'Var', (38, 46))
14381	27734950	Whether the co-existing PIK3CA mutations cause primary resistance to EGFR TKI in lung adenocarcinoma was still not well studied.	('EGFR', 'Gene', '1956', (69, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('EGFR', 'Gene', (69, 73))	('primary resistance', 'MPA', (47, 65))	('lung adenocarcinoma', 'Disease', (81, 100))	('PIK3CA', 'Gene', '5290', (24, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))
14382	27734950	Although having EGFR mutations could predict a favorable EGFR TKI treatment response, acquired resistance develops eventually.	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('EGFR', 'Gene', (57, 61))	('acquired resistance', 'MPA', (86, 105))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
14383	27734950	Secondary EGFR c.2369C > T (p.T790M) mutation is detected in 50-60% of lung adenocarcinoma patients after acquiring resistance to EGFR TKIs.	('EGFR', 'Gene', '1956', (10, 14))	('patients', 'Species', '9606', (91, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('p.T790M', 'Mutation', 'rs121434569', (28, 35))	('EGFR', 'Gene', (10, 14))	('lung adenocarcinoma', 'Disease', (71, 90))	('c.2369C > T', 'Mutation', 'rs121434569', (15, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))	('EGFR', 'Gene', '1956', (130, 134))	('c.2369C > T', 'Var', (15, 26))	('EGFR', 'Gene', (130, 134))
14384	27734950	In about 5% of the patients with acquired resistance to EGFR TKIs, PIK3CA mutations had also been reported to play a role.	('PIK3CA', 'Gene', '5290', (67, 73))	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (56, 60))	('mutations', 'Var', (74, 83))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('PIK3CA', 'Gene', (67, 73))
14386	27734950	The role of PIK3CA mutations in acquired EGFR TKI resistance needs to be clarified.	('PIK3CA', 'Gene', '5290', (12, 18))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (19, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('EGFR', 'Gene', '1956', (41, 45))	('PIK3CA', 'Gene', (12, 18))
14388	27734950	Interactions between PIK3CA and EGFR mutations are not clear.	('PIK3CA', 'Gene', (21, 27))	('EGFR', 'Gene', '1956', (32, 36))	('mutations', 'Var', (37, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('Interactions', 'Reg', (0, 12))	('PIK3CA', 'Gene', '5290', (21, 27))
14389	27734950	To understand the impact of PIK3CA mutation on clinical characteristics of advanced lung adenocarcinoma and the treatment response of EGFR TKIs, we examined PIK3CA and EGFR mutations from lung adenocarcinoma patients, and analyzed their clinical treatment outcomes.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('EGFR', 'Gene', '1956', (134, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('patients', 'Species', '9606', (208, 216))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (134, 138))	('EGFR', 'Gene', (168, 172))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('PIK3CA', 'Gene', (28, 34))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('PIK3CA', 'Gene', (157, 163))	('mutations', 'Var', (173, 182))	('lung adenocarcinoma', 'Disease', (84, 103))	('PIK3CA', 'Gene', '5290', (28, 34))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('PIK3CA', 'Gene', '5290', (157, 163))	('lung adenocarcinoma', 'Disease', (188, 207))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (188, 207))
14392	27734950	Of the 1068 patients, there were 1029 patients who had adequate tissue for both EGFR and PIK3CA mutation analysis (Supplemental Table 1).	('patients', 'Species', '9606', (12, 20))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('mutation', 'Var', (96, 104))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('patients', 'Species', '9606', (38, 46))
14398	27734950	Only 74 patients had adequate paired tissue specimens of EGFR TKI-naive and acquired resistance to EGFR TKI for EGFR and PIK3CA mutation analysis (Supplemental Tables 2 and 3).	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('EGFR', 'Gene', (99, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('PIK3CA', 'Gene', (121, 127))	('EGFR', 'Gene', '1956', (57, 61))	('PIK3CA', 'Gene', '5290', (121, 127))	('EGFR', 'Gene', '1956', (112, 116))	('mutation', 'Var', (128, 136))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (57, 61))	('patients', 'Species', '9606', (8, 16))
14401	27734950	There were 485 (63.8%) EGFR mutations and 14 (1.8%) PIK3CA mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('PIK3CA', 'Gene', (52, 58))	('EGFR', 'Gene', '1956', (23, 27))	('PIK3CA', 'Gene', '5290', (52, 58))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
14402	27734950	The PIK3CA mutation types included 2 c.1624G > A (p.E542K), 7 c.1633G > A (p.E545K), 1 c.1633G > C (p.E545Q), and 4 c.3140A > G (p.H1047R).	('c.3140A > G', 'Mutation', 'rs121913279', (116, 127))	('c.3140A > G', 'Var', (116, 127))	('p.E545Q', 'Mutation', 'rs104886003', (100, 107))	('p.H1047R', 'Mutation', 'rs121913279', (129, 137))	('PIK3CA', 'Gene', (4, 10))	('c.1624G > A', 'Var', (37, 48))	('c.1633G > A', 'Var', (62, 73))	('c.1633G > C', 'Var', (87, 98))	('c.1624G > A', 'Mutation', 'rs121913273', (37, 48))	('PIK3CA', 'Gene', '5290', (4, 10))	('c.1633G > A', 'Mutation', 'rs104886003', (62, 73))	('c.1633G > C', 'Mutation', 'rs104886003', (87, 98))	('p.E545K', 'Mutation', 'rs104886003', (75, 82))	('p.E542K', 'Mutation', 'rs121913273', (50, 57))
14404	27734950	There were no differences between PIK3CA mutation and tissue specimen sources (p = 0.239).	('mutation', 'Var', (41, 49))	('PIK3CA', 'Gene', (34, 40))	('PIK3CA', 'Gene', '5290', (34, 40))
14405	27734950	No obvious clinical characteristics correlated with PIK3CA mutations except tumor staging at initial diagnosis (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PIK3CA', 'Gene', (52, 58))	('mutations', 'Var', (59, 68))	('PIK3CA', 'Gene', '5290', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
14406	27734950	PIK3CA mutation-positive patients were at earlier cancer stage at initial diagnosis than PIK3CA mutation-negative patients.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation-positive', 'Var', (7, 24))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (114, 122))
14407	27734950	Twelve of 14 PIK3CA mutation-positive patients (85.7%) had coexisting EGFR mutations, including: 6 with deletions in exon-19, 4 c.2573T > G (p.L858R), one c.2156G > C (p.G719A) and one p.D770 > GY.	('GY', 'Chemical', 'MESH:C022013', (194, 196))	('p.G719A', 'Mutation', 'rs121913428', (168, 175))	('PIK3CA', 'Gene', (13, 19))	('EGFR', 'Gene', '1956', (70, 74))	('c.2156G > C', 'Mutation', 'rs121913428', (155, 166))	('p.L858R', 'Mutation', 'rs121434568', (141, 148))	('patients', 'Species', '9606', (38, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('p.D770 > GY', 'Var', (185, 196))	('PIK3CA', 'Gene', '5290', (13, 19))	('EGFR', 'Gene', (70, 74))	('c.2573T > G', 'Mutation', 'rs121434568', (128, 139))	('c.2156G > C', 'Var', (155, 166))	('deletions', 'Var', (104, 113))	('mutation-positive', 'Reg', (20, 37))	('c.2573T > G', 'Var', (128, 139))
14408	27734950	Deletions in exon-19 and c.2573T > G (p.L858R) are termed 'classical' activating EGFR mutations, which are associated with good treatment response to EGFR-TKI.	('EGFR', 'Gene', (150, 154))	('c.2573T > G', 'Mutation', 'rs121434568', (25, 36))	('p.L858R', 'Mutation', 'rs121434568', (38, 45))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('150', '154'))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('c.2573T > G', 'Var', (25, 36))	('EGFR', 'Gene', '1956', (150, 154))	('Deletions in', 'Var', (0, 12))	('EGFR', 'Gene', (81, 85))
14409	27734950	Patients with c.2156G > C (p.G719A) mutation also have moderate EGFR TKI sensitivity.	('c.2156G > C (p.G719A', 'Var', (14, 34))	('c.2156G > C', 'Mutation', 'rs121913428', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('p.G719A', 'Mutation', 'rs121913428', (27, 34))
14410	27734950	NSCLC with p.D770 > GY of exon 20 mutation leads to resistance to EGFR TKI treatment.	('resistance', 'MPA', (52, 62))	('leads', 'Reg', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('GY', 'Chemical', 'MESH:C022013', (20, 22))	('p.D770 > GY', 'Var', (11, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('NSCLC', 'Disease', (0, 5))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
14411	27734950	To evaluate the impact of PIK3CA mutations on EGFR TKI treatment responses, we focused on the 344 EGFR TKI-treated EGFR mutant lung adenocarcinoma patients with EGFR TKI-naive tissue specimens (Fig.	('PIK3CA', 'Gene', '5290', (26, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (115, 119))	('mutant', 'Var', (120, 126))	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', (161, 165))	('patients', 'Species', '9606', (147, 155))	('PIK3CA', 'Gene', (26, 32))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (161, 165))	('lung adenocarcinoma', 'Disease', (127, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
14414	27734950	Of the 344 EGFR mutation-positive patients, there were 6 PIK3CA mutation-positive patients.	('PIK3CA', 'Gene', '5290', (57, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('patients', 'Species', '9606', (82, 90))	('mutation-positive', 'Var', (16, 33))	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', '1956', (11, 15))	('patients', 'Species', '9606', (34, 42))	('PIK3CA', 'Gene', (57, 63))
14415	27734950	There were no significant differences in clinical characteristics between patients with and without PIK3CA mutations (Table 2).	('PIK3CA', 'Gene', '5290', (100, 106))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (107, 116))	('PIK3CA', 'Gene', (100, 106))
14418	27734950	The patient with PD had a coexisting insensitive EGFR mutation in exon 20, p.D770 > GY.	('EGFR', 'Gene', '1956', (49, 53))	('p.D770 > GY', 'Var', (75, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('patient', 'Species', '9606', (4, 11))	('PD', 'Disease', 'MESH:D010300', (17, 19))	('GY', 'Chemical', 'MESH:C022013', (84, 86))
14424	27734950	The OS also did not reach significant differences between PIK3CA mutation-positive patients (25.1 months) and those with wild type PIK3CA (21.4 months; p = 0.247) (Fig.	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('mutation-positive', 'Var', (65, 82))	('PIK3CA', 'Gene', (131, 137))	('patients', 'Species', '9606', (83, 91))	('PIK3CA', 'Gene', '5290', (131, 137))
14426	27734950	101 (48.8%) patients had acquired EGFR c.2369C > T (p.T790M) mutations.	('patients', 'Species', '9606', (12, 20))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('p.T790M', 'Mutation', 'rs121434569', (52, 59))	('c.2369C > T', 'Mutation', 'rs121434569', (39, 50))	('EGFR', 'Gene', '1956', (34, 38))	('c.2369C > T', 'Var', (39, 50))
14428	27734950	Among these, 6 patients (6 of 207; 2.9%) had PIK3CA mutations.	('mutations', 'Var', (52, 61))	('PIK3CA', 'Gene', (45, 51))	('patients', 'Species', '9606', (15, 23))	('PIK3CA', 'Gene', '5290', (45, 51))
14429	27734950	All of the 6 PIK3CA mutation positive patients with acquired resistance to EGFR TKIs had coexisting EGFR mutations, including: 2 with deletions in exon 19, 3 c.2573T > G (p.L858R) and one c.2573T > G (p.L858R) + c.2327G > A (p.R776H).	('c.2573T > G', 'Mutation', 'rs121434568', (158, 169))	('EGFR', 'Gene', '1956', (100, 104))	('p.L858R', 'Mutation', 'rs121434568', (171, 178))	('PIK3CA', 'Gene', (13, 19))	('c.2573T > G', 'Mutation', 'rs121434568', (188, 199))	('EGFR', 'Gene', (100, 104))	('c.2573T > G', 'Var', (188, 199))	('patients', 'Species', '9606', (38, 46))	('c.2573T > G', 'Var', (158, 169))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('PIK3CA', 'Gene', '5290', (13, 19))	('EGFR', 'Gene', '1956', (75, 79))	('p.L858R', 'Mutation', 'rs121434568', (201, 208))	('c.2327G > A', 'Mutation', 'rs483352806', (212, 223))	('deletions in', 'Var', (134, 146))	('p.R776H', 'Mutation', 'rs483352806', (225, 232))	('EGFR', 'Gene', (75, 79))
14430	27734950	The PIK3CA mutation types included 1 c.1624G > A (p.E542K), 3 c.1633G > A (p.E545K), 1 c.3140A > T (p.H1047L) and 1 c.3140A > G (p.H1047R).	('c.3140A > T', 'Mutation', 'rs121913279', (87, 98))	('c.3140A > G', 'Var', (116, 127))	('c.3140A > G', 'Mutation', 'rs121913279', (116, 127))	('p.H1047R', 'Mutation', 'rs121913279', (129, 137))	('PIK3CA', 'Gene', (4, 10))	('p.H1047L', 'Mutation', 'rs121913279', (100, 108))	('c.1624G > A', 'Var', (37, 48))	('c.1633G > A', 'Var', (62, 73))	('c.3140A > T', 'Var', (87, 98))	('c.1624G > A', 'Mutation', 'rs121913273', (37, 48))	('PIK3CA', 'Gene', '5290', (4, 10))	('c.1633G > A', 'Mutation', 'rs104886003', (62, 73))	('p.E545K', 'Mutation', 'rs104886003', (75, 82))	('p.E542K', 'Mutation', 'rs121913273', (50, 57))
14434	27734950	31 of the 74 patients (41.9%) had acquired EGFR c.2369C > T (p.T790M).	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('patients', 'Species', '9606', (13, 21))	('c.2369C > T', 'Var', (48, 59))	('EGFR', 'Gene', '1956', (43, 47))	('p.T790M', 'Mutation', 'rs121434569', (61, 68))	('EGFR', 'Gene', (43, 47))	('c.2369C > T', 'Mutation', 'rs121434569', (48, 59))
14435	27734950	Only one patient (1.4%) had PIK3CA mutation alteration after acquiring TKI resistance.	('mutation alteration', 'Var', (35, 54))	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (28, 34))	('patient', 'Species', '9606', (9, 16))
14436	27734950	The initial surgically resected lung adenocarcinoma showed wild type PIK3CA and EGFR c.2573T > G (p.L858R) mutation.	('c.2573T > G', 'Mutation', 'rs121434568', (85, 96))	('p.L858R', 'Mutation', 'rs121434568', (98, 105))	('c.2573T > G', 'Var', (85, 96))	('lung adenocarcinoma', 'Disease', (32, 51))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (32, 51))	('PIK3CA', 'Gene', (69, 75))	('PIK3CA', 'Gene', '5290', (69, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 51))
14438	27734950	Cancer cells in MPE had coexisting acquired PIK3CA c.1633G > A (p.E545K) mutation and EGFR c.2369C > T (p.T790M), in addition to EGFR c.2573T > G (p.L858R).	('p.E545K', 'Mutation', 'rs104886003', (64, 71))	('p.L858R', 'Mutation', 'rs121434568', (147, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('EGFR', 'Gene', (129, 133))	('PIK3CA', 'Gene', (44, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('c.2573T > G', 'Mutation', 'rs121434568', (134, 145))	('EGFR', 'Gene', '1956', (86, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('EGFR', 'Gene', '1956', (129, 133))	('c.1633G > A', 'Var', (51, 62))	('c.1633G > A', 'Mutation', 'rs104886003', (51, 62))	('p.T790M', 'Mutation', 'rs121434569', (104, 111))	('c.2573T > G', 'Var', (134, 145))	('PIK3CA', 'Gene', '5290', (44, 50))	('c.2369C > T', 'Mutation', 'rs121434569', (91, 102))	('Cancer', 'Disease', (0, 6))	('EGFR', 'Gene', (86, 90))	('c.2369C > T', 'Var', (91, 102))
14439	27734950	This study showed that the PIK3CA mutation could be detected in a small proportion (1.8%) of lung adenocarcinomas, but with high concomitant EGFR mutations.	('lung adenocarcinomas', 'Disease', (93, 113))	('mutations', 'Var', (146, 155))	('EGFR', 'Gene', '1956', (141, 145))	('detected', 'Reg', (52, 60))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (93, 113))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (93, 113))	('PIK3CA', 'Gene', (27, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('EGFR', 'Gene', (141, 145))	('PIK3CA', 'Gene', '5290', (27, 33))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
14440	27734950	PIK3CA mutation did not confer primary resistance to EGFR TKIs, nor was it associated with a shorter PFS.	('PIK3CA', 'Gene', (0, 6))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))
14442	27734950	According to the paired tissue specimens between EGFR TKI-naive and acquired resistance to EGFR TKI, the acquired PIK3CA c.1633G > A (p.E545K) mutation can be detected in only one of 74 patients (1.4%).	('PIK3CA', 'Gene', '5290', (114, 120))	('c.1633G > A', 'Mutation', 'rs104886003', (121, 132))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (91, 95))	('p.E545K', 'Mutation', 'rs104886003', (134, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('c.1633G > A', 'Var', (121, 132))	('PIK3CA', 'Gene', (114, 120))	('EGFR', 'Gene', '1956', (91, 95))	('patients', 'Species', '9606', (186, 194))
14444	27734950	showed that 6 patients with PIK3CA mutation had a shorter time to tumor progression (TTP) after EGFR TKI treatment, but the EGFR TKI treatment response was not associated to PIK3CA mutation (p = 0.61).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PIK3CA', 'Gene', (174, 180))	('time', 'MPA', (58, 62))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (96, 100))	('tumor', 'Disease', (66, 71))	('PIK3CA', 'Gene', (28, 34))	('EGFR', 'Gene', (124, 128))	('PIK3CA', 'Gene', '5290', (174, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('PIK3CA', 'Gene', '5290', (28, 34))	('shorter', 'NegReg', (50, 57))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', '1956', (96, 100))
14445	27734950	Besides, other studies showed that PIK3CA mutation was not associated with EGFR-TKI efficacy or shorter TTP.	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('mutation', 'Var', (42, 50))	('PIK3CA', 'Gene', (35, 41))	('EGFR', 'Gene', '1956', (75, 79))	('PIK3CA', 'Gene', '5290', (35, 41))	('EGFR', 'Gene', (75, 79))
14446	27734950	The present study also showed that PIK3CA mutation had no impact on treatment response or PFS of EGFR TKI in EGFR mutation-positive patients.	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', '1956', (109, 113))	('treatment response', 'CPA', (68, 86))	('EGFR', 'Gene', (97, 101))	('mutation', 'Var', (42, 50))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', '5290', (35, 41))	('EGFR', 'Gene', (109, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('patients', 'Species', '9606', (132, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
14447	27734950	The present study showed that a PIK3CA mutation positive patient had PD of EGFR TKI treatment.	('PIK3CA', 'Gene', '5290', (32, 38))	('mutation', 'Var', (39, 47))	('patient', 'Species', '9606', (57, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('PD', 'Disease', 'MESH:D010300', (69, 71))	('EGFR', 'Gene', (75, 79))	('PIK3CA', 'Gene', (32, 38))
14448	27734950	The patient had concomitant EGFR exon 20 mutation, which is associated with poor gefitinib treatment response.	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('patient', 'Species', '9606', (4, 11))	('mutation', 'Var', (41, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('gefitinib', 'Chemical', 'MESH:D000077156', (81, 90))
14449	27734950	Therefore, the difference may result from the presence of concomitant EGFR mutations, which is the most critical point in deciding EGFR TKI treatment response.	('result from', 'Reg', (30, 41))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))
14452	27734950	In addition, the French NCI's Lung Cancer Mutation Consortium (LCMC) collected 10000 NSCLC for analysis, and the most common co-existing mutations with other drivers in NSCLC is PIK3CA mutation.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('PIK3CA', 'Gene', (178, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('NSCLC', 'Disease', (169, 174))	('Lung Cancer', 'Phenotype', 'HP:0100526', (30, 41))	('mutations', 'Var', (137, 146))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('PIK3CA', 'Gene', '5290', (178, 184))	("NCI's Lung Cancer", 'Disease', (24, 41))	("NCI's Lung Cancer", 'Disease', 'MESH:D008175', (24, 41))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))
14453	27734950	A single tumor harboring two or more coexisting PI3K pathway mutations would suggest that there would be no selective advantage for cells bearing redundant mutations.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (61, 70))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('tumor', 'Disease', (9, 14))	('PI3K', 'Gene', (48, 52))
14455	27734950	Further studies are necessary to determine whether PIK3CA mutation is a redundancy mutation in addition to EGFR mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('PIK3CA', 'Gene', '5290', (51, 57))
14458	27734950	For example: EGFR c.2369C > T (p.T790M) in exon 20, a secondary EGFR mutation, is detected in approximately half of NSCLC patients after acquiring resistance to EGFR-TKIs.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('c.2369C > T', 'Mutation', 'rs121434569', (18, 29))	('EGFR', 'Gene', (161, 165))	('p.T790M', 'Mutation', 'rs121434569', (31, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('c.2369C > T', 'Var', (18, 29))	('patients', 'Species', '9606', (122, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('detected', 'Reg', (82, 90))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', '1956', (161, 165))	('EGFR', 'Gene', (64, 68))	('NSCLC', 'Disease', (116, 121))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
14459	27734950	reported that PIK3CA mutation is also associated with acquired resistance to EGFR TKI treatment.	('associated', 'Reg', (38, 48))	('acquired resistance', 'MPA', (54, 73))	('mutation', 'Var', (21, 29))	('EGFR', 'Gene', '1956', (77, 81))	('PIK3CA', 'Gene', (14, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('PIK3CA', 'Gene', '5290', (14, 20))	('EGFR', 'Gene', (77, 81))
14460	27734950	The present study also found an acquired PIK3CA mutation change but concomitant with EGFR c.2369C > T (p.T790M) mutation.	('c.2369C > T', 'Mutation', 'rs121434569', (90, 101))	('EGFR', 'Gene', (85, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('p.T790M', 'Mutation', 'rs121434569', (103, 110))	('PIK3CA', 'Gene', (41, 47))	('p.T790M', 'Var', (103, 110))	('c.2369C > T (p.T790M', 'Var', (90, 110))	('PIK3CA', 'Gene', '5290', (41, 47))	('EGFR', 'Gene', '1956', (85, 89))
14462	27734950	Routine clinical pathological examination and EGFR mutation analysis caused substantial attrition of tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
14463	27734950	In IPASS trial, only 36% of patients had adequate tissue specimens for EGFR mutation testing.	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('mutation', 'Var', (76, 84))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (28, 36))
14468	27734950	PIK3CA mutation rates of lung adenocarcinoma ranged from 1.5% to 7.7% in different studies.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (25, 44))	('PIK3CA', 'Gene', (0, 6))	('to 7', 'Species', '1214577', (62, 66))	('PIK3CA', 'Gene', '5290', (0, 6))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (25, 44))	('mutation', 'Var', (7, 15))	('lung adenocarcinoma', 'Disease', (25, 44))
14470	27734950	Our study showed that PIK3CA mutation rate was 1.8% in EGFR TKI-naive groups and 2.9% in acquired resistance to EGFR TKI group.	('EGFR', 'Gene', (112, 116))	('mutation', 'Var', (29, 37))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('PIK3CA', 'Gene', '5290', (22, 28))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (112, 116))	('PIK3CA', 'Gene', (22, 28))
14471	27734950	Of the EGFR TKI-treated subgroup and patients with acquired resistance to treatment, we only detected 6 patients with PIK3CA mutants.	('EGFR', 'molecular_function', 'GO:0005006', ('7', '11'))	('EGFR', 'Gene', (7, 11))	('patients', 'Species', '9606', (37, 45))	('PIK3CA', 'Gene', '5290', (118, 124))	('mutants', 'Var', (125, 132))	('PIK3CA', 'Gene', (118, 124))	('patients', 'Species', '9606', (104, 112))	('EGFR', 'Gene', '1956', (7, 11))
14473	27734950	Assuming the frequency of PIK3CA mutants is 5% and a 95% confidence interval of +/-3%, we estimated that 203 patients would be needed.	('PIK3CA', 'Gene', '5290', (26, 32))	('mutants', 'Var', (33, 40))	('PIK3CA', 'Gene', (26, 32))	('patients', 'Species', '9606', (109, 117))
14475	27734950	Although the test could not allow the detection of all variants, our mutation detection method covered more than 90% of the PIK3CA mutations in all lung cancer histology of the COSMIC database.	('mutations', 'Var', (131, 140))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('PIK3CA', 'Gene', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('PIK3CA', 'Gene', '5290', (124, 130))
14477	27734950	's study, which enrolled 1125 lung adenocarcinoma patients for the detection of four PIK3CA mutation types (c.1624G > A (p.E542K), c.1633G > A (p.E545K), c.3140A > G (p.H1047R), and c.3140A > T (p.H1047L)) by mass spectrometry-based nucleic acid assay.	('c.1624G > A', 'Var', (108, 119))	('c.3140A > T', 'Var', (182, 193))	('p.E545K', 'Mutation', 'rs104886003', (144, 151))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (30, 49))	('p.E542K', 'Mutation', 'rs121913273', (121, 128))	('p.H1047L', 'Mutation', 'rs121913279', (195, 203))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('p.H1047R', 'Mutation', 'rs121913279', (167, 175))	('c.1624G > A', 'Mutation', 'rs121913273', (108, 119))	('c.3140A > G', 'Var', (154, 165))	('patients', 'Species', '9606', (50, 58))	('PIK3CA', 'Gene', '5290', (85, 91))	('c.3140A > T', 'Mutation', 'rs121913279', (182, 193))	('c.1633G > A', 'Var', (131, 142))	('c.3140A > G', 'Mutation', 'rs121913279', (154, 165))	('nucleic acid', 'cellular_component', 'GO:0005561', ('233', '245'))	('c.1633G > A', 'Mutation', 'rs104886003', (131, 142))	('lung adenocarcinoma', 'Disease', (30, 49))	('PIK3CA', 'Gene', (85, 91))
14479	27734950	However, Sanger sequencing had been used to estimate the mosaic level of PIK3CA mutation as low as 7% in patients with megalencephaly syndrome, caused by mutations in PIK3CA, PIK3R2 and AKT3.	('PIK3CA', 'Gene', '5290', (73, 79))	('patients', 'Species', '9606', (105, 113))	('PIK3CA', 'Gene', '5290', (167, 173))	('AKT3', 'Gene', (186, 190))	('PIK3R2', 'Gene', '5296', (175, 181))	('megalencephaly syndrome', 'Disease', 'MESH:D058627', (119, 142))	('mutations', 'Var', (154, 163))	('AKT3', 'Gene', '10000', (186, 190))	('caused by', 'Reg', (144, 153))	('PIK3CA', 'Gene', (73, 79))	('PIK3R2', 'Gene', (175, 181))	('megalencephaly', 'Phenotype', 'HP:0001355', (119, 133))	('PIK3CA', 'Gene', (167, 173))	('megalencephaly syndrome', 'Disease', (119, 142))
14480	27734950	In addition, our study group had mixed in different extent with EGFR mutant cell and wild-type cells to detect limitation of RT-PCR by using isolated RNA as the template followed Sanger sequencing.	('RNA', 'cellular_component', 'GO:0005562', ('150', '153'))	('mutant', 'Var', (69, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))
14481	27734950	We could detect as low as 3% of mutant cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutant', 'Var', (32, 38))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
14482	27734950	Furthermore, if PIK3CA mutation(s) caused resistance to EGFR TKI, the cancer cells with PIK3CA mutation would proliferates with tumor progression; therefore the population of PIK3CA mutant cells would increase and not be in low percentage mosaicism.	('PIK3CA', 'Gene', '5290', (88, 94))	('EGFR', 'Gene', '1956', (56, 60))	('PIK3CA', 'Gene', '5290', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PIK3CA', 'Gene', '5290', (16, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('proliferates', 'PosReg', (110, 122))	('PIK3CA', 'Gene', (88, 94))	('cancer', 'Disease', (70, 76))	('mutation', 'Var', (95, 103))	('PIK3CA', 'Gene', (175, 181))	('increase', 'PosReg', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('EGFR', 'Gene', (56, 60))	('tumor', 'Disease', (128, 133))	('PIK3CA', 'Gene', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutation', 'Var', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
14483	27734950	First, the patients enrolled in the study were all Asian, a population known to have high EGFR mutation rate.	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('EGFR', 'Gene', (90, 94))	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (95, 103))
14484	27734950	Second, the number of PIK3CA mutation positive patients was too small to draw a definitive conclusion.	('mutation', 'Var', (29, 37))	('PIK3CA', 'Gene', (22, 28))	('patients', 'Species', '9606', (47, 55))	('PIK3CA', 'Gene', '5290', (22, 28))
14486	27734950	Third, in order to improve the detection sensitivity of PIK3CA mutation by RT-PCR, the more comprehensive method, for example: next-generation sequence, may be the alternative choice to detect different mutation types.	('PIK3CA', 'Gene', (56, 62))	('improve', 'PosReg', (19, 26))	('PIK3CA', 'Gene', '5290', (56, 62))	('mutation', 'Var', (63, 71))
14489	27734950	In conclusion, PIK3CA mutation may not be associated with primary resistance to EGFR TKI in lung adenocarcinoma patients.	('mutation', 'Var', (22, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('PIK3CA', 'Gene', '5290', (15, 21))	('EGFR', 'Gene', '1956', (80, 84))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('lung adenocarcinoma', 'Disease', (92, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('PIK3CA', 'Gene', (15, 21))
14509	27734950	The RNA extracted from patients' pleural effusions were collected for RT-PCR amplification using the QIAGEN OneStep RT-PCR kit (Qiagen, Hilden, Germany) and primers as follows: exon 9, 5'-TGGTCTGTATCCCGAGAAGC-3' (forward) and 5'-GGCCAATCTTTTACCAAGCA-3' (reverse); and exon 20, 5'-ACGTGTGCCATTTGTTTTGA-3' (forward) and 5'-GGTCTTTGCCTGCTGAGAGT-3' (reverse).	('pleural effusions', 'Disease', (33, 50))	('pleural effusions', 'Disease', 'MESH:D010996', (33, 50))	('exon 9', 'Var', (177, 183))	('exon 20', 'Var', (268, 275))	('pleural effusions', 'Phenotype', 'HP:0002202', (33, 50))	('patients', 'Species', '9606', (23, 31))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('pleural effusion', 'Phenotype', 'HP:0002202', (33, 49))
14513	27734950	The Role of PIK3CA Mutations among Lung Adenocarcinoma Patients with Primary and Acquired Resistance to EGFR Tyrosine Kinase Inhibition.	('Adenocarcinoma', 'Disease', 'MESH:D000230', (40, 54))	('PIK3CA', 'Gene', '5290', (12, 18))	('Mutations', 'Var', (19, 28))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('Adenocarcinoma', 'Disease', (40, 54))	('Patients', 'Species', '9606', (55, 63))	('PIK3CA', 'Gene', (12, 18))
14534	27536145	In addition, tumoral paraneoplastic effect by secretion of tumor growth factor alpha leads to keratinocyte proliferation and the development of AN.	('tumor', 'Disease', (13, 18))	('tumoral paraneoplastic', 'Disease', 'MESH:D010257', (13, 35))	('tumor', 'Disease', (59, 64))	('AN', 'Phenotype', 'HP:0000956', (144, 146))	('keratinocyte proliferation', 'CPA', (94, 120))	('secretion', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('keratinocyte proliferation', 'biological_process', 'GO:0043616', ('94', '120'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumoral paraneoplastic', 'Disease', (13, 35))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('secretion', 'biological_process', 'GO:0046903', ('46', '55'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
14589	27401458	Cd-treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung.	('increased', 'PosReg', (20, 29))	('mouse', 'Species', '10090', (174, 179))	('Cd-treated', 'Var', (0, 10))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('methacholine', 'Chemical', 'MESH:D016210', (60, 72))	('Cd', 'Chemical', 'MESH:D002104', (122, 124))	('altered', 'Reg', (125, 132))	('abundance of', 'MPA', (137, 149))	('mice', 'Species', '10090', (11, 15))	('airway hyperresponsiveness', 'Disease', 'MESH:D000402', (30, 56))	('Cd', 'Chemical', 'MESH:D002104', (0, 2))	('airway hyperresponsiveness', 'Disease', (30, 56))
14694	27401458	Blood Cd is associated with metabolic syndrome (Lee and Kim 2016), which may cause or contribute to asthma symptoms (Serafino-Agrusa et al.	('metabolic syndrome', 'Disease', (28, 46))	('Blood Cd', 'Var', (0, 8))	('cause', 'Reg', (77, 82))	('asthma symptoms', 'Disease', 'MESH:D001249', (100, 115))	('asthma', 'Phenotype', 'HP:0002099', (100, 106))	('associated', 'Reg', (12, 22))	('contribute', 'Reg', (86, 96))	('Cd', 'Chemical', 'MESH:D002104', (6, 8))	('metabolic syndrome', 'Disease', 'MESH:D008659', (28, 46))	('asthma symptoms', 'Disease', (100, 115))
14737	33731188	Dysregulation of ECM dynamics leads to various pathological conditions and is crucial in cancer development and progression.	('leads to', 'Reg', (30, 38))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('pathological conditions', 'Disease', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
14744	33731188	During adult life an intense splicing activity of the FN1 gene occurs in angiogenesis, tissue repair, fibrosis and of relevance in cancer where FN1 modifications strongly contribute to the age-related alterations in the ECM biosynthesis and degradation, thus modulating the tumor microenvironment (TME) composition and cancer progression.	('biosynthesis', 'biological_process', 'GO:0009058', ('224', '236'))	('contribute', 'Reg', (171, 181))	('ECM biosynthesis', 'MPA', (220, 236))	('cancer', 'Disease', (319, 325))	('tumor', 'Disease', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('FN1', 'Gene', (144, 147))	('degradation', 'MPA', (241, 252))	('FN1', 'Gene', (54, 57))	('modifications', 'Var', (148, 161))	('alterations', 'Reg', (201, 212))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('modulating', 'Reg', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('degradation', 'biological_process', 'GO:0009056', ('241', '252'))	('cancer', 'Disease', (131, 137))	('fibrosis', 'Disease', 'MESH:D005355', (102, 110))	('fibrosis', 'Disease', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('angiogenesis', 'biological_process', 'GO:0001525', ('73', '85'))
14748	33731188	The role of EDA in pathological processes such as cancer has been demonstrated by the work of Manabe and colleagues who revealed the importance of EDA+ FN1 in promoting cell cycle progression through the induction of cyclin D1 expression, hyperphosphorylation of pRb, and activation of mitogen-activated protein kinase extracellular signal regulated kinase 2 (ERK2).	('cyclin', 'molecular_function', 'GO:0016538', ('217', '223'))	('cancer', 'Disease', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('activation', 'PosReg', (272, 282))	('cyclin D1', 'Gene', '595', (217, 226))	('ERK2', 'Gene', '5594', (360, 364))	('extracellular', 'cellular_component', 'GO:0005576', ('319', '332'))	('ERK2', 'Gene', (360, 364))	('ERK2', 'molecular_function', 'GO:0004707', ('360', '364'))	('cell cycle', 'biological_process', 'GO:0007049', ('169', '179'))	('extracellular signal regulated kinase 2', 'Gene', '5594', (319, 358))	('hyperphosphorylation', 'MPA', (239, 259))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('EDA+ FN1', 'Var', (147, 155))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('pRb', 'Gene', (263, 266))	('cell cycle progression', 'CPA', (169, 191))	('extracellular signal regulated kinase 2', 'Gene', (319, 358))	('promoting', 'PosReg', (159, 168))	('expression', 'MPA', (227, 237))	('pRb', 'Gene', '5925', (263, 266))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('239', '259'))	('cyclin D1', 'Gene', (217, 226))
14753	33731188	It has been shown that the activation of TLR4 by EDA+ FN in mesenchymal cells leads to a pro-fibrotic gene program characterized by the up-regulation of genes involved in wound healing, tissue repair and ECM remodelling.	('TLR4', 'Gene', (41, 45))	('pro-fibrotic gene program', 'MPA', (89, 114))	('wound healing', 'biological_process', 'GO:0042060', ('171', '184'))	('regulation', 'biological_process', 'GO:0065007', ('139', '149'))	('EDA+ FN', 'Var', (49, 56))	('genes', 'MPA', (153, 158))	('activation', 'PosReg', (27, 37))	('TLR4', 'Gene', '7099', (41, 45))	('up-regulation', 'PosReg', (136, 149))
14754	33731188	EDB deficient mice develop normally and are fertile.	('deficient', 'Var', (4, 13))	('mice', 'Species', '10090', (14, 18))	('EDB', 'Gene', (0, 3))	('develop', 'CPA', (19, 26))
14757	33731188	By the use of biologically active recombinant EDB+ cFN it was observed that EDB+ cFN is incorporated more efficiently into the ECM and EDB-/- embryonic fibroblasts (MEFs) grow slowly and produce thinner and shorter fibrils compared to control MEFs, indicating a role of this domain in the efficacious assembly of FN1 ECM.	('slowly', 'NegReg', (176, 182))	('MEFs', 'CellLine', 'CVCL:9115', (243, 247))	('grow', 'CPA', (171, 175))	('MEFs', 'CellLine', 'CVCL:9115', (165, 169))	('EDB-/-', 'Var', (135, 141))	('EDB+ cFN', 'Var', (76, 84))	('shorter', 'NegReg', (207, 214))
14759	33731188	The alpha5beta1 integrin is the primary receptor mediating the assembly process, as demonstrated by blocking antibodies against anti-integrin or anti-FN1.	('anti-FN1', 'Var', (145, 153))	('beta1 integrin', 'Gene', (10, 24))	('beta1 integrin', 'Gene', '3688', (10, 24))	('anti-integrin', 'Protein', (128, 141))
14767	33731188	The cryptic FN1 sites reside within the FNIII modules which, upon mechanical cell traction, expose cryptic binding sites allowing FN matrix assembly, as demonstrated by antibodies that recognize this region and by specific FN1 deletions, indicating that the III2 repeat is a critical module for fibrils formation.	('formation', 'biological_process', 'GO:0009058', ('303', '312'))	('cryptic', 'Gene', '55997', (99, 106))	('cryptic', 'Gene', (99, 106))	('deletions', 'Var', (227, 236))	('cryptic', 'Gene', '55997', (4, 11))	('FN1', 'Gene', (223, 226))	('cryptic', 'Gene', (4, 11))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
14786	33731188	When fibrosis is in advanced stage, the high ECM stiffness induces fibroblasts to co-express EDA+ FN and LTBP-1 favoring their interaction in the ECM, suggesting that the inhibition of LTBP-1 and EDA+ FN interaction may reduce the TGF-beta1 reservoir in the ECM and fibrosis.	('inhibition', 'Var', (171, 181))	('fibrosis', 'Disease', 'MESH:D005355', (266, 274))	('LTBP-1', 'Gene', (185, 191))	('LTBP-1', 'Gene', '4052', (105, 111))	('TGF-beta1', 'Gene', '7040', (231, 240))	('LTBP-1', 'Gene', '4052', (185, 191))	('TGF-beta1', 'Gene', (231, 240))	('reduce', 'NegReg', (220, 226))	('LTBP-1', 'Gene', (105, 111))	('fibrosis', 'Disease', (266, 274))	('fibrosis', 'Disease', 'MESH:D005355', (5, 13))	('fibrosis', 'Disease', (5, 13))	('interaction', 'Interaction', (127, 138))
14787	33731188	The interference with the contractile function of myofibroblasts may be another potential therapeutic option for fibrosis, as suggested by Torr and coauthors who have differentiated human pulmonary fibroblasts in myofibroblasts by TGF-beta1 treatment and then inhibited fibrillogenesis by pharmacologic disruption of the transcription factor megakaryoblastic leukemia-1 (MKL1)/serum response factor (SRF), or by of the depletion of MKL1/SRF target gene, the alpha-SMA.	('disruption', 'Var', (303, 313))	('serum response factor', 'Gene', '6722', (377, 398))	('SRF', 'Gene', (437, 440))	('alpha-SMA', 'Gene', (458, 467))	('fibrillogenesis', 'CPA', (270, 285))	('inhibited', 'NegReg', (260, 269))	('MKL1', 'Gene', '57591', (371, 375))	('TGF-beta1', 'Gene', (231, 240))	('megakaryoblastic leukemia-1', 'Gene', (342, 369))	('fibrosis', 'Disease', 'MESH:D005355', (113, 121))	('fibrosis', 'Disease', (113, 121))	('alpha-SMA', 'Gene', '58', (458, 467))	('serum response factor', 'Gene', (377, 398))	('TGF-beta1', 'Gene', '7040', (231, 240))	('MKL1', 'Gene', '57591', (432, 436))	('MKL1', 'Gene', (371, 375))	('transcription', 'biological_process', 'GO:0006351', ('321', '334'))	('human', 'Species', '9606', (182, 187))	('megakaryoblastic leukemia-1', 'Gene', '57591', (342, 369))	('MKL1', 'Gene', (432, 436))	('SRF', 'Gene', '6722', (400, 403))	('depletion', 'MPA', (419, 428))	('SRF', 'Gene', (400, 403))	('transcription factor', 'molecular_function', 'GO:0000981', ('321', '341'))	('SRF', 'Gene', '6722', (437, 440))	('leukemia', 'Phenotype', 'HP:0001909', (359, 367))
14791	33731188	FN1 assembly has been suggested as a new hallmark of CAFs that promote tumor invasion as indicated in colon cancer-derived CAFs, where CAF contractility induces FN1 assembly and tumor cell invasion.	('tumor', 'Disease', (178, 183))	('contractility', 'Var', (139, 152))	('assembly', 'MPA', (165, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('induces', 'Reg', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('promote', 'PosReg', (63, 70))	('colon cancer', 'Disease', (102, 114))	('FN1', 'Protein', (161, 164))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
14813	33731188	These data have a strong clinical implication since in primary tumors high hMENA11a correlates with low stromal FN1 and a favorable clinical outcome of early node-negative non-small-cell lung cancer (NSCLC) patients, providing a new tool for the stratification of patient risk, guiding their clinical management.	('hMENA', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patients', 'Species', '9606', (207, 215))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('hMENA', 'Gene', '55740', (75, 80))	('SCLC', 'Phenotype', 'HP:0030357', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('NSCLC', 'Disease', (200, 205))	('tumors', 'Disease', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('low', 'NegReg', (100, 103))	('patient', 'Species', '9606', (264, 271))	('high', 'Var', (70, 74))	('patient', 'Species', '9606', (207, 214))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
14816	33731188	Moreover, FN1 also induces cell proliferation regulating cancerous inhibitor of protein phosphatase 2A (CIP2A) expression via its stabilization mediated by beta catenin in bladder cancer.	('beta catenin', 'Gene', (156, 168))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('cell proliferation', 'CPA', (27, 45))	('CIP2A', 'Gene', (104, 109))	('FN1', 'Var', (10, 13))	('cancerous inhibitor of protein phosphatase 2A', 'Gene', (57, 102))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('expression', 'MPA', (111, 121))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('80', '102'))	('bladder cancer', 'Disease', (172, 186))	('stabilization', 'MPA', (130, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('cancerous inhibitor of protein phosphatase 2A', 'Gene', '57650', (57, 102))	('induces', 'PosReg', (19, 26))	('CIP2A', 'Gene', '57650', (104, 109))	('beta catenin', 'Gene', '1499', (156, 168))
14829	33731188	Indeed, in the absence of TLR3, FN1 and the other upregulated genes, neutrophil recruitment and lung metastasis are reduced.	('FN1', 'Gene', (32, 35))	('absence', 'Var', (15, 22))	('TLR3', 'Gene', '142980', (26, 30))	('lung metastasis', 'CPA', (96, 111))	('reduced', 'NegReg', (116, 123))	('TLR3', 'Gene', (26, 30))	('neutrophil recruitment', 'CPA', (69, 91))
14861	33731188	Mechanistically, FN1 sustains the cell viability and proliferation and in parallel reduces the docetaxel-induced apoptosis inhibiting the caspase 8.	('caspase 8', 'Gene', '841', (138, 147))	('inhibiting', 'NegReg', (123, 133))	('caspase 8', 'Gene', (138, 147))	('reduces', 'NegReg', (83, 90))	('FN1', 'Var', (17, 20))	('docetaxel-induced apoptosis', 'MPA', (95, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('docetaxel', 'Chemical', 'MESH:D000077143', (95, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('cell viability', 'CPA', (34, 48))
14873	33731188	In human lung cancer cells unfolded type III domain of FN1 inhibited TRAIL induced apoptosis through the activation of a PI3K/Akt/alphavbeta5 signaling pathway.	('human', 'Species', '9606', (3, 8))	('inhibited', 'NegReg', (59, 68))	('PI3', 'Gene', '5266', (121, 124))	('Akt', 'Gene', (126, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('activation', 'PosReg', (105, 115))	('Akt', 'Gene', '207', (126, 129))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('FN1', 'Gene', (55, 58))	('apoptosis', 'CPA', (83, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('TRAIL', 'Gene', '8743', (69, 74))	('PI3', 'Gene', (121, 124))	('domain', 'Var', (45, 51))	('signaling pathway', 'biological_process', 'GO:0007165', ('142', '159'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TRAIL', 'Gene', (69, 74))	('lung cancer', 'Disease', (9, 20))
14893	33692946	Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.	('TIM-3', 'Gene', (10, 15))	('patients', 'Species', '9606', (76, 84))	('expression', 'Var', (16, 26))	('TCGA', 'Disease', (71, 75))	('TIM-3', 'Gene', '84868', (10, 15))	('worse OS', 'Disease', (54, 62))
14915	33692946	reported a significant association between TIM-3 expression and worse OS in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('worse OS', 'Disease', (64, 72))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('TIM-3', 'Gene', '84868', (43, 48))	('TIM-3', 'Gene', (43, 48))	('expression', 'Var', (49, 59))
14936	33692946	Of these eligible studies, only three articles reported that TIM-3 expression was correlated with worse OS in cervical cancer (n= 43 cases), gastric cancer (n=305 cases), and colorectal cancer (n=201 cases).	('correlated with', 'Reg', (82, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('gastric cancer', 'Disease', (141, 155))	('TIM-3', 'Gene', '84868', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('expression', 'Var', (67, 77))	('colorectal cancer', 'Disease', (175, 192))	('cancer', 'Disease', (119, 125))	('TIM-3', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (186, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
14937	33692946	The result from 22 studies indicated that the expression of TIM-3 led to poorer OS (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001) (Figure 2), including 3317 malignant tumor patients.	('TIM-3', 'Gene', '84868', (60, 65))	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('malignant tumor', 'Disease', (152, 167))	('poorer', 'NegReg', (73, 79))	('malignant tumor', 'Disease', 'MESH:D009369', (152, 167))	('patients', 'Species', '9606', (168, 176))	('TIM-3', 'Gene', (60, 65))
14940	33692946	The results by age group showed that TIM-3 expression was correlated with worse OS in the elder age group (> 60 years: n = 8 studies with 1600 cases: HR = 2.10, 95% CI = 1.34-3.31, P = 0.001) and the younger group (<= 60 years: n = 10 studies with 1348 cases: HR = 1.45, 95% CI = 1.01-2.08, P = 0.046).	('TIM-3', 'Gene', '84868', (37, 42))	('expression', 'Var', (43, 53))	('TIM-3', 'Gene', (37, 42))
14941	33692946	The results grouped by ethnicity showed that TIM-3 expression was associated with poor OS in Asian populations (n = 16 studies with 2452 cases: HR = 1.64, 95% CI = 1.14-2.35, P = 0.007), but not in European populations (n = 6 studies with 865 cases: P = 0.203).	('poor OS', 'Disease', (82, 89))	('TIM-3', 'Gene', (45, 50))	('expression', 'Var', (51, 61))	('TIM-3', 'Gene', '84868', (45, 50))
14945	33692946	The re-calculated result from the remaining studies showed that TIM-3 expression was still significantly correlated with shorter OS (HR= 1.71, 95% CI = 1.44-2.04, P < 0.001), with no heterogeneity (P = 0.102).	('shorter OS', 'Disease', (121, 131))	('expression', 'Var', (70, 80))	('TIM-3', 'Gene', '84868', (64, 69))	('TIM-3', 'Gene', (64, 69))
14959	33692946	TIM-3 expression is related to worse prognosis in some cancers, such as gastric cancer and ovarian cancer, but is not correlated with prognosis in some cancers, such as renal cell carcinoma and sarcoma.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('expression', 'Var', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('cancers', 'Disease', (152, 159))	('gastric cancer', 'Disease', (72, 86))	('renal cell carcinoma', 'Disease', (169, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('cancers', 'Disease', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('TIM-3', 'Gene', '84868', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TIM-3', 'Gene', (0, 5))
14962	33692946	reported that TIM-3 single nucleotide polymorphisms (SNPs) were correlated with an increased cancer risk (case-control studies with 4852 participants).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TIM-3', 'Gene', (14, 19))	('participants', 'Species', '9606', (137, 149))	('TIM-3', 'Gene', '84868', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('single nucleotide polymorphisms', 'Var', (20, 51))
14963	33692946	reported that TIM-3 expression was associated with shorter OS in solid tumors (n=869 patients).	('TIM-3', 'Gene', (14, 19))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
14977	33692946	These analyses suggest that TIM-3 could become an independent prognostic marker for predicting worse OS, and targeting TIM-3 is a potentially effective approach for cancer immunotherapy.	('TIM-3', 'Gene', '84868', (119, 124))	('TIM-3', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('targeting', 'Var', (109, 118))	('TIM-3', 'Gene', '84868', (28, 33))	('worse OS', 'Disease', (95, 103))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('TIM-3', 'Gene', (119, 124))
14979	33692946	reported that TIM-3 expression was correlated with worse CSS in clear cell renal cell carcinoma (n=137 cases), but Burugu 2018 et al.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('TIM-3', 'Gene', (14, 19))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 95))	('clear cell renal cell carcinoma', 'Disease', (64, 95))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (64, 95))
14980	33692946	reported that TIM-3 expression was related to favorable CSS in a large cohort of breast cancer (> 3000 cases).	('breast cancer', 'Disease', (81, 94))	('TIM-3', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
14986	33692946	Subgroup analysis by ethnicity demonstrated that TIM-3 expression was related to worse OS in Asian populations, but not in European populations.	('TIM-3', 'Gene', (49, 54))	('worse OS', 'Disease', (81, 89))	('TIM-3', 'Gene', '84868', (49, 54))	('expression', 'Var', (55, 65))
14999	33692946	The present study provided more evidence that TIM-3 expression was significantly associated with worse OS, and it might be a useful prognosticator in malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('malignant tumors', 'Disease', (150, 166))	('malignant tumors', 'Disease', 'MESH:D009369', (150, 166))	('worse OS', 'Disease', (97, 105))	('TIM-3', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('TIM-3', 'Gene', '84868', (46, 51))	('expression', 'Var', (52, 62))	('associated', 'Reg', (81, 91))
15003	33057152	SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3'-splice sites and subsequent aberrant junctions.	('branchpoint recognition', 'MPA', (90, 113))	('SF3B1', 'Gene', (0, 5))	('corrupt', 'NegReg', (82, 89))	('SF3B1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('SF3B1', 'Gene', '23451', (0, 5))	('SF3B1', 'Gene', '23451', (68, 73))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('mutants', 'Var', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (56, 62))
15005	33057152	While the most of aberrant 3'-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('lung adenocarcinomas', 'Disease', (142, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('mutations', 'Var', (70, 79))	('SF3B1', 'Gene', (64, 69))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (142, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (142, 161))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (142, 162))	('SF3B1', 'Gene', (103, 108))	("3'-splice patterns", 'MPA', (27, 45))	('SF3B1', 'Gene', '23451', (64, 69))	('explained', 'Reg', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SF3B1', 'Gene', '23451', (103, 108))
15006	33057152	Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('SUGP1', 'Gene', '57794', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('SUGP1', 'Gene', (130, 135))	('loss-of-heterozygosity', 'NegReg', (84, 106))	('splicing', 'biological_process', 'GO:0045292', ('114', '122'))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
15008	33057152	Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.	('SF3B1', 'Gene', (82, 87))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('genocopy', 'Var', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('SUGP1', 'Gene', (67, 72))	('lung adenocarcinoma', 'Disease', (101, 120))	('mutations', 'Var', (88, 97))	('SF3B1', 'Gene', '23451', (82, 87))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (101, 120))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SUGP1', 'Gene', '57794', (67, 72))
15010	33057152	Catalog of splicing factors with frequent and recurrent somatic mutations in tumors include SF3B1, U2AF1, and SRSF2 with heterozygous missense mutations and ZRSR2 with loss of function mutations.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('missense mutations', 'Var', (134, 152))	('SF3B1', 'Gene', '23451', (92, 97))	('U2AF', 'cellular_component', 'GO:0089701', ('99', '103'))	('loss of function', 'NegReg', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (64, 73))	('ZRSR2', 'Gene', (157, 162))	('splicing', 'biological_process', 'GO:0045292', ('11', '19'))	('mutations', 'Var', (185, 194))	('U2AF1', 'Gene', (99, 104))	('SF3B1', 'Gene', (92, 97))	('SRSF2', 'Gene', (110, 115))
15011	33057152	Mutations in these genes are mutually exclusive and present in up to half of myelodysplasia, in chronic lymphocytic leukemia and in a significant number of solid tumors, including uveal melanoma (UM), lung adenocarcinoma, and other malignancies.	('UM', 'Phenotype', 'HP:0007716', (196, 198))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (96, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('myelodysplasia', 'Disease', (77, 91))	('chronic lymphocytic leukemia', 'Disease', (96, 124))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('malignancies', 'Disease', 'MESH:D009369', (232, 244))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (96, 124))	('malignancies', 'Disease', (232, 244))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('lung adenocarcinoma', 'Disease', (201, 220))	('Mutations', 'Var', (0, 9))	('myelodysplasia', 'Phenotype', 'HP:0002863', (77, 91))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('myelodysplasia', 'Disease', 'MESH:D009190', (77, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (201, 220))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (201, 220))	('melanoma', 'Disease', (186, 194))	('present', 'Reg', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('tumors', 'Disease', (162, 168))
15012	33057152	Cancer mutations of U1 spliceosomal small nuclear RNA (snRNA RNU1) were recently found in about 50% of the SHH medulloblastoma subtype and extremely rare in other types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('medulloblastoma', 'Phenotype', 'HP:0002885', (111, 126))	('found', 'Reg', (81, 86))	('Cancer', 'Disease', (0, 6))	('SHH medulloblastoma', 'Disease', 'MESH:D008527', (107, 126))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('SHH medulloblastoma', 'Disease', (107, 126))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('small nuclear RNA', 'molecular_function', 'GO:0005570', ('36', '53'))	('snRNA RNU1', 'Gene', (55, 65))	('mutations', 'Var', (7, 16))
15013	33057152	Recurrent mutations were reported in other splicing genes, including PHF5A, RBM10, and FUBP1, putatively implicated in cancer.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('RBM10', 'Gene', (76, 81))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('PHF5A', 'Gene', (69, 74))	('cancer', 'Disease', (119, 125))	('FUBP1', 'Gene', (87, 92))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
15018	33057152	Missense mutations found in SF3B1 map to the surface of the HEAT-repeat domains (H3-H6) in the region that interacts with the intron between the BP and 3'ss with the hotspots at codon positions R625, K666, and K700.	('K700', 'Var', (210, 214))	('R625', 'Var', (194, 198))	('SF3B1', 'Gene', (28, 33))	('K666', 'Var', (200, 204))	('SF3B1', 'Gene', '23451', (28, 33))	('Missense mutations', 'Var', (0, 18))
15019	33057152	demonstrated that cancer-associated mutations of SF3B1 mainly disrupt SF3B1 interaction with SUGP1 during BP recognition and that the loss of this interaction solely accounts for the splicing errors caused by SF3B1 mutations.	('SF3B1', 'Gene', '23451', (49, 54))	('disrupt', 'NegReg', (62, 69))	('SF3B1', 'Gene', (209, 214))	('SF3B1', 'Gene', '23451', (70, 75))	('interaction', 'Interaction', (76, 87))	('mutations', 'Var', (36, 45))	('SUGP1', 'Gene', '57794', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('splicing', 'biological_process', 'GO:0045292', ('183', '191'))	('SF3B1', 'Gene', (70, 75))	('SF3B1', 'Gene', (49, 54))	('SF3B1', 'Gene', '23451', (209, 214))	('splicing', 'MPA', (183, 191))	('SUGP1', 'Gene', (93, 98))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
15020	33057152	We started from a large-scale analysis of the TCGA series of 3'ss splicing aberrations associated with SF3B1 mutations, questioning if all aberrant pattern has a corresponding SF3B1 mutation.	('associated', 'Reg', (87, 97))	('SF3B1', 'Gene', (103, 108))	('SF3B1', 'Gene', (176, 181))	('mutations', 'Var', (109, 118))	('SF3B1', 'Gene', '23451', (103, 108))	('SF3B1', 'Gene', '23451', (176, 181))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))
15021	33057152	We detected tumors with an aberrant splicing pattern, which were wild-type for SF3B1, and found that these tumors were recurrently mutated for SUGP1.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SUGP1', 'Gene', '57794', (143, 148))	('mutated', 'Var', (131, 138))	('tumors', 'Disease', (107, 113))	('splicing pattern', 'MPA', (36, 52))	('SF3B1', 'Gene', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('SUGP1', 'Gene', (143, 148))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('tumors', 'Disease', (12, 18))	('SF3B1', 'Gene', '23451', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
15022	33057152	We further demonstrated that SUPG1 alterations mimic the 3'ss aberration pattern found in the SF3B1-mutant context.	('SF3B1', 'Gene', '23451', (94, 99))	('SUPG1', 'Gene', (29, 34))	("3'ss", 'MPA', (57, 61))	('alterations', 'Var', (35, 46))	('SF3B1', 'Gene', (94, 99))
15023	33057152	For a comprehensive view of pathogenic mutations inducing usage of cryptic 3'ss as observed in a SF3B1-mutant context (we will denote by SF3B1mut all SF3B1 mutations that lead to aberrant 3'ss usage), we used a Sequence Bloom Tree (SBT) constructed from RNA-seq data for a total of 11,350 different samples and 33 tumor types from TCGA (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('SF3B1', 'Gene', '23451', (97, 102))	('SF3B1', 'Gene', (150, 155))	('SF3B1', 'Gene', '23451', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('mutations', 'Var', (156, 165))	('SF3B1', 'Gene', (137, 142))	('SF3B1', 'Gene', '23451', (150, 155))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (314, 319))	('RNA', 'cellular_component', 'GO:0005562', ('254', '257'))	('SF3B1', 'Gene', (97, 102))
15027	33057152	These high SBT-score cases were thoroughly verified for SF3B1 mutations in exome and RNA sequencing data using IGV.	('SF3B1', 'Gene', '23451', (56, 61))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('SF3B1', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))
15029	33057152	Cases showing no read supporting an SF3B1 hotspot mutation in the RNA-seq data had consistently low SBT scores.	('RNA', 'cellular_component', 'GO:0005562', ('66', '69'))	('SF3B1', 'Gene', (36, 41))	('SBT scores', 'MPA', (100, 110))	('hotspot', 'PosReg', (42, 49))	('SF3B1', 'Gene', '23451', (36, 41))	('low', 'NegReg', (96, 99))	('mutation', 'Var', (50, 58))
15030	33057152	SF3B1 mutations at positions 742, 741, and 633 represented the lower limit of SBT scores observed in tumors mutated for SF3B1 in the 500-800aa region.	('mutated', 'Var', (108, 115))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SF3B1', 'Gene', '23451', (0, 5))	('SF3B1', 'Gene', '23451', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', (101, 107))
15031	33057152	Two UCEC cases displayed identical mutations p.R549C and elevated SBT scores, possibly defining the N-terminal limit (domain H1) of functional sites for which mutations could induce 3'ss aberrations.	('p.R549C', 'Var', (45, 52))	('elevated', 'PosReg', (57, 65))	('p.R549C', 'Mutation', 'rs1172363633', (45, 52))	('SBT scores', 'MPA', (66, 76))
15032	33057152	The set of 366 3'ss aberrant junctions was selected from ubiquitously-expressed exons (CQ >= 0.3 in 95% cases) in an unsupervised manner: the junction was included if aberrant and corresponding canonical junction were expressed (AQ >= 0.4 and CQ >= 0.5) and splicing index SI >= 0.15 at least in one sample.	('aberrant', 'Var', (167, 175))	('splicing index SI >= 0.15', 'Var', (258, 283))	('SI', 'Chemical', '-', (273, 275))	('splicing', 'biological_process', 'GO:0045292', ('258', '266'))
15033	33057152	Principal component analysis (PCA) of cryptic 3'ss usage characterized by SI showed the main source of variation to be SF3B1 mutations and the phenotype is characterized by increased expression of cryptic 3'ss (Fig.	('SI', 'Chemical', '-', (74, 76))	('mutations', 'Var', (125, 134))	('SF3B1', 'Gene', (119, 124))	('expression', 'Species', '29278', (183, 193))	('increased', 'PosReg', (173, 182))	('expression', 'MPA', (183, 193))	('SF3B1', 'Gene', '23451', (119, 124))
15035	33057152	This result represents the exhaustive list of the TCGA cases with 3'ss aberrations characteristic to SF3B1 hotspots mutations (Supplementary Fig.	('SF3B1', 'Gene', '23451', (101, 106))	('mutations', 'Var', (116, 125))	('SF3B1', 'Gene', (101, 106))	('TCGA', 'Disease', (50, 54))
15037	33057152	Mutational analysis of RNA processing genes (GO:0006396) of the nine SF3B1-like cases revealed mutations in SUGP1 (also known as Splicing Factor 4 or SF4) as the only common event for five cases: four missense (p.L515P, p.G519V, p.R625T, and p.P636L) and one stop-gain (p.G26*) mutations.	('p.R625T', 'Var', (229, 236))	('p.R625T', 'Mutation', 'p.R625T', (229, 236))	('p.P636L', 'Var', (242, 249))	('p.G26*', 'Var', (270, 276))	('p.G519V', 'Var', (220, 227))	('RNA processing', 'biological_process', 'GO:0006396', ('23', '37'))	('SF3B1', 'Gene', (69, 74))	('p.P636L', 'Mutation', 'p.P636L', (242, 249))	('p.G26*', 'Mutation', 'p.26dup', (270, 276))	('p.L515P', 'Mutation', 'p.L515P', (211, 218))	('SUGP1', 'Gene', '57794', (108, 113))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('mutations', 'Var', (95, 104))	('p.G519V', 'Mutation', 'p.G519V', (220, 227))	('Splicing', 'biological_process', 'GO:0045292', ('129', '137'))	('SF3B1', 'Gene', '23451', (69, 74))	('SUGP1', 'Gene', (108, 113))
15039	33057152	Given that only eight cases out of the entire TCGA series carried SUGP1 variants with RNA-seq VAF > 0.3 and LOH, enrichment of SUGP1 variant + LOH (SUGP1LOH/mut) within cases with a SF3B1-like phenotype is highly significant (p < 10-8, Fisher's exact test adjusted for multiple testing).	('variant + LOH', 'Var', (133, 146))	('SUGP1', 'Gene', '57794', (127, 132))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('SF3B1', 'Gene', (182, 187))	('variants', 'Var', (72, 80))	('SUGP1', 'Gene', '57794', (66, 71))	('SUGP1', 'Gene', '57794', (148, 153))	('SUGP1', 'Gene', (127, 132))	('SF3B1', 'Gene', '23451', (182, 187))	('SUGP1', 'Gene', (66, 71))	('SUGP1', 'Gene', (148, 153))
15040	33057152	Worth noting that beside five SUGP1 mutations + LOH associated with an SF3B1-like phenotype, there are three missense mutations + LOH and more than 50 missense and deleterious mutations in heterozygous state found in the TCGA (Fig.	('SF3B1', 'Gene', (71, 76))	('SUGP1', 'Gene', '57794', (30, 35))	('SUGP1', 'Gene', (30, 35))	('associated', 'Reg', (52, 62))	('SF3B1', 'Gene', '23451', (71, 76))	('mutations +', 'Var', (36, 47))
15042	33057152	We further mined the four SF3B1-like cases associated with neither SF3B1 nor SUGP1 mutation.	('SF3B1', 'Gene', (26, 31))	('SUGP1', 'Gene', (77, 82))	('SF3B1', 'Gene', '23451', (67, 72))	('SF3B1', 'Gene', '23451', (26, 31))	('mutation', 'Var', (83, 91))	('SUGP1', 'Gene', '57794', (77, 82))	('SF3B1', 'Gene', (67, 72))
15048	33057152	SUGP1 interacts with SF3B1 and SF3B1 hotspot mutations disrupt this interaction.	('mutations', 'Var', (45, 54))	('SUGP1', 'Gene', '57794', (0, 5))	('disrupt', 'NegReg', (55, 62))	('SF3B1', 'Gene', (21, 26))	('SUGP1', 'Gene', (0, 5))	('SF3B1', 'Gene', (31, 36))	('interacts', 'Interaction', (6, 15))	('SF3B1', 'Gene', '23451', (21, 26))	('SF3B1', 'Gene', '23451', (31, 36))	('interaction', 'Interaction', (68, 79))
15049	33057152	Moreover, aberrant recognition of BPs and cryptic 3'ss was shown for SUGP1 KD and for double mutations in G-patch domain of SUGP1.	('SUGP1', 'Gene', (124, 129))	('double mutations in', 'Var', (86, 105))	('KD', 'Disease', 'MESH:C537017', (75, 77))	('SUGP1', 'Gene', '57794', (69, 74))	('SUGP1', 'Gene', '57794', (124, 129))	('SUGP1', 'Gene', (69, 74))
15050	33057152	Here we detected five mutations in SUGP1 associated with LOH and SF3B1-like splicing pattern in cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('associated', 'Reg', (41, 51))	('splicing', 'biological_process', 'GO:0045292', ('76', '84'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SF3B1', 'Gene', (65, 70))	('LOH', 'Disease', (57, 60))	('SUGP1', 'Gene', '57794', (35, 40))	('mutations', 'Var', (22, 31))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('SF3B1', 'Gene', '23451', (65, 70))	('SUGP1', 'Gene', (35, 40))	('cancers', 'Disease', (96, 103))
15051	33057152	Interestingly, missense mutations do not target any known interaction domain of SUGP1 and are located before and after its G-patch domain.	('missense mutations', 'Var', (15, 33))	('SUGP1', 'Gene', (80, 85))	('SUGP1', 'Gene', '57794', (80, 85))
15052	33057152	We assessed the impact of SUGP1 alterations found in cancers, including LOH and mutations, on splicing.	('SUGP1', 'Gene', '57794', (26, 31))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('mutations', 'Var', (80, 89))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('SUGP1', 'Gene', (26, 31))	('splicing', 'biological_process', 'GO:0045292', ('94', '102'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('LOH', 'Disease', (72, 75))
15053	33057152	Using HEK293T cells (wild-type for both SUGP1 and SF3B1), we performed siRNA-mediated SUGP1 knockdown and overexpression of the SUGP1 L515P, R625T, and P636L mutants.	('SUGP1', 'Gene', '57794', (40, 45))	('L515P', 'SUBSTITUTION', 'None', (134, 139))	('SUGP1', 'Gene', (128, 133))	('SF3B1', 'Gene', (50, 55))	('SUGP1', 'Gene', '57794', (128, 133))	('P636L', 'Var', (152, 157))	('SUGP1', 'Gene', (40, 45))	('P636L', 'Mutation', 'p.P636L', (152, 157))	('SF3B1', 'Gene', '23451', (50, 55))	('expression', 'Species', '29278', (110, 120))	('SUGP1', 'Gene', '57794', (86, 91))	('HEK293T', 'CellLine', 'CVCL:0063', (6, 13))	('L515P', 'Var', (134, 139))	('R625T', 'Mutation', 'p.R625T', (141, 146))	('R625T', 'Var', (141, 146))	('SUGP1', 'Gene', (86, 91))
15055	33057152	The knockdown of SUGP1 using four different siRNAs consistently and significantly induced the SF3B1mut-aberrant pattern (p < 0.05 to <0.0005, depending on the siRNA and junctions; Fig.	('SF3B1', 'Gene', '23451', (94, 99))	('SUGP1', 'Gene', '57794', (17, 22))	('SUGP1', 'Gene', (17, 22))	('SF3B1', 'Gene', (94, 99))	('knockdown', 'Var', (4, 13))	('induced', 'PosReg', (82, 89))
15056	33057152	Transiently overexpressed SUGP1 mutants induced either significant but modest effects on splicing (L515P and P636L) or no significant effect (R625T) (Fig.	('SUGP1', 'Gene', '57794', (26, 31))	('P636L', 'Var', (109, 114))	('mutants', 'Var', (32, 39))	('splicing', 'MPA', (89, 97))	('SUGP1', 'Gene', (26, 31))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('L515P', 'Var', (99, 104))	('R625T', 'Mutation', 'p.R625T', (142, 147))	('P636L', 'Mutation', 'p.P636L', (109, 114))	('L515P', 'SUBSTITUTION', 'None', (99, 104))
15057	33057152	The p.G26* stop mutation, located at the very beginning of the gene, was well expressed in the tumor, suggesting an alternative initiation of translation bypassing the Nonsense-Mediated mRNA Decay (NMD) in this sample (Supplementary Fig.	('translation', 'biological_process', 'GO:0006412', ('142', '153'))	('p.G26*', 'SUBSTITUTION', 'None', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('Nonsense-Mediated mRNA Decay', 'biological_process', 'GO:0000184', ('168', '196'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p.G26*', 'Var', (4, 10))	('tumor', 'Disease', (95, 100))
15058	33057152	Indeed, we demonstrated by expressing SUGP1 cDNA carrying this G26* mutation the existence of this alternative initiation coding an N-terminal truncated protein (Supplementary Fig.	('SUGP1', 'Gene', '57794', (38, 43))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('G26*', 'Var', (63, 67))	('SUGP1', 'Gene', (38, 43))	('G26*', 'SUBSTITUTION', 'None', (63, 67))
15060	33057152	To determine whether SUGP1 loss affects U2 recognition of the BP in a similar manner, we performed a splice-reporter assay with SF3B1mut-sensitive junctions (ENOSF1 and TMEM14C) containing adenine mutants inactivating either the canonical or cryptic BPs.	('SF3B1', 'Gene', '23451', (128, 133))	('adenine', 'Chemical', 'MESH:D000225', (189, 196))	('SUGP1', 'Gene', '57794', (21, 26))	('mutants', 'Var', (197, 204))	('SUGP1', 'Gene', (21, 26))	('SF3B1', 'Gene', (128, 133))	('loss', 'NegReg', (27, 31))
15061	33057152	Our results showed that mutants disrupting the BP' abolish the splice aberration induced by siRNA-mediated SUGP1 knockdown (Fig.	('knockdown', 'MPA', (113, 122))	('splice aberration', 'MPA', (63, 80))	('mutants', 'Var', (24, 31))	('SUGP1', 'Gene', '57794', (107, 112))	('SUGP1', 'Gene', (107, 112))
15075	33057152	Hierarchical clustering on the aberrant junctions with high loadings demonstrates background level in cryptic 5'ss and aberrant exon usage in both SUGP1alt and SF3B1mut groups.	('alt', 'molecular_function', 'GO:0004021', ('152', '155'))	('SF3B1', 'Gene', (160, 165))	('SUGP1', 'Gene', '57794', (147, 152))	('SF3B1', 'Gene', '23451', (160, 165))	('aberrant exon', 'Var', (119, 132))	('SUGP1', 'Gene', (147, 152))
15078	33057152	The condition for PC selection to separate Control and SF3B1mut or SUGP1alt groups accounts for transcriptional heterogeneity and follows the assumption that aberrant junctions show up almost exclusively in the groups with alteration in a splicing factor (if many controls behave similar to mutated cases, the feature is not specific to the mutated cases even though the test shows significant differences (Supplementary Figs.	('SF3B1', 'Gene', '23451', (55, 60))	('splicing', 'MPA', (239, 247))	('SUGP1', 'Gene', (67, 72))	('alt', 'molecular_function', 'GO:0004021', ('72', '75'))	('alteration', 'Var', (223, 233))	('SF3B1', 'Gene', (55, 60))	('splicing', 'biological_process', 'GO:0045292', ('239', '247'))	('SUGP1', 'Gene', '57794', (67, 72))
15082	33057152	To evaluate if SUGP1 alterations are indeed the causes of the abnormal splicing pattern, we set up two experimental models using HEK293T and isogenic HAP1 cell lines and analyzed their RNA-seq data.	('HAP1', 'Gene', (150, 154))	('SUGP1', 'Gene', (15, 20))	('HEK293T', 'CellLine', 'CVCL:0063', (129, 136))	('splicing', 'biological_process', 'GO:0045292', ('71', '79'))	('SUGP1', 'Gene', '57794', (15, 20))	('RNA', 'cellular_component', 'GO:0005562', ('185', '188'))	('HAP1', 'Gene', '9001', (150, 154))	('alterations', 'Var', (21, 32))
15087	33057152	The subset of aberrant junctions with  SImax > 1 in either SUGP1KD or SF3B1K700E (74 and 49 junctions, respectively, 97 in total) showed coherent overexpression with increased usage of cryptic 3'ss located 10-30nts upstream of the canonical 3'ss (Fig.	('overexpression', 'PosReg', (146, 160))	('expression', 'Species', '29278', (150, 160))	('SF3B1', 'Gene', (70, 75))	('SImax > 1', 'Var', (39, 48))	('SI', 'Chemical', '-', (39, 41))	('SUGP1KD', 'Gene', '57794', (59, 66))	('SF3B1', 'Gene', '23451', (70, 75))	('SUGP1KD', 'Gene', (59, 66))
15090	33057152	HAP1SUGP1-P636L cells displayed splice aberrations consistent with the SF3B1mut pattern, and mainly characterized by the usage of cryptic 3'ss at 10-25nts upstream the canonical 3'ss (Fig.	('SF3B1', 'Gene', (71, 76))	('HAP1SUGP1-P636L', 'Var', (0, 15))	('P636L', 'Mutation', 'p.P636L', (10, 15))	('SF3B1', 'Gene', '23451', (71, 76))	('splice aberrations', 'MPA', (32, 50))
15092	33057152	Strikingly, siRNA-knockdown of the SUGP1P636L further increased the aberrant splice index, implying that SUGP1 mutations lead to a partial loss of function (hypomorphic mutations) accentuated by the mutant knockdown (Fig.	('mutations', 'Var', (111, 120))	('aberrant splice index', 'MPA', (68, 89))	('SUGP1', 'Gene', (105, 110))	('loss', 'NegReg', (139, 143))	('increased', 'PosReg', (54, 63))	('SUGP1', 'Gene', '57794', (35, 40))	('SUGP1', 'Gene', (35, 40))	('SUGP1', 'Gene', '57794', (105, 110))
15093	33057152	These experiments elucidated the respective role of reduced SUGP1 expression by LOH and of hypomorphic mutations found combined in tumors and demonstrated that SUGP1 phenocopies SF3B1 3'ss aberration at the whole transcriptome level.	('mutations', 'Var', (103, 112))	('SUGP1', 'Gene', '57794', (60, 65))	('reduced', 'NegReg', (52, 59))	('SUGP1', 'Gene', (160, 165))	('expression', 'Species', '29278', (66, 76))	('SF3B1', 'Gene', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('SUGP1', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('SF3B1', 'Gene', '23451', (178, 183))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('SUGP1', 'Gene', '57794', (160, 165))
15095	33057152	Starting from the pan-cancer SF3B1-like 3'ss aberration pattern, we explained almost all cases either by new SF3B1 mutations outside of the known hotspots or by SUGP1 alterations.	('mutations', 'Var', (115, 124))	('SF3B1', 'Gene', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('SF3B1', 'Gene', '23451', (29, 34))	('SUGP1', 'Gene', '57794', (161, 166))	('SUGP1', 'Gene', (161, 166))	('cancer', 'Disease', (22, 28))	('SF3B1', 'Gene', '23451', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SF3B1', 'Gene', (29, 34))
15096	33057152	Only two SF3B1-like cases were not associated with either SF3B1 or SUGP1 alterations and only one of these cases (LAML) had a strong alteration pattern, whereas the SKCM case associated with weak 3'ss aberration pattern could be false positive.	('SF3B1', 'Gene', '23451', (9, 14))	('alterations', 'Var', (73, 84))	('SF3B1', 'Gene', (58, 63))	('SUGP1', 'Gene', (67, 72))	('false', 'biological_process', 'GO:0071878', ('229', '234'))	('SF3B1', 'Gene', '23451', (58, 63))	('false', 'biological_process', 'GO:0071877', ('229', '234'))	('SF3B1', 'Gene', (9, 14))	('SUGP1', 'Gene', '57794', (67, 72))
15101	33057152	We further validated the dysfunction of SUGP1 mutants by RNA-seq analyses of original isogenic models.	('SUGP1', 'Gene', '57794', (40, 45))	('mutants', 'Var', (46, 53))	('SUGP1', 'Gene', (40, 45))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))
15102	33057152	Our data are in line with the previously suggested mechanism of the disruption of SUGP1/SF3B1 interaction induced by the pathologic mutants.	('SF3B1', 'Gene', '23451', (88, 93))	('SUGP1', 'Gene', (82, 87))	('mutants', 'Var', (132, 139))	('interaction', 'Interaction', (94, 105))	('SF3B1', 'Gene', (88, 93))	('SUGP1', 'Gene', '57794', (82, 87))
15103	33057152	We also provide direct experimental evidences supporting that the depletion of SUGP1 together with expression of a SUGP1 mutation induce the SF3B1mut-splice pattern in a cumulative manner, which fits the co-occurrence of LOH and SUGP1 mutations in tumors.	('SUGP1', 'Gene', (115, 120))	('induce', 'PosReg', (130, 136))	('SF3B1', 'Gene', '23451', (141, 146))	('SUGP1', 'Gene', (229, 234))	('SUGP1', 'Gene', '57794', (79, 84))	('fits', 'Disease', (195, 199))	('tumors', 'Disease', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('SUGP1', 'Gene', (79, 84))	('mutation', 'Var', (121, 129))	('SF3B1', 'Gene', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('SUGP1', 'Gene', '57794', (115, 120))	('SUGP1', 'Gene', '57794', (229, 234))	('expression', 'Species', '29278', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('fits', 'Disease', 'MESH:D012640', (195, 199))	('depletion', 'MPA', (66, 75))
15105	33057152	However, large depletion of SUGP1 expression, often combined with SUPG1 hypomorphic variants, are not only tolerated by tumor cells but likely to be associated with the oncogenic process.	('depletion', 'MPA', (15, 24))	('SUGP1', 'Gene', '57794', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('SUGP1', 'Gene', (28, 33))	('associated', 'Reg', (149, 159))	('SUPG1', 'Gene', (66, 71))	('variants', 'Var', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))	('expression', 'Species', '29278', (34, 44))
15114	33057152	Cases with mutations in U2AF1, SRSF2 and out of hotspot region SF3B1 were extracted from the vcf files from the TCGA.	('U2AF1', 'Gene', (24, 29))	('mutations', 'Var', (11, 20))	('SF3B1', 'Gene', (63, 68))	('SF3B1', 'Gene', '23451', (63, 68))	('SRSF2', 'Gene', (31, 36))	('U2AF', 'cellular_component', 'GO:0089701', ('24', '28'))
15115	33057152	Proximal 3' junctions 5-50nts upstream to canonical 3'ss were selected for further analysis if at least one case in the series satisfy the condition SI >= 0.15, AQ >= 0.4, and CQ >= 0.5 (n = 975 junctions).	('SI', 'Chemical', '-', (149, 151))	('CQ >= 0.5', 'Var', (176, 185))	('AQ >= 0.4', 'Var', (161, 170))	('SI >= 0.15', 'Var', (149, 159))
15118	33057152	SUGP1 mutations were extracted from vcf files from the TCGA (exome VAF > 0.1, RNA-seq VAF > 0.3 for missense mutations).	('missense', 'Var', (100, 108))	('SUGP1', 'Gene', (0, 5))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('SUGP1', 'Gene', '57794', (0, 5))
15119	33057152	Cases with the lowest RNA-seq coverage (n = 75) and cases with U2AF1 34F/Y mutations (n = 8) or RBM10 inactivation (n = 20) were excluded.	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('inactivation', 'Var', (102, 114))	('U2AF', 'cellular_component', 'GO:0089701', ('63', '67'))	('34F/Y', 'Var', (69, 74))	('U2AF1', 'Gene', (63, 68))	('34F/Y', 'SUBSTITUTION', 'None', (69, 74))
15120	33057152	Minimal requirements for an aberrant junction to be included were: SI >= 0.1, AQ >= 0.4, and CQ >= 0.5 in at least one case.	('SI', 'Chemical', '-', (67, 69))	('CQ >= 0.5', 'Var', (93, 102))	('SI >= 0.1', 'Var', (67, 76))	('AQ >= 0.4', 'Var', (78, 87))
15121	33057152	Half-canonical 3' proximal (n = 5357), half-canonical 5' proximal (n = 1788), half-canonical distant (n = 6303) and aberrant exon (n = 2501) junctions in SUGP1 altered (n = 5, including mutated and low expression cases), SF3B1 mutated (n = 6) and control (n = 400) groups were compared using the bioinformatics protocol described below.	('SUGP1', 'Gene', '57794', (154, 159))	('mutated', 'Var', (227, 234))	('expression', 'Species', '29278', (202, 212))	('SUGP1', 'Gene', (154, 159))	('mutated', 'Var', (186, 193))	('SF3B1', 'Gene', (221, 226))	('SF3B1', 'Gene', '23451', (221, 226))	('aberrant', 'Var', (116, 124))
15125	33057152	We consider a junction (i) as shared if SImax > SIQ95 (95 quantile of the Controls) for both groups; (ii) as definitively not shared if one SImax > SIQ95 and the other SImax < SIQ75; (iii) as not determined otherwise.	('SI', 'Chemical', '-', (168, 170))	('SI', 'Chemical', '-', (140, 142))	('SI', 'Chemical', '-', (176, 178))	('SI', 'Chemical', '-', (48, 50))	('SImax > SIQ95', 'Var', (40, 53))	('SI', 'Chemical', '-', (148, 150))	('SImax < SIQ75', 'Var', (168, 181))	('SImax > SIQ95', 'Var', (140, 153))	('SI', 'Chemical', '-', (40, 42))
15127	33057152	Minimal requirements for an aberrant junction to be included were: SI >= 0.1, AQ >= 0.2, and CQ >= 0.5 in at least one case; junctions with CQ < 0.5 or AQ > 0.4 (not expressed canonical or well-expressed aberrant) in the control groups were excluded.	('AQ > 0.4', 'Var', (152, 160))	('CQ >= 0.5', 'Var', (93, 102))	('CQ < 0.5', 'Var', (140, 148))	('SI', 'Chemical', '-', (67, 69))
15129	33057152	To characterize effect of SUGP1 knockdown and SF3B1K700E overexpression, we used relative shift in maximal splice indexes:  SImax = (max(SIExp) - max(SIControl))/max(SIControl)).	('SUGP1', 'Gene', '57794', (26, 31))	('SI', 'Chemical', '-', (137, 139))	('SI', 'Chemical', '-', (124, 126))	('knockdown', 'Var', (32, 41))	('SUGP1', 'Gene', (26, 31))	('SF3B1', 'Gene', (46, 51))	('expression', 'Species', '29278', (61, 71))	('SI', 'Chemical', '-', (166, 168))	('SI', 'Chemical', '-', (150, 152))	('SF3B1', 'Gene', '23451', (46, 51))
15133	33057152	A point mutation in SUGP1 resulting in P636L amino-acid substitution was introduced using CRISPR/cas9-stimulated homology-directed repair to generate isogenic HAP1 cell lines.	('SUGP1', 'Gene', '57794', (20, 25))	('cas', 'cellular_component', 'GO:0005650', ('97', '100'))	('P636L amino-acid substitution', 'Var', (39, 68))	('homology-directed repair', 'biological_process', 'GO:0000724', ('113', '137'))	('HAP1', 'Gene', '9001', (159, 163))	('SUGP1', 'Gene', (20, 25))	('HAP1', 'Gene', (159, 163))	('P636L', 'Mutation', 'p.P636L', (39, 44))
15141	33057152	pCDNA3.1-Flag vectors containing wild-type and mutated SUGP1 were synthesized by Genscript Corporation.	('SUGP1', 'Gene', '57794', (55, 60))	('SUGP1', 'Gene', (55, 60))	('mutated', 'Var', (47, 54))
15142	33057152	Wild-type and mutated SF3B1, as well as BP and BP' mutants of TMEM14C and ENOSF1 constructs were previously described.	('mutated', 'Var', (14, 21))	('SF3B1', 'Gene', (22, 27))	('SF3B1', 'Gene', '23451', (22, 27))	('TMEM14C', 'Gene', (62, 69))	('ENOSF1', 'Gene', (74, 80))
15144	33057152	Proteins were transferred to nitrocellulose membranes followed by immunoblotting with specific primary antibodies for SUGP1 (1:1,000; HPA004890, Sigma), Flag (1:1,000, #3165; Sigma), and beta-actin (1:2,000; #5313; Sigma).	('SUGP1', 'Gene', '57794', (118, 123))	('1:1,000', 'Var', (159, 166))	('SUGP1', 'Gene', (118, 123))
15145	33057152	AH and MHS are inventors of a patent pending related to SUGP1 and SF3B1 mutations effects.	('mutations', 'Var', (72, 81))	('SUGP1', 'Gene', '57794', (56, 61))	('SF3B1', 'Gene', (66, 71))	('SUGP1', 'Gene', (56, 61))	('AH', 'Disease', 'MESH:D007039', (0, 2))	('SF3B1', 'Gene', '23451', (66, 71))
15151	32767982	m6A RNA modification occurs by methylation of the sixth N atom of adenine (A) in mRNAs or ncRNAs.	('methylation', 'MPA', (31, 42))	('RNA modification', 'biological_process', 'GO:0009451', ('4', '20'))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('m6A', 'Var', (0, 3))	('adenine', 'Chemical', 'MESH:D000225', (66, 73))
15154	32767982	Recent studies have shown that m6A modification acts a vital role in the diagnosis, treatment and prognosis of cancer patients as well as in carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('modification', 'Var', (35, 47))	('m6A', 'Protein', (31, 34))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))	('carcinogenesis', 'Disease', (141, 155))
15157	32767982	m6A modification can affect ncRNA splicing and maturation involved in carcinogenesis (Table 1).	('m6A modification', 'Var', (0, 16))	('maturation', 'MPA', (47, 57))	('modification', 'Var', (4, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('ncRNA splicing', 'MPA', (28, 42))	('carcinogenesis', 'Disease', (70, 84))	('affect', 'Reg', (21, 27))	('splicing', 'biological_process', 'GO:0045292', ('34', '42'))
15161	32767982	METTL3/14 depletion promotes myeloid differentiation and suppresses the progression of acute myeloid leukemia (AML).	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (87, 109))	('AML', 'Disease', 'MESH:D015470', (111, 114))	('suppresses', 'NegReg', (57, 67))	('myeloid differentiation', 'CPA', (29, 52))	('AML', 'Disease', (111, 114))	('promotes', 'PosReg', (20, 28))	('METTL3/14', 'Gene', (0, 9))	('METTL3/14', 'Gene', '56339;57721', (0, 9))	('depletion', 'Var', (10, 19))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (87, 109))	('AML', 'Phenotype', 'HP:0004808', (111, 114))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute myeloid leukemia', 'Disease', (87, 109))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))
15165	32767982	FTO shares the motifs with Fe (II)- and 2-oxoglutarate-dependent oxygenase and is related to increased fat mass.	('oxygenase', 'molecular_function', 'GO:0016701', ('65', '74'))	('increased', 'PosReg', (93, 102))	('FTO', 'Var', (0, 3))	('fat', 'Gene', (103, 106))	('Fe (II)', 'Chemical', '-', (27, 34))	('fat', 'Gene', '2195', (103, 106))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (40, 54))
15169	32767982	YTHDF1 controls pre-crossing axon guidance in the spinal cord by regulating m6A-modified Robo3.1.	('pre', 'molecular_function', 'GO:0003904', ('16', '19'))	('axon guidance', 'biological_process', 'GO:0007411', ('29', '42'))	('Robo3.1', 'MPA', (89, 96))	('YTHDF1', 'Gene', '54915', (0, 6))	('m6A-modified', 'Var', (76, 88))	('axon', 'cellular_component', 'GO:0030424', ('29', '33'))	('YTHDF1', 'Gene', (0, 6))
15171	32767982	As is known to us, the dysregulation of miRNAs is involved in various bio-behaviors, such as mouse prenatal development, immune response, inflammatory response and carcinogenesis.	('dysregulation', 'Var', (23, 36))	('mouse', 'Species', '10090', (93, 98))	('miRNAs', 'Protein', (40, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('carcinogenesis', 'Disease', (164, 178))	('immune response', 'biological_process', 'GO:0006955', ('121', '136'))	('inflammatory response', 'biological_process', 'GO:0006954', ('138', '159'))	('involved', 'Reg', (50, 58))
15173	32767982	METTL3 suppresses osteogenic processes by promoting the maturation of miR-7212-5p and downregulating its target fibroblast growth factor receptor 3 (FGFR3).	('fibroblast growth factor receptor 3', 'Gene', (112, 147))	('miR-7212-5p', 'Chemical', '-', (70, 81))	('promoting', 'PosReg', (42, 51))	('downregulating', 'NegReg', (86, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('fibroblast growth factor receptor 3', 'Gene', '2261', (112, 147))	('osteogenic processes', 'CPA', (18, 38))	('FGFR3', 'Gene', '2261', (149, 154))	('METTL3', 'Gene', (0, 6))	('suppresses', 'NegReg', (7, 17))	('miR-7212-5p', 'Var', (70, 81))	('FGFR3', 'Gene', (149, 154))	('maturation', 'CPA', (56, 66))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('112', '136'))
15174	32767982	m6A methylation can modify the maturation of miRNAs involved in cell proliferation and tumorigenesis (Fig.	('miRNAs', 'MPA', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cell proliferation', 'CPA', (64, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('tumor', 'Disease', (87, 92))	('methylation', 'Var', (4, 15))	('modify', 'Reg', (20, 26))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('m6A', 'Var', (0, 3))	('maturation', 'MPA', (31, 41))
15175	32767982	miR-25-3p acts as a pivotal role in pancreatic ductal adenocarcinoma (PDAC).	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('miR-25-3p', 'Var', (0, 9))	('pancreatic ductal adenocarcinoma', 'Disease', (36, 68))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (36, 68))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (36, 68))	('PDAC', 'Chemical', '-', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('miR-25-3p', 'Chemical', '-', (0, 9))
15177	32767982	METTL3 also enhances the binding of pri-miR-221/222 with DGCR8 involved in the proliferation of bladder cancer.	('miR-221', 'Gene', '407006', (40, 47))	('binding', 'Interaction', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('DGCR8', 'Gene', (57, 62))	('miR-221', 'Gene', (40, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))	('METTL3', 'Var', (0, 6))	('DGCR8', 'Gene', '54487', (57, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('bladder cancer', 'Disease', (96, 110))	('enhances', 'PosReg', (12, 20))
15178	32767982	m6A modification affects arsenite-induced carcinogenesis via modifying multiple miRNAs (miR-106b, miR-18a/b, miR-3607, miR-423, miR-30a, miR-320b/d/e).	('miR-18a/b', 'Gene', (98, 107))	('miR-106b', 'Gene', '406900', (88, 96))	('miR-3607', 'Gene', '100500805', (109, 117))	('miR-320b/d/e', 'Var', (137, 149))	('miR-30a', 'Gene', '407029', (128, 135))	('miR-423', 'Gene', (119, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('arsenite-induced', 'MPA', (25, 41))	('arsenite', 'Chemical', 'MESH:C015001', (25, 33))	('affects', 'Reg', (17, 24))	('modification', 'Var', (4, 16))	('modifying', 'Reg', (61, 70))	('carcinogenesis', 'Disease', (42, 56))	('miR-106b', 'Gene', (88, 96))	('miR-423', 'Gene', '494335', (119, 126))	('miR-18a/b', 'Gene', '406953', (98, 107))	('miR-30a', 'Gene', (128, 135))	('miR-3607', 'Gene', (109, 117))
15182	32767982	LncRNAs, a subgroup of non-coding RNAs over 200 nucleotides in length can be modified by m6A methylation in cancer (Fig.	('m6A methylation', 'Var', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('modified', 'Reg', (77, 85))	('methylation', 'Var', (93, 104))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
15183	32767982	m6A methylation facilitates lncRNA X-inactive specific transcript (XIST)-mediated transcriptional repression.	('XIST', 'Gene', '7503', (67, 71))	('X-inactive specific transcript', 'Gene', (35, 65))	('XIST', 'Gene', (67, 71))	('X-inactive specific transcript', 'Gene', '7503', (35, 65))	('methylation', 'Var', (4, 15))	('facilitates', 'PosReg', (16, 27))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('m6A methylation', 'Var', (0, 15))
15184	32767982	YTHDC1 preferentially recognizes the m6A residues of XIST and RBM15/15B and participates in XIST-mediated gene silencing.	('XIST', 'Gene', '7503', (53, 57))	('XIST', 'Gene', '7503', (92, 96))	('YTHDC1', 'Gene', (0, 6))	('YTHDC1', 'Gene', '91746', (0, 6))	('participates', 'Reg', (76, 88))	('XIST', 'Gene', (53, 57))	('XIST', 'Gene', (92, 96))	('RBM15', 'Gene', '64783', (62, 67))	('m6A', 'Var', (37, 40))	('gene', 'MPA', (106, 110))	('gene silencing', 'biological_process', 'GO:0016458', ('106', '120'))	('RBM15', 'Gene', (62, 67))	('preferentially', 'PosReg', (7, 21))
15199	32767982	ALKBH5 favors the invasion and metastasis of gastric cancer (GC) by demethylating lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1).	('ALKBH5', 'Gene', (0, 6))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (31, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('demethylating', 'Var', (68, 81))	('ALKBH5', 'Gene', '54890', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GC', 'Phenotype', 'HP:0012126', (61, 63))	('metastasis of gastric cancer', 'Disease', (31, 59))	('favors', 'PosReg', (7, 13))	('NEAT1', 'Gene', '283131', (132, 137))	('invasion', 'CPA', (18, 26))	('lncRNA', 'MPA', (82, 88))	('NEAT1', 'Gene', (132, 137))
15202	32767982	Minigenes of ribosomes-circRNAs (Ribo-circRNAs) can facilitate protein translation in drosophila heads and circ-ZNF609 boosts protein translation and myoblasts cell proliferation.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('ZNF609', 'Gene', (112, 118))	('protein translation', 'biological_process', 'GO:0006412', ('63', '82'))	('drosophila', 'Species', '7227', (86, 96))	('facilitate', 'PosReg', (52, 62))	('boosts', 'PosReg', (119, 125))	('ZNF609', 'Gene', '23060', (112, 118))	('protein translation', 'MPA', (126, 145))	('myoblasts cell proliferation', 'CPA', (150, 178))	('protein translation', 'MPA', (63, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('Minigenes', 'Var', (0, 9))	('protein translation', 'biological_process', 'GO:0006412', ('126', '145'))
15204	32767982	Mammalian cells can recognize the m6A modification on circRNAs to inhibit innate immunity by abrogating immune gene activation and adjuvant activity.	('abrogating', 'NegReg', (93, 103))	('Mammalian', 'Species', '9606', (0, 9))	('adjuvant activity', 'CPA', (131, 148))	('immune gene activation', 'CPA', (104, 126))	('inhibit', 'NegReg', (66, 73))	('innate immunity', 'biological_process', 'GO:0045087', ('74', '89'))	('innate immunity', 'CPA', (74, 89))	('m6A', 'Var', (34, 37))
15205	32767982	In addition, the dysregulation of circRNAs is associated with the progression of multiple cancers, such as breast cancer, gastric cancer (GC), gallbladder cancer and cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (147, 161))	('cancer', 'Disease', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gallbladder cancer', 'Disease', 'MESH:D005706', (143, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('multiple cancers', 'Disease', 'MESH:D009369', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('associated', 'Reg', (46, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('dysregulation', 'Var', (17, 30))	('gastric cancer', 'Disease', (122, 136))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('multiple cancers', 'Disease', (81, 97))	('breast cancer', 'Disease', (107, 120))	('gallbladder cancer', 'Disease', (143, 161))	('cancer', 'Disease', (155, 161))	('circRNAs', 'Gene', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (130, 136))	('GC', 'Phenotype', 'HP:0012126', (138, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', (114, 120))
15207	32767982	m6A modification can be involved in the progression of GC by regulating circRNA poliovirus receptor-related 3 (circPVRL3).	('regulating', 'Reg', (61, 71))	('involved', 'Reg', (24, 32))	('circRNA', 'MPA', (72, 79))	('GC', 'Phenotype', 'HP:0012126', (55, 57))	('poliovirus', 'Species', '138950', (80, 90))	('m6A', 'Var', (0, 3))
15209	32767982	miR-149-3p inhibits adipogenesis lineage differentiation and potentiates osteogenic lineage differentiation by targeting FTO.	('adipogenesis', 'biological_process', 'GO:0060612', ('20', '32'))	('inhibits', 'NegReg', (11, 19))	('potentiates', 'PosReg', (61, 72))	('miR-149-3p', 'Var', (0, 10))	('osteogenic lineage differentiation', 'CPA', (73, 107))	('miR-149-3p', 'Chemical', '-', (0, 10))	('adipogenesis', 'biological_process', 'GO:0045444', ('20', '32'))	('FTO', 'Gene', (121, 124))	('adipogenesis', 'MPA', (20, 32))
15214	32767982	miR-141 suppresses the proliferation of pancreatic cancer by forming the miR-141/IGF2BP2/P13K/Akt axis.	('suppresses', 'NegReg', (8, 18))	('P13K', 'Var', (89, 93))	('IGF2BP2', 'Gene', '10644', (81, 88))	('Akt', 'Gene', (94, 97))	('miR-141', 'Gene', '406933', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('IGF2BP2', 'Gene', (81, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('proliferation', 'CPA', (23, 36))	('Akt', 'Gene', '207', (94, 97))	('miR-141', 'Gene', (0, 7))	('P13K', 'SUBSTITUTION', 'None', (89, 93))	('pancreatic cancer', 'Disease', (40, 57))	('miR-141', 'Gene', '406933', (0, 7))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))	('miR-141', 'Gene', (73, 80))
15227	32767982	m6A methylation serves as new biomarkers for diagnosis and prognosis in cancer.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('methylation', 'Var', (4, 15))	('m6A', 'Protein', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('cancer', 'Disease', (72, 78))
15233	32767982	m6A methylation also participates in drug resistance and cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('methylation', 'Var', (4, 15))	('participates', 'Reg', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('drug resistance', 'CPA', (37, 52))	('drug resistance', 'Phenotype', 'HP:0020174', (37, 52))	('drug resistance', 'biological_process', 'GO:0009315', ('37', '52'))	('drug resistance', 'biological_process', 'GO:0042493', ('37', '52'))	('m6A methylation', 'Var', (0, 15))
15243	32767982	The interaction between m6A methylation and ncRNAs can impact the different life activities including cancer cell proliferation, invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('interaction', 'Interaction', (4, 15))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('impact', 'Reg', (55, 61))	('methylation', 'Var', (28, 39))	('m6A', 'Protein', (24, 27))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))
15247	32364222	miR-219a-5p enhances the radiosensitivity of non-small cell lung cancer cells through targeting CD164 Lung cancer is one of the leading causes of cancer-associated mortality.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mortality', 'Disease', (164, 173))	('cancer', 'Disease', (65, 71))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (49, 71))	('Lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('radiosensitivity', 'MPA', (25, 41))	('miR-219a-5p', 'Var', (0, 11))	('mortality', 'Disease', 'MESH:D003643', (164, 173))	('Lung cancer', 'Disease', (102, 113))	('CD164', 'Gene', (96, 101))	('miR-219a-5p', 'Chemical', '-', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (107, 113))	('enhances', 'PosReg', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))
15253	32364222	miR-219a-5p expression level was negatively associated with radioresistance in NSCLC cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('radioresistance', 'CPA', (60, 75))	('miR-219a-5p', 'Var', (0, 11))	('negatively', 'NegReg', (33, 43))	('miR-219a-5p', 'Chemical', '-', (0, 11))	('NSCLC', 'Disease', (79, 84))
15256	32364222	miR-219a-5p could directly bind in the 3'UTR of CD164 and negatively regulated CD164 expression.	('expression', 'MPA', (85, 95))	('negatively regulated', 'NegReg', (58, 78))	('miR-219a-5p', 'Var', (0, 11))	('CD164', 'Gene', (79, 84))	('CD164', 'Gene', (48, 53))	('CD164', 'Gene', '8763', (48, 53))	('CD164', 'Gene', '8763', (79, 84))	('miR-219a-5p', 'Chemical', '-', (0, 11))	('bind', 'Interaction', (27, 31))
15259	32364222	Down-regulation of CD164 significantly inhibited the effect of anti-miR-219a-5p on radiosensitive A549 and H358 cells.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('effect', 'MPA', (53, 59))	('CD164', 'Gene', '8763', (19, 24))	('inhibited', 'NegReg', (39, 48))	('miR-219a-5p', 'Chemical', '-', (68, 79))	('anti-miR-219a-5p', 'Var', (63, 79))	('Down-regulation', 'NegReg', (0, 15))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('H358', 'CellLine', 'CVCL:1559', (107, 111))	('CD164', 'Gene', (19, 24))
15260	32364222	miR-219a-5p or down-regulation of CD164 could increase apoptosis and gamma-H2A histone family member X (gamma-H2AX) expression in radioresistant cells in vitro and in vivo.	('expression', 'MPA', (116, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('increase', 'PosReg', (46, 54))	('down-regulation', 'NegReg', (15, 30))	('miR-219a-5p', 'Var', (0, 11))	('CD164', 'Gene', (34, 39))	('miR-219a-5p', 'Chemical', '-', (0, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('CD164', 'Gene', '8763', (34, 39))	('gamma-H2A', 'Chemical', '-', (69, 78))	('gamma-H2A', 'Chemical', '-', (104, 113))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('apoptosis', 'CPA', (55, 64))	('gamma-H2AX', 'Gene', (104, 114))
15261	32364222	Up-regulation of CD164 could inhibit the effect of miR-219a-5p on apoptosis and gamma-H2AX expression.	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('regulation', 'biological_process', 'GO:0065007', ('3', '13'))	('gamma-H2AX', 'Protein', (80, 90))	('miR-219a-5p', 'Var', (51, 62))	('inhibit', 'NegReg', (29, 36))	('CD164', 'Gene', (17, 22))	('Up-regulation', 'PosReg', (0, 13))	('CD164', 'Gene', '8763', (17, 22))	('apoptosis', 'CPA', (66, 75))	('miR-219a-5p', 'Chemical', '-', (51, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))
15262	32364222	Our results indicated that miR-219a-5p could inhibit CD164, promote DNA damage and apoptosis and enhance irradiation-induced cytotoxicity.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('promote', 'PosReg', (60, 67))	('DNA damage', 'CPA', (68, 78))	('CD164', 'Gene', '8763', (53, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('miR-219a-5p', 'Var', (27, 38))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('inhibit', 'NegReg', (45, 52))	('enhance', 'PosReg', (97, 104))	('miR-219a-5p', 'Chemical', '-', (27, 38))	('apoptosis', 'CPA', (83, 92))	('cytotoxicity', 'Disease', (125, 137))	('CD164', 'Gene', (53, 58))
15272	32364222	In recent years, emerging studies indicate that dysregulation of microRNAs (miRNAs) is associated with radioresistance of many types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('associated', 'Reg', (87, 97))	('dysregulation', 'Var', (48, 61))	('microRNAs', 'Protein', (65, 74))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('radioresistance', 'CPA', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
15275	32364222	In the present study, we aimed to investigate whether the dysregulation of miR-219a-5p is involved in radioresistance of NSCLC.	('miR-219a-5p', 'Chemical', '-', (75, 86))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('dysregulation', 'Var', (58, 71))	('involved', 'Reg', (90, 98))	('miR-219a-5p', 'Gene', (75, 86))
15293	32364222	HEK293 cells were co-transfected with 100 nM miR-219-5p inhibitor, miR-219-5p mimics or miR-NC, 250 ng pGL3 reporter vector carrying CD164-3'UTR with WT or mutant miR-219-5p binding site, 25 ng of the phRL-SV40 control vector (Promega, Madison, WI, U.S.A.) in 24-well plates.	('miR', 'Gene', (88, 91))	('pGL', 'molecular_function', 'GO:0004598', ('103', '106'))	('CD164', 'Gene', (133, 138))	('miR-219-5p', 'Chemical', '-', (67, 77))	('binding', 'molecular_function', 'GO:0005488', ('174', '181'))	('CD164', 'Gene', '8763', (133, 138))	('miR-219-5p', 'Chemical', '-', (163, 173))	('miR-219-5p', 'Chemical', '-', (45, 55))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('mutant', 'Var', (156, 162))	('miR', 'Gene', '220972', (163, 166))	('miR', 'Gene', (163, 166))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))	('miR', 'Gene', '220972', (88, 91))
15310	32364222	A total of 4 x 106 A549 radioresistant cells transfected with miR-219a-5p and pcDNA-CD164 were injected into the mouse mammary fat pads to develop xenograft tumors.	('miR-219a-5p', 'Var', (62, 73))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('CD164', 'Gene', '8763', (84, 89))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('miR-219a-5p', 'Chemical', '-', (62, 73))	('develop', 'PosReg', (139, 146))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mouse', 'Species', '10090', (113, 118))	('CD164', 'Gene', (84, 89))
15315	32364222	The results showed that miR-219a-5p expression in serum and lung tissue of tumor patients was significantly lower than that in matched control samples (Figure 1A,C).	('miR-219a-5p', 'Var', (24, 35))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('miR-219a-5p', 'Chemical', '-', (24, 35))	('lower', 'NegReg', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
15316	32364222	In addition, miR-219a-5p expression in serum and lung tissue of radioresistant patients was significantly lower than that in radiosensitive samples (Figure 1B,D).	('radioresistant', 'Disease', (64, 78))	('lower', 'NegReg', (106, 111))	('expression', 'MPA', (25, 35))	('miR-219a-5p', 'Chemical', '-', (13, 24))	('patients', 'Species', '9606', (79, 87))	('miR-219a-5p', 'Var', (13, 24))
15317	32364222	We also determined the cell viabilities and expression levels of miR-219a-5p in a series of NSCLC cell lines after 5 Gy of gamma-ray irradiation.	('miR-219a-5p', 'Chemical', '-', (65, 76))	('miR-219a-5p', 'Var', (65, 76))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('NSCLC', 'Disease', (92, 97))
15318	32364222	We revealed that the expression level of miR-219a-5p was negatively correlated with the viability of NSCLC cells treated by irradiation (Figure 1E,F).	('miR-219a-5p', 'Var', (41, 52))	('NSCLC', 'Disease', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('negatively', 'NegReg', (57, 67))	('miR-219a-5p', 'Chemical', '-', (41, 52))	('expression level', 'MPA', (21, 37))
15319	32364222	The results indicated that dysregulation of miR-219a-5p expression may be associated with radioresistance in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('miR-219a-5p', 'Chemical', '-', (44, 55))	('radioresistance', 'CPA', (90, 105))	('dysregulation', 'Var', (27, 40))	('miR-219a-5p', 'Gene', (44, 55))	('NSCLC', 'Disease', (109, 114))	('associated', 'Reg', (74, 84))
15324	32364222	In Figure 2C, we showed that miR-219a-5p expression was decreased in radioresistant A549-RR and H358-RR cells, compared with the parental radiosensitive cells.	('miR-219a-5p', 'Chemical', '-', (29, 40))	('expression', 'MPA', (41, 51))	('decreased', 'NegReg', (56, 65))	('miR-219a-5p', 'Var', (29, 40))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('H358-RR', 'CellLine', 'CVCL:1559', (96, 103))	('radioresistant', 'CPA', (69, 83))
15326	32364222	As shown in Figure 2D,E, transfection of miR-219a-5p significantly decreased cell viability under basal condition and reduced cell viability in response to different doses of irradiation.	('cell viability', 'CPA', (126, 140))	('miR-219a-5p', 'Var', (41, 52))	('reduced', 'NegReg', (118, 125))	('transfection', 'Var', (25, 37))	('miR-219a-5p', 'Chemical', '-', (41, 52))	('decreased', 'NegReg', (67, 76))	('cell viability', 'CPA', (77, 91))
15330	32364222	The results indicated that miR-219a-5p could regulate radiosensitivity in NSCLC cells.	('miR-219a-5p', 'Var', (27, 38))	('regulate', 'Reg', (45, 53))	('NSCLC', 'Disease', (74, 79))	('radiosensitivity', 'CPA', (54, 70))	('miR-219a-5p', 'Chemical', '-', (27, 38))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
15331	32364222	To investigate the mechanism of miR-219a-5p-induced regulation of radiosensitivity of NSCLC cells, we performed informatics analysis.	('miR-219a-5p', 'Chemical', '-', (32, 43))	('NSCLC', 'Disease', (86, 91))	('miR-219a-5p-induced', 'Var', (32, 51))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))
15332	32364222	We found that there was a putative binding site of miR-219a-5p in the 3'UTR of CD164 (Figure 3A).	('binding', 'Interaction', (35, 42))	('miR-219a-5p', 'Var', (51, 62))	('CD164', 'Gene', (79, 84))	('CD164', 'Gene', '8763', (79, 84))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('miR-219a-5p', 'Chemical', '-', (51, 62))
15335	32364222	Transfection of miR-219a-5p in radioresistant A549-RR and H358-RR cells induced a significant decrease in CD164 mRNA (Figure 3D) and protein (Figure 3E) expression.	('miR-219a-5p', 'Chemical', '-', (16, 27))	('CD164', 'Gene', (106, 111))	('CD164', 'Gene', '8763', (106, 111))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('A549', 'CellLine', 'CVCL:0023', (46, 50))	('H358-RR', 'CellLine', 'CVCL:1559', (58, 65))	('miR-219a-5p', 'Var', (16, 27))	('decrease', 'NegReg', (94, 102))
15336	32364222	Luciferase reporter assay showed that in radioresistant A549-RR and H358-RR cells, miR-219a-5p could decrease CD164-WT luciferase activity but not CD164-MUT luciferase activity (Figure 3F,G).	('luciferase activity', 'molecular_function', 'GO:0050248', ('157', '176'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('157', '176'))	('miR-219a-5p', 'Var', (83, 94))	('CD164', 'Gene', '8763', (147, 152))	('decrease', 'NegReg', (101, 109))	('miR-219a-5p', 'Chemical', '-', (83, 94))	('luciferase activity', 'molecular_function', 'GO:0047077', ('119', '138'))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('CD164', 'Gene', (147, 152))	('H358-RR', 'CellLine', 'CVCL:1559', (68, 75))	('luciferase activity', 'molecular_function', 'GO:0045289', ('119', '138'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('119', '138'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('157', '176'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('119', '138'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('157', '176'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('119', '138'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('157', '176'))	('CD164', 'Gene', '8763', (110, 115))	('CD164', 'Gene', (110, 115))	('activity', 'MPA', (130, 138))
15337	32364222	The results indicated that miR-219a-5p directly regulated CD164 mRNA level.	('miR-219a-5p', 'Var', (27, 38))	('CD164', 'Gene', (58, 63))	('miR-219a-5p', 'Chemical', '-', (27, 38))	('CD164', 'Gene', '8763', (58, 63))	('regulated', 'Reg', (48, 57))
15339	32364222	We showed that miR-219a-5p-induced decrease in cell viability in irradiation-treated cells was inhibited by pcDNA-CD164 (Figure 3H,I).	('miR-219a-5p', 'Chemical', '-', (15, 26))	('inhibited', 'NegReg', (95, 104))	('decrease', 'NegReg', (35, 43))	('miR-219a-5p-induced', 'Var', (15, 34))	('CD164', 'Gene', (114, 119))	('cell viability', 'CPA', (47, 61))	('CD164', 'Gene', '8763', (114, 119))
15341	32364222	These results suggested that miR-219a-5p enhanced radiosensitivity through inhibition of CD164 via directly targeting its 3'UTR.	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (41, 66))	('miR-219a-5p', 'Chemical', '-', (29, 40))	('enhanced', 'PosReg', (41, 49))	('CD164', 'Gene', (89, 94))	('inhibition', 'NegReg', (75, 85))	('radiosensitivity', 'CPA', (50, 66))	('CD164', 'Gene', '8763', (89, 94))	('miR-219a-5p', 'Var', (29, 40))	('targeting', 'Reg', (108, 117))
15342	32364222	Transfection of anti-miR-219a-5p in radiosensitive A549-RS and H358-RS cells induced a significant increase in CD164 mRNA (Figure 4A) and protein (Figure 4B) levels.	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('miR-219a-5p', 'Chemical', '-', (21, 32))	('CD164', 'Gene', (111, 116))	('increase', 'PosReg', (99, 107))	('anti-miR-219a-5p', 'Var', (16, 32))	('CD164', 'Gene', '8763', (111, 116))	('H358-RS', 'CellLine', 'CVCL:1559', (63, 70))
15343	32364222	Luciferase reporter assay showed that in radiosensitive A549-RS and H358-RS cells, anti-miR-219a-5p could increase CD164-WT luciferase activity but not CD164-MUT luciferase activity (Figure 4C,D).	('CD164', 'Gene', '8763', (115, 120))	('luciferase activity', 'molecular_function', 'GO:0047077', ('162', '181'))	('CD164', 'Gene', (115, 120))	('CD164', 'Gene', '8763', (152, 157))	('luciferase activity', 'molecular_function', 'GO:0050248', ('124', '143'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('162', '181'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('124', '143'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('162', '181'))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('activity', 'MPA', (135, 143))	('CD164', 'Gene', (152, 157))	('luciferase activity', 'molecular_function', 'GO:0050248', ('162', '181'))	('miR-219a-5p', 'Chemical', '-', (88, 99))	('luciferase activity', 'molecular_function', 'GO:0050397', ('162', '181'))	('anti-miR-219a-5p', 'Var', (83, 99))	('increase', 'PosReg', (106, 114))	('luciferase activity', 'molecular_function', 'GO:0047077', ('124', '143'))	('H358-RS', 'CellLine', 'CVCL:1559', (68, 75))	('luciferase activity', 'molecular_function', 'GO:0045289', ('124', '143'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('124', '143'))
15345	32364222	We showed that anti-miR-219a-5p-induced increase in cell viability in irradiation-treated cells was inhibited by shCD164 (Figure 4E,F).	('shCD164', 'Chemical', '-', (113, 120))	('anti-miR-219a-5p-induced', 'Var', (15, 39))	('cell viability', 'CPA', (52, 66))	('increase', 'PosReg', (40, 48))	('shCD164', 'Var', (113, 120))	('inhibited', 'NegReg', (100, 109))	('miR-219a-5p', 'Chemical', '-', (20, 31))
15347	32364222	These results suggested that inhibition of miR-219a-5p promoted radioresistance in NSCLC cells through regulation of CD164.	('NSCLC', 'Disease', (83, 88))	('miR-219a-5p', 'Gene', (43, 54))	('regulation', 'Reg', (103, 113))	('radioresistance in', 'CPA', (64, 82))	('miR-219a-5p', 'Chemical', '-', (43, 54))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('CD164', 'Gene', (117, 122))	('promoted', 'PosReg', (55, 63))	('CD164', 'Gene', '8763', (117, 122))	('inhibition', 'Var', (29, 39))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))
15350	32364222	In the miR-219a-5p transfection group, the tumor size and weight significantly decreased after irradiation, compared with mice treated by irradiation alone.	('miR-219a-5p transfection', 'Var', (7, 31))	('mice', 'Species', '10090', (122, 126))	('decreased', 'NegReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miR-219a-5p', 'Chemical', '-', (7, 18))	('tumor', 'Disease', (43, 48))
15351	32364222	In addition, transfection of pcDNA-CD164 significantly inhibited the effect of miR-219a-5p on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('transfection', 'Var', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CD164', 'Gene', '8763', (35, 40))	('tumor', 'Disease', (94, 99))	('CD164', 'Gene', (35, 40))	('miR-219a-5p', 'Chemical', '-', (79, 90))	('effect', 'MPA', (69, 75))	('inhibited', 'NegReg', (55, 64))
15353	32364222	miR-219a-5p significantly increased the mRNA and protein levels of CD164 in tumors.	('CD164', 'Gene', (67, 72))	('miR-219a-5p', 'Var', (0, 11))	('CD164', 'Gene', '8763', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (26, 35))	('miR-219a-5p', 'Chemical', '-', (0, 11))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))
15354	32364222	These results indicated that miR-219a-5p increased the radiosensitivity of NSCLC cells through targeting CD164 in vivo.	('CD164', 'Gene', (105, 110))	('increased', 'PosReg', (41, 50))	('miR-219a-5p', 'Chemical', '-', (29, 40))	('CD164', 'Gene', '8763', (105, 110))	('radiosensitivity', 'CPA', (55, 71))	('targeting', 'Reg', (95, 104))	('NSCLC', 'Disease', (75, 80))	('miR-219a-5p', 'Var', (29, 40))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
15356	32364222	As shown in Figure 6A,B, miR-219a-5p transfection significantly increased irradiation-induced apoptosis in radioresistant A549-RR and H358-RR cells.	('miR-219a-5p transfection', 'Var', (25, 49))	('increased irradiation', 'Phenotype', 'HP:0011133', (64, 85))	('irradiation-induced apoptosis', 'CPA', (74, 103))	('H358-RR', 'CellLine', 'CVCL:1559', (134, 141))	('miR-219a-5p', 'Chemical', '-', (25, 36))	('increased', 'PosReg', (64, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))
15357	32364222	Up-regulation of CD164 repressed miR-219a-5p-induced effect on apoptosis (Figure 6A,B).	('regulation', 'biological_process', 'GO:0065007', ('3', '13'))	('miR-219a-5p', 'Chemical', '-', (33, 44))	('miR-219a-5p-induced', 'Var', (33, 52))	('CD164', 'Gene', (17, 22))	('Up-regulation', 'PosReg', (0, 13))	('CD164', 'Gene', '8763', (17, 22))	('apoptosis', 'CPA', (63, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
15358	32364222	Overexpression of CD164 could also decrease apoptosis induced by irradiation in radioresistant A549-RR and H358-RR cells (Figure 6A,B).	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('H358-RR', 'CellLine', 'CVCL:1559', (107, 114))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('CD164', 'Gene', (18, 23))	('decrease', 'NegReg', (35, 43))	('CD164', 'Gene', '8763', (18, 23))	('Overexpression', 'Var', (0, 14))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
15359	32364222	In xenograft tumor tissues, irradiation-induced increase in Bax expression and decrease in Bcl-2 expression were enhanced by miR-219a-5p (Figure 6C-E).	('tumor', 'Disease', (13, 18))	('Bax', 'Gene', (60, 63))	('miR-219a-5p', 'Chemical', '-', (125, 136))	('decrease', 'NegReg', (79, 87))	('Bax', 'Gene', '581', (60, 63))	('Bcl-2', 'Gene', '596', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('miR-219a-5p', 'Var', (125, 136))	('Bcl-2', 'molecular_function', 'GO:0015283', ('91', '96'))	('Bcl-2', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('enhanced', 'PosReg', (113, 121))	('increase', 'PosReg', (48, 56))
15360	32364222	This effect of miR-219a-5p was inhibited by CD164 (Figure 6C-E).	('CD164', 'Gene', '8763', (44, 49))	('CD164', 'Gene', (44, 49))	('miR-219a-5p', 'Chemical', '-', (15, 26))	('miR-219a-5p', 'Var', (15, 26))
15364	32364222	Furthermore, miR-219a-5p-induced increase in gamma-H2AX expression was significantly inhibited by up-regulation of CD164 (Figure 6F-I).	('CD164', 'Gene', '8763', (115, 120))	('gamma-H2AX', 'Protein', (45, 55))	('inhibited', 'NegReg', (85, 94))	('miR-219a-5p', 'Chemical', '-', (13, 24))	('increase', 'PosReg', (33, 41))	('up-regulation', 'PosReg', (98, 111))	('expression', 'MPA', (56, 66))	('miR-219a-5p-induced', 'Var', (13, 32))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('CD164', 'Gene', (115, 120))
15367	32364222	Emerging evidence supports the notion that dysregulation of miRNAs plays an important role in the occurrence of radioresistance in NSCLC.	('dysregulation', 'Var', (43, 56))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('NSCLC', 'Disease', (131, 136))	('radioresistance', 'CPA', (112, 127))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))
15368	32364222	However, the mechanism of miRNAs dysregulation-induced radioresistance in NSCLC is far from being completely understood.	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('dysregulation-induced', 'Var', (33, 54))	('NSCLC', 'Disease', (74, 79))	('radioresistance', 'CPA', (55, 70))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
15373	32364222	In the present study, we verified the expression pattern of miR-219a-5p in patients and identified that miR-219a-5p levels in serum and lung tissues in tumor patients were increased, compared with matched control samples.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('increased', 'PosReg', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('miR-219a-5p', 'Chemical', '-', (60, 71))	('miR-219a-5p', 'Var', (104, 115))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', (152, 157))	('levels', 'MPA', (116, 122))	('patients', 'Species', '9606', (158, 166))	('miR-219a-5p', 'Chemical', '-', (104, 115))
15374	32364222	Moreover, miR-219a-5p levels in serum and lung tissues in radioresistant patients were higher than that in radiosensitive patients.	('radioresistant', 'Disease', (58, 72))	('miR-219a-5p', 'Var', (10, 21))	('patients', 'Species', '9606', (122, 130))	('miR-219a-5p', 'Chemical', '-', (10, 21))	('patients', 'Species', '9606', (73, 81))	('higher', 'PosReg', (87, 93))
15375	32364222	We also used cells and xenograft tumor mice to verify the role of miR-219a-5p.	('miR-219a-5p', 'Var', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('miR-219a-5p', 'Chemical', '-', (66, 77))	('tumor', 'Disease', (33, 38))	('mice', 'Species', '10090', (39, 43))
15376	32364222	We revealed that up-regulation of miR-219a-5p significantly increased the radiosensitivity in radioresistant NSCLC cells in vitro and in vivo.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('miR-219a-5p', 'Var', (34, 45))	('miR-219a-5p', 'Chemical', '-', (34, 45))	('increased', 'PosReg', (60, 69))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('NSCLC', 'Disease', (109, 114))	('up-regulation', 'PosReg', (17, 30))
15378	32364222	The results suggest that, in addition to previously reported tumor-suppressive role, miR-219a-5p also plays a role in promoting radiosensitivity in NSCLC.	('miR-219a-5p', 'Chemical', '-', (85, 96))	('NSCLC', 'Disease', (148, 153))	('radiosensitivity', 'MPA', (128, 144))	('promoting', 'PosReg', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('miR-219a-5p', 'Var', (85, 96))
15380	32364222	It is also shown that inhibition of CD164 expression in colon cancer cell line HCT116 reduces cancer cell proliferation, mobility, and metastasis in vitro and in vivo.	('inhibition', 'Var', (22, 32))	('CD164', 'Gene', (36, 41))	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('reduces', 'NegReg', (86, 93))	('CD164', 'Gene', '8763', (36, 41))	('mobility', 'CPA', (121, 129))	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
15386	32364222	miR-219a-5p could also directly regulate the mRNA 3'UTR of CD164.	("mRNA 3'UTR", 'MPA', (45, 55))	('regulate', 'Reg', (32, 40))	('miR-219a-5p', 'Var', (0, 11))	('CD164', 'Gene', (59, 64))	('CD164', 'Gene', '8763', (59, 64))	('miR-219a-5p', 'Chemical', '-', (0, 11))
15387	32364222	The results suggested that miR-219a-5p could regulate radiosensitivity in NSCLC via directly regulating CD164 expression.	('CD164', 'Gene', '8763', (104, 109))	('miR-219a-5p', 'Var', (27, 38))	('regulate', 'Reg', (45, 53))	('NSCLC', 'Disease', (74, 79))	('expression', 'MPA', (110, 120))	('miR-219a-5p', 'Chemical', '-', (27, 38))	('radiosensitivity', 'MPA', (54, 70))	('CD164', 'Gene', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('regulating', 'Reg', (93, 103))
15389	32364222	In the current study, we also examined the role of miR-219a-5p and CD164 in the regulation of apoptosis in the context of irradiation.	('CD164', 'Gene', (67, 72))	('miR-219a-5p', 'Var', (51, 62))	('CD164', 'Gene', '8763', (67, 72))	('regulation of apoptosis', 'biological_process', 'GO:0042981', ('80', '103'))	('miR-219a-5p', 'Chemical', '-', (51, 62))
15390	32364222	Our results showed that miR-219a-5p significantly enhanced irradiation-induced apoptosis in vitro and in vivo.	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('miR-219a-5p', 'Var', (24, 35))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('miR-219a-5p', 'Chemical', '-', (24, 35))	('enhanced', 'PosReg', (50, 58))	('irradiation-induced apoptosis', 'CPA', (59, 88))
15392	32364222	Overexpression of CD164 could inhibit miR-219a-5p-induced enhancement of apoptosis in response to irradiation.	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('men', 'Species', '9606', (65, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('inhibit', 'NegReg', (30, 37))	('CD164', 'Gene', (18, 23))	('miR-219a-5p', 'Chemical', '-', (38, 49))	('apoptosis', 'CPA', (73, 82))	('CD164', 'Gene', '8763', (18, 23))	('miR-219a-5p-induced', 'Var', (38, 57))	('enhancement', 'PosReg', (58, 69))
15395	32364222	Up-regulation of CD164 could inhibit miR-219a-5p-induced up-regulation of gamma-H2AX in irradiation-treated cells.	('regulation', 'biological_process', 'GO:0065007', ('3', '13'))	('miR-219a-5p', 'Chemical', '-', (37, 48))	('inhibit', 'NegReg', (29, 36))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('miR-219a-5p-induced', 'Var', (37, 56))	('CD164', 'Gene', (17, 22))	('Up-regulation', 'PosReg', (0, 13))	('up-regulation', 'PosReg', (57, 70))	('gamma-H2AX', 'Protein', (74, 84))	('CD164', 'Gene', '8763', (17, 22))
15397	32364222	In summary, our results revealed that miR-219a-5p enhanced radiosensitivity in NSCLC cells in vitro and in vivo.	('radiosensitivity', 'MPA', (59, 75))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('miR-219a-5p', 'Chemical', '-', (38, 49))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (50, 75))	('enhanced', 'PosReg', (50, 58))	('NSCLC', 'Disease', (79, 84))	('miR-219a-5p', 'Var', (38, 49))
15398	32364222	miR-219a-5p could inhibit CD164, promote DNA damage and apoptosis and enhance irradiation-induced cytotoxicity (Figure 7).	('inhibit', 'NegReg', (18, 25))	('promote', 'PosReg', (33, 40))	('CD164', 'Gene', (26, 31))	('cytotoxicity', 'Disease', (98, 110))	('miR-219a-5p', 'Var', (0, 11))	('enhance', 'PosReg', (70, 77))	('DNA damage', 'CPA', (41, 51))	('CD164', 'Gene', '8763', (26, 31))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('miR-219a-5p', 'Chemical', '-', (0, 11))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))
15437	32430670	In contrast, coarse spiculations, thickened bronchovascular bundles and a low proportion of ground glass attenuation in the tumour are associated with a higher incidence of lymph node metastases and vascular invasion.	('metastases', 'Disease', (184, 194))	('coarse spiculations', 'Var', (13, 32))	('metastases', 'Disease', 'MESH:D009362', (184, 194))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('bronchovascular bundles', 'CPA', (44, 67))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('vascular invasion', 'CPA', (199, 216))	('tumour', 'Disease', (124, 130))
15439	32430670	The presence of a concave cut or notch in the margin of the tumour is also considered an unfavourable prognostic indicator.	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('notch', 'Var', (33, 38))	('tumour', 'Disease', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))
15474	32181989	Anaplastic lymphoma kinase (ALK) was first discovered in 1994 in anaplastic large cell lymphoma (ALCL).1 Subsequent studies have found that inflammatory myofibroblastic tumors and neuroblastomas are associated with ALK gene mutations.2 In 2007, Soda et al.	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('neuroblastomas', 'Phenotype', 'HP:0003006', (180, 194))	('ALK', 'Gene', '238', (28, 31))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (65, 95))	('neuroblastomas', 'Disease', (180, 194))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (140, 175))	('ALK', 'Gene', (28, 31))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('neuroblastomas', 'Disease', 'MESH:D009447', (180, 194))	('cell lymphoma', 'Phenotype', 'HP:0012191', (82, 95))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (153, 175))	('lymphoma', 'Disease', (11, 19))	('ALK', 'Gene', '238', (215, 218))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('lymphoma', 'Disease', 'MESH:D008223', (11, 19))	('inflammatory myofibroblastic tumors', 'Disease', (140, 175))	('ALK', 'Gene', (215, 218))	('mutations.2', 'Var', (224, 235))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('lymphoma', 'Disease', (87, 95))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('ALCL', 'Phenotype', 'HP:0012193', (97, 101))	('lymphoma', 'Disease', 'MESH:D008223', (87, 95))
15487	32181989	Preliminary clinical trial results have been reported in the 2017 European Society for Medical Oncology Asia Congress.11  Adult patients (aged 18-65) with a locally advanced or metastatic malignancy harboring a genetic alteration in ALK, who had disease progression despite underlying standard chemotherapy or had no effective standard therapy, were included in this study.	('genetic alteration', 'Var', (211, 229))	('Oncology', 'Phenotype', 'HP:0002664', (95, 103))	('malignancy', 'Disease', (188, 198))	('ALK', 'Gene', (233, 236))	('patients', 'Species', '9606', (128, 136))	('malignancy', 'Disease', 'MESH:D009369', (188, 198))	('ALK', 'Gene', '238', (233, 236))
15518	32181989	ALK positivity in patients with mesothelioma was confirmed by immunohistochemistry.	('mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('positivity', 'Var', (4, 14))	('ALK', 'Gene', (0, 3))	('mesothelioma', 'Disease', (32, 44))	('patients', 'Species', '9606', (18, 26))	('ALK', 'Gene', '238', (0, 3))
15530	32181989	Grade 3 elevated alkaline phosphatase and glutamyl transpeptidase (>2.0-5.0 x upper normal [ULN]) occurred in a patient who was treated with CT-707450 mg once a day.	('elevated', 'PosReg', (8, 16))	('patient', 'Species', '9606', (112, 119))	('phosphatase', 'molecular_function', 'GO:0016791', ('26', '37'))	('elevated alkaline phosphatase', 'Phenotype', 'HP:0003155', (8, 37))	('glutamyl transpeptidase', 'Enzyme', (42, 65))	('CT-707450', 'Chemical', '-', (141, 150))	('alkaline phosphatase', 'MPA', (17, 37))	('CT-707450 mg', 'Var', (141, 153))
15549	32181989	Patient 2010 had a temporal lobe metastasis, and the metastasis was significantly reduced after taking CT-707600 mg once a day for one week.	('CT-707600 mg', 'Var', (103, 115))	('reduced', 'NegReg', (82, 89))	('temporal lobe metastasis', 'CPA', (19, 43))	('Patient', 'Species', '9606', (0, 7))	('CT-707600', 'Chemical', '-', (103, 112))
15564	32181989	Preclinical studies have shown that CT-707 has a higher inhibitory activity against mutant kinases than crizotinib (CT-707 IC50 = 3.8 nM; crizotinibIC50 = 15.9 nM).	('CT-707', 'Chemical', '-', (116, 122))	('CT-707', 'Chemical', '-', (36, 42))	('inhibitory activity', 'MPA', (56, 75))	('mutant', 'Var', (84, 90))	('crizotinibIC50', 'Chemical', '-', (138, 152))	('higher', 'PosReg', (49, 55))	('crizotinib', 'Chemical', 'MESH:D000077547', (104, 114))	('crizotinib', 'Chemical', 'MESH:D000077547', (138, 148))
15565	32181989	The kinase inhibition studies of four ALK mutant kinases expressed by eukaryotic insect expression systems revealed that CT-707 more effectively inhibits four common crizotinib-resistant ALK kinase mutants, including ALK L1196M, ALK F1174L, ALK G1296S, and ALK R1275Q in vitro.	('ALK', 'Gene', (229, 232))	('ALK', 'Gene', '238', (38, 41))	('crizotinib', 'Chemical', 'MESH:D000077547', (166, 176))	('ALK', 'Gene', '238', (187, 190))	('R1275Q', 'Mutation', 'rs113994087', (261, 267))	('ALK', 'Gene', (38, 41))	('ALK', 'Gene', (187, 190))	('ALK', 'Gene', '238', (241, 244))	('L1196M', 'Var', (221, 227))	('ALK', 'Gene', '238', (257, 260))	('ALK', 'Gene', (257, 260))	('ALK', 'Gene', (241, 244))	('L1196M', 'Mutation', 'rs1057519784', (221, 227))	('G1296S', 'Mutation', 'p.G1296S', (245, 251))	('R1275Q', 'Var', (261, 267))	('ALK', 'Gene', '238', (217, 220))	('G1296S', 'Var', (245, 251))	('F1174L', 'Mutation', 'rs863225281', (233, 239))	('F1174L', 'Var', (233, 239))	('CT-707', 'Chemical', '-', (121, 127))	('ALK', 'Gene', (217, 220))	('ALK', 'Gene', '238', (229, 232))	('inhibits', 'NegReg', (145, 153))
15575	32181989	In conclusion, the results of this study suggest that CT-707 is effective in Chinese patients with tumors harboring ALK rearrangements.	('rearrangements', 'Var', (120, 134))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('CT-707', 'Chemical', '-', (54, 60))	('ALK', 'Gene', (116, 119))	('patients', 'Species', '9606', (85, 93))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('ALK', 'Gene', '238', (116, 119))	('CT-707', 'Var', (54, 60))
15596	31358815	It is easy to understand that the T cell immunity co-stimulatory genes may act as tumor suppressors because the stimulation of T cell activity by such genes can enhance the anti-tumor immunity of the tumor microenvironment (TME).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (178, 183))	('stimulation', 'PosReg', (112, 123))	('enhance', 'PosReg', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('genes', 'Var', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
15600	31358815	The underlying biological mechanisms may include multiple possibilities, such as 1) PD-1 activation increases cancer cell apoptosis through upregulation of pro-apoptotic proteins such as BIM; 2) PD-1 activation impedes cancer cell cycle progression at the G1-S checkpoint through multiple complex mechanisms, including the upregulation of the G1 phase inhibitor p15INK4 and indirectly increasing inhibition of cyclin-dependent kinase 2.	('impedes', 'NegReg', (211, 218))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('cell cycle', 'biological_process', 'GO:0007049', ('226', '236'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('PD-1', 'Gene', (195, 199))	('PD-1 activation increases cancer', 'Disease', (84, 116))	('cyclin-dependent kinase 2', 'Gene', '100154715', (410, 435))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cyclin-dependent kinase 2', 'Gene', (410, 435))	('inhibition', 'MPA', (396, 406))	('cyclin', 'molecular_function', 'GO:0016538', ('410', '416'))	('cancer', 'Disease', (110, 116))	('upregulation', 'PosReg', (323, 335))	('G1-S checkpoint', 'biological_process', 'GO:0000075', ('256', '271'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('PD-1 activation increases cancer', 'Disease', 'MESH:D010300', (84, 116))	('p15INK4', 'Var', (362, 369))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('G1 phase', 'biological_process', 'GO:0051318', ('343', '351'))
15608	31358815	The expression of each of the 31 genes did not change significantly across the 1103 CCLE cancer cell lines stratified by the overall mutation status of the set of 31 immune coinhibitory/costimulatory genes (Fig.	('cancer', 'Disease', (89, 95))	('mutation', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
15616	31358815	The functional impact of knocking down the 31 immune coinhibitory/costimulatory genes (Table 1) on tumor survival was further analyzed by using the RNAi screening data from the cancer dependency map project that performed genome-wide scale loss-of-function screens in diverse human cancer cell lines.	('tumor', 'Disease', (99, 104))	('cancer', 'Disease', (177, 183))	('knocking down', 'Var', (25, 38))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer dependency', 'Disease', 'MESH:D009369', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('RNAi', 'biological_process', 'GO:0016246', ('148', '152'))	('loss-of-function', 'NegReg', (240, 256))	('human', 'Species', '9606', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer dependency', 'Disease', (177, 194))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Disease', (282, 288))
15632	31358815	5, higher expressions of Immu6Metagene signature were significantly associated with prolonged OS (overall survival) in breast (Fig.	('Immu6Metagene', 'Chemical', '-', (25, 38))	('higher', 'PosReg', (3, 9))	('Immu6Metagene', 'Var', (25, 38))	('expressions', 'MPA', (10, 21))
15635	31358815	In addition, higher expressions of Immu6Metagene signature were significantly associated with prolonged progression-free survival (PFS) or recurrence-free survival (RFS) in breast (Fig.	('recurrence-free survival', 'CPA', (139, 163))	('Immu6Metagene', 'Chemical', '-', (35, 48))	('Immu6Metagene', 'Var', (35, 48))	('progression-free survival', 'CPA', (104, 129))	('expressions', 'MPA', (20, 31))	('higher', 'PosReg', (13, 19))	('prolonged', 'PosReg', (94, 103))
15647	31358815	Because the higher and lower expression levels of the Immu6Metagene signature separated the low-risk group with good survival outcome from the high-risk group with poor survival outcome, it is interesting to investigate whether there were significant pathway activity changes between the low risk group with high Immu6Metagene expression and the high-risk group with low Immu6Metagene expression.	('high Immu6Metagene expression', 'Var', (308, 337))	('activity', 'MPA', (259, 267))	('Immu6Metagene', 'Chemical', '-', (54, 67))	('expression levels', 'MPA', (29, 46))	('Immu6Metagene', 'Chemical', '-', (371, 384))	('changes', 'Reg', (268, 275))	('Immu6Metagene', 'Chemical', '-', (313, 326))	('lower', 'NegReg', (23, 28))
15650	31358815	As for the tumors of the CESC cohort, interferon alpha (IFNalpha) and gamma (IFNgamma) responses and apoptosis of cancer cells were significantly elevated while the oncogenesis related pathways of glycolysis, MYC signaling, TGF-beta signaling, angiogenesis, EMT, hypoxia and mitotic process were significantly inhibited in the patients of the high Immu6Metagene signature expression compared to the low expression (Fig.	('interferon alpha (IFNalpha) and gamma (IFNgamma)', 'Gene', '3439', (38, 86))	('signaling', 'biological_process', 'GO:0023052', ('233', '242'))	('EMT', 'biological_process', 'GO:0001837', ('258', '261'))	('high Immu6Metagene', 'Var', (343, 361))	('oncogenesis', 'biological_process', 'GO:0007048', ('165', '176'))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('oncogenesis related pathways', 'Pathway', (165, 193))	('apoptosis', 'CPA', (101, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('elevated', 'PosReg', (146, 154))	('hypoxia', 'Disease', (263, 270))	('glycolysis', 'MPA', (197, 207))	('angiogenesis', 'biological_process', 'GO:0001525', ('244', '256'))	('mitotic process', 'CPA', (275, 290))	('MYC signaling', 'MPA', (209, 222))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('glycolysis', 'biological_process', 'GO:0006096', ('197', '207'))	('signaling', 'biological_process', 'GO:0023052', ('213', '222'))	('hypoxia', 'Disease', 'MESH:D000860', (263, 270))	('EMT', 'CPA', (258, 261))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('inhibited', 'NegReg', (310, 319))	('angiogenesis', 'CPA', (244, 256))	('patients', 'Species', '9606', (327, 335))	('TGF-beta signaling', 'MPA', (224, 242))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('interferon alpha (IFNalpha) and gamma (IFNgamma', 'Gene', (38, 85))	('Immu6Metagene', 'Chemical', '-', (348, 361))	('tumors', 'Disease', (11, 17))	('cancer', 'Disease', (114, 120))
15652	31358815	Interestingly, these three types of cancers had a common set of five oncogenesis related pathways that were significantly inhibited in the tumors of the good prognostic patients with high Immu6Metagene signature expression.	('oncogenesis related pathways', 'Pathway', (69, 97))	('patients', 'Species', '9606', (169, 177))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('inhibited', 'NegReg', (122, 131))	('cancers', 'Disease', (36, 43))	('oncogenesis', 'biological_process', 'GO:0007048', ('69', '80'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Immu6Metagene', 'Chemical', '-', (188, 201))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('high', 'Var', (183, 187))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
15654	31358815	These analyses indicated that higher expression of the Immu6Metagene signature could be associated with the suppressed activities of the above five oncogenic pathways, which may contribute to the good survival outcome in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('Immu6Metagene', 'Chemical', '-', (55, 68))	('cancer', 'Disease', (221, 227))	('Immu6Metagene', 'Var', (55, 68))	('higher', 'PosReg', (30, 36))	('patients', 'Species', '9606', (228, 236))	('contribute', 'Reg', (178, 188))	('suppressed', 'NegReg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('expression', 'MPA', (37, 47))	('oncogenic pathways', 'Pathway', (148, 166))	('activities', 'MPA', (119, 129))
15691	31358815	Therefore, the role of CEACAM1 in cancer cells may be different from its role of inhibiting anti-tumor immune responses in T cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (97, 102))	('CEACAM1', 'Var', (23, 30))	('cancer', 'Disease', (34, 40))
15699	31358815	RNAi experiments followed up by NGS (next generation sequencing) showed that the cancer cells with CTLA4 knocked down gained proliferation advantages (Fig.	('CTLA4', 'Gene', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('knocked down', 'Var', (105, 117))	('proliferation advantages', 'CPA', (125, 149))
15716	31358815	The knockdown of LRIG1 caused the more favorable proliferation of the corresponding 22 cancer cell lines (Figs 2 and 3).	('LRIG1', 'Gene', (17, 22))	('cancer', 'Disease', (87, 93))	('more', 'PosReg', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('knockdown', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
15720	31358815	In addition, this study suggested that PDCD1LG2 (PD-L2) and TNFRSF18 could be the suppressor of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TNFRSF18', 'Gene', (60, 68))	('tumor', 'Disease', (96, 101))	('PDCD1LG2', 'Var', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
15743	31358815	This was demonstrated by the experiment revealing that Lrig1 KO mice developed higher grade gliomas than did wild-type mice.	('mice', 'Species', '10090', (119, 123))	('Lrig1 KO', 'Var', (55, 63))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('mice', 'Species', '10090', (64, 68))
15744	31358815	Reciprocally, the ectopic expression of LRIG1 in the high-grade human glioma cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro.	('human', 'Species', '9606', (64, 69))	('glioma', 'Disease', (70, 76))	('ectopic expression', 'Var', (18, 36))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('decreased', 'NegReg', (87, 96))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('reduced', 'NegReg', (169, 176))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('cell migration', 'biological_process', 'GO:0016477', ('177', '191'))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('cell migration in vitro', 'CPA', (177, 200))	('LRIG1', 'Gene', (40, 45))	('mice', 'Species', '10090', (152, 156))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
15747	31358815	However, previous research did show that expression of PD-L2 on the tumor cells promotes CD8 T cell-mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity.	('tumor', 'Disease', (68, 73))	('CD8', 'Gene', (89, 92))	('PD-L2', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('CD8', 'Gene', '925', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('expression', 'Var', (41, 51))	('promotes', 'PosReg', (80, 88))	('tumor', 'Disease', (122, 127))
15750	31358815	Yet, novel tumor suppressor function of TNFRSF18 had begun to be uncovered especially in the case of multiple myeloma, which is based on the observation that the tumor cell proliferation was significantly inhibited both in vitro and in vivo in mice injected with TNFRSF18 compared to the empty control.	('inhibited', 'NegReg', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mice', 'Species', '10090', (244, 248))	('TNFRSF18', 'Gene', (40, 48))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (162, 167))	('TNFRSF18', 'Var', (263, 271))	('multiple myeloma', 'Disease', 'MESH:D009101', (101, 117))	('multiple myeloma', 'Phenotype', 'HP:0006775', (101, 117))	('multiple myeloma', 'Disease', (101, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
15762	31358815	Previous research showed that melanoma contains the most mutations and hence - in theory - can be addressed by the broadest CD8 TCR repertoire.	('TCR', 'biological_process', 'GO:0006283', ('128', '131'))	('mutations', 'Var', (57, 66))	('CD8', 'Gene', (124, 127))	('TCR', 'cellular_component', 'GO:0042101', ('128', '131'))	('CD8', 'Gene', '925', (124, 127))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))
15766	31358815	However, these mutational and transcriptional alterations have more value as a roadmap to tumor-immune interactions rather than as true predictive biomarkers.	('alterations', 'Var', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
15768	31358815	Finally, the pathway analysis across multiple types of cancers revealed that a common set of five oncogenic pathways were significantly inhibited in the tumors of the patients with good survival outcome and high Immu6Metagene signature expression (Fig.	('high', 'Var', (207, 211))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('oncogenic pathways', 'Pathway', (98, 116))	('inhibited', 'NegReg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Immu6Metagene', 'Chemical', '-', (212, 225))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', (55, 62))
15771	31358815	found that single-agent PD-1/PD-L1 inhibition had little effect, but co-targeting TGF-beta produced a robust antitumor immune response that could prevent the development of metastasis and eliminate established metastases in a mouse model.	('tumor', 'Disease', (113, 118))	('development of metastasis', 'CPA', (158, 183))	('immune response', 'biological_process', 'GO:0006955', ('119', '134'))	('metastases', 'Disease', 'MESH:D009362', (210, 220))	('co-targeting', 'Var', (69, 81))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('prevent', 'NegReg', (146, 153))	('eliminate', 'NegReg', (188, 197))	('TGF-beta', 'Gene', (82, 90))	('metastases', 'Disease', (210, 220))	('mouse', 'Species', '10090', (226, 231))
15782	31358815	The deletion of such gene by its shRNAs resulted in the lower proportion of cancer cells expressing those shRNAs, which can be detected by NGS (next-generation-sequencing) and finally reflected by the lower score.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lower', 'NegReg', (56, 61))	('deletion', 'Var', (4, 12))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
15803	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))	('male tumor', 'Disease', (87, 97))	('expression', 'Var', (118, 128))	('TSPY1', 'Gene', (61, 66))	('TSPY1', 'Gene', '7258', (61, 66))	('TSPY1', 'Gene', '7258', (112, 117))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))
15858	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))
15888	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).	('knocked', 'Var', (8, 15))	('RAF', 'Gene', (241, 244))	('ERK', 'molecular_function', 'GO:0004707', ('255', '258'))	('mTOR', 'Gene', (227, 231))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('BCL2', 'molecular_function', 'GO:0015283', ('233', '237'))	('AKT', 'Gene', (220, 223))	('reduction', 'NegReg', (162, 171))	('mTOR', 'Gene', '2475', (227, 231))	('BCL2', 'Gene', '596', (233, 237))	('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))
15899	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))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))	('p-ERK', 'Gene', '9451', (341, 346))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('p-ERK', 'Gene', (341, 346))	('decrease', 'Var', (177, 185))	('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))	('ERK', 'molecular_function', 'GO:0004707', ('343', '346'))	('RAF', 'Gene', '22882', (329, 332))	('expression', 'MPA', (229, 239))	('MEK', 'Gene', (336, 339))	('TSPY1', 'Gene', (106, 111))	('upregulated', 'PosReg', (206, 217))	('BCL2', 'molecular_function', 'GO:0015283', ('321', '325'))	('mTOR', 'Gene', (315, 319))	('RAF', 'Gene', (329, 332))	('protein', 'cellular_component', 'GO:0003675', ('288', '295'))
15906	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))	('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))	('tumor', 'Disease', (160, 165))	('TSPY1', 'Gene', (37, 42))	('ectopic activation', 'Var', (86, 104))
15913	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))
15951	30854452	We extracted radiomics features in the MTV, penumbra, and MTV plus penumbra regions in both cohorts using The Quantitative Image Feature Engine implemented in MATLAB R2016B (The MathWorks, Natick, MA).	('R2016B', 'SUBSTITUTION', 'None', (166, 172))	('R2016B', 'Var', (166, 172))	('MTV plus penumbra', 'Disease', 'MESH:D007625', (58, 75))	('MTV plus penumbra', 'Disease', (58, 75))
15994	30155324	As a targeted therapy, crizotinib has received approval for treatment of a distinct subgroup of non-small-cell lung cancers mediated by rearrangements of ALK or ROS1 .	('mediated by', 'Reg', (124, 135))	('non-small-cell lung cancers', 'Disease', 'MESH:D002289', (96, 123))	('ROS1', 'Gene', (161, 165))	('ALK', 'Gene', (154, 157))	('crizotinib', 'Chemical', 'MESH:D000077547', (23, 33))	('ROS1', 'Gene', '6098', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('non-small-cell lung cancers', 'Disease', (96, 123))	('ALK', 'Gene', '238', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('rearrangements', 'Var', (136, 150))	('lung cancers', 'Phenotype', 'HP:0100526', (111, 123))
16008	30155324	Given the presence of a ROS1 gene rearrangement, the patient was started on oral crizotinib therapy (250 mg twice daily) 10 weeks prior to her presentation.	('crizotinib', 'Chemical', 'MESH:D000077547', (81, 91))	('ROS1', 'Gene', (24, 28))	('ROS1', 'Gene', '6098', (24, 28))	('presence', 'Var', (10, 18))	('patient', 'Species', '9606', (53, 60))
16101	29983647	According to the literature, high expression of PD L1 is associated with shorter overall survival in patients with non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('non-small cell lung cancer', 'Disease', (115, 141))	('high expression', 'Var', (29, 44))	('PD L1', 'Gene', (48, 53))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (115, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('shorter', 'NegReg', (73, 80))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('overall survival', 'MPA', (81, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (115, 141))
16102	29983647	found a strong pathological role for cyclin D1 deregulation in bronchial neoplasia.	('bronchial neoplasia', 'Disease', (63, 82))	('neoplasia', 'Phenotype', 'HP:0002664', (73, 82))	('bronchial neoplasia', 'Phenotype', 'HP:0030077', (63, 82))	('cyclin D1', 'Protein', (37, 46))	('bronchial neoplasia', 'Disease', 'MESH:D009369', (63, 82))	('deregulation', 'Var', (47, 59))	('cyclin', 'molecular_function', 'GO:0016538', ('37', '43'))
16120	28256574	In the past three decades, molecular tumour profiling and functional studies have led to the identification and validation of critical genes and pathways, which are dysregulated or mutated in specific tumour types.	('tumour', 'Disease', (201, 207))	('molecular tumour', 'Disease', 'MESH:D009386', (27, 43))	('tumour', 'Disease', (37, 43))	('molecular tumour', 'Disease', (27, 43))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('mutated', 'Var', (181, 188))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (201, 207))
16123	28256574	Examples for successfully targeted cancer drivers include ERBB2 overexpression in breast cancer, BRAF mutations in melanoma, ABL1 rearrangements in chronic myeloid leukaemia (CML), KIT mutations in gastrointestinal stroma tumours (GIST), and anaplastic lymphoma kinase (ALK) rearrangements or epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC).	('small cell lung cancer', 'Disease', (350, 372))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ERBB2', 'Gene', '2064', (58, 63))	('cancer', 'Disease', (366, 372))	('NSCLC', 'Phenotype', 'HP:0030358', (374, 379))	('cancer', 'Disease', (89, 95))	('epidermal growth factor receptor', 'Gene', (293, 325))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('293', '316'))	('BRAF', 'Gene', '673', (97, 101))	('anaplastic lymphoma kinase', 'Gene', '238', (242, 268))	('epidermal growth factor receptor', 'Gene', '1956', (293, 325))	('gastrointestinal stroma tumours', 'Disease', 'MESH:D004067', (198, 229))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (361, 372))	('anaplastic lymphoma kinase', 'Gene', (242, 268))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (346, 372))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (156, 173))	('CML', 'Disease', 'MESH:D015464', (175, 178))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('327', '331'))	('EGFR', 'Gene', (327, 331))	('mutations', 'Var', (102, 111))	('CML', 'Disease', (175, 178))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (350, 372))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (148, 173))	('mutations', 'Var', (333, 342))	('BRAF', 'Gene', (97, 101))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (242, 261))	('KIT', 'molecular_function', 'GO:0005020', ('181', '184'))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('gastrointestinal stroma tumours', 'Disease', (198, 229))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('lymphoma', 'Phenotype', 'HP:0002665', (253, 261))	('ABL1', 'Gene', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('SCLC', 'Phenotype', 'HP:0030357', (375, 379))	('ALK', 'Gene', '238', (270, 273))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('rearrangements', 'Var', (130, 144))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('breast cancer', 'Disease', (82, 95))	('NSCLC', 'Disease', 'MESH:D002289', (374, 379))	('ALK', 'Gene', (270, 273))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('chronic myeloid leukaemia', 'Disease', (148, 173))	('melanoma', 'Disease', (115, 123))	('ABL1', 'Gene', '25', (125, 129))	('CML', 'Phenotype', 'HP:0005506', (175, 178))	('tumours', 'Phenotype', 'HP:0002664', (222, 229))	('overexpression', 'PosReg', (64, 78))	('ERBB2', 'Gene', (58, 63))	('small cell lung cancer', 'Disease', 'MESH:D055752', (350, 372))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (148, 173))	('mutations', 'Var', (185, 194))	('cancer', 'Disease', (35, 41))	('NSCLC', 'Disease', (374, 379))
16126	28256574	This revealed that similar cancer driver mutations initially discovered in a single tumour entity are present also in tumours of other anatomical sites.	('mutations', 'Var', (41, 50))	('tumour', 'Disease', (84, 90))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumour', 'Disease', (118, 124))	('tumours', 'Disease', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
16127	28256574	For example, oncogenic BRAF mutations occur in 100% of hairy cell leukaemias, ~50% of melanomas, ~50% of papillary thyroid cancers, ~10% of brain tumours, ~10% of colorectal cancers (CRCs) and with lower frequency in a variety of other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('hairy cell leukaemias', 'Disease', 'MESH:D007943', (55, 76))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('brain tumours', 'Disease', (140, 153))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('BRAF', 'Gene', '673', (23, 27))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('BRAF', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (174, 180))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (105, 130))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('colorectal cancers', 'Disease', (163, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cancer', 'Disease', (236, 242))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (105, 130))	('brain tumours', 'Disease', 'MESH:D001932', (140, 153))	('brain tumours', 'Phenotype', 'HP:0030692', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('mutations', 'Var', (28, 37))	('hairy cell leukaemias', 'Disease', (55, 76))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('papillary thyroid cancers', 'Disease', (105, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('melanomas', 'Disease', (86, 95))	('colorectal cancers', 'Disease', 'MESH:D015179', (163, 181))	('cancer', 'Disease', (123, 129))
16143	28256574	Such differences are most obvious in hereditary cancer predisposition syndromes such as familial adenomatous polyposis (FAP) caused by adenomatous polyposis coli (APC) germline mutations.	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (88, 118))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (97, 118))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (135, 161))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (135, 156))	('hereditary cancer', 'Disease', 'MESH:D009369', (37, 54))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (135, 161))	('APC', 'Phenotype', 'HP:0005227', (163, 166))	('germline mutations', 'Var', (168, 186))	('APC', 'cellular_component', 'GO:0005680', ('163', '166'))	('APC', 'Disease', 'MESH:D011125', (163, 166))	('adenomatous polyposis coli', 'Disease', (135, 161))	('familial adenomatous polyposis', 'Disease', (88, 118))	('hereditary cancer', 'Disease', (37, 54))	('caused by', 'Reg', (125, 134))	('APC', 'Disease', (163, 166))
16145	28256574	Similar associations are true for other germline mutations, such as those affecting BRCA1 and BRCA2 (which cause hereditary breast and ovarian cancer syndrome), cadherin 1 (CDH1) (also known as E-cadherin; which cause hereditary diffuse gastric cancer syndrome), RB1 (Retinoblastoma), von Hippel-Lindau tumour suppressor (VHL, which causes von Hippel-Lindau Syndrome and clear cell renal cell cancer (ccRCC) predisposition) and KIT (which cause gastrointestinal stromal tumour predisposition) (Figure 1).	('von Hippel-Lindau tumour', 'Disease', (285, 309))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (268, 282))	('clear cell renal cell cancer', 'Disease', 'MESH:C538614', (371, 399))	('renal cell cancer', 'Phenotype', 'HP:0005584', (382, 399))	('von Hippel-Lindau Syndrome', 'Disease', (340, 366))	('RB1', 'Gene', '5925', (263, 266))	('CDH1', 'Gene', '999', (173, 177))	('von Hippel-Lindau Syndrome', 'Disease', 'MESH:D006623', (340, 366))	('gastrointestinal stromal tumour', 'Disease', (445, 476))	('E-cadherin', 'Gene', (194, 204))	('gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (445, 476))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (445, 476))	('clear cell renal cell cancer', 'Disease', (371, 399))	('mutations', 'Var', (49, 58))	('E-cadherin', 'Gene', '999', (194, 204))	('cause', 'Reg', (212, 217))	('VHL', 'Gene', (322, 325))	('KIT', 'molecular_function', 'GO:0005020', ('428', '431'))	('CDH1', 'Gene', (173, 177))	('cadherin 1', 'Gene', '999', (161, 171))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (285, 309))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (218, 260))	('BRCA2', 'Gene', (94, 99))	('tumour', 'Phenotype', 'HP:0002664', (470, 476))	('cause', 'Reg', (107, 112))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('VHL', 'Gene', '7428', (322, 325))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (113, 158))	('Retinoblastoma', 'Disease', 'MESH:D012175', (268, 282))	('clear cell renal cell cancer', 'Phenotype', 'HP:0006770', (371, 399))	('Retinoblastoma', 'Disease', (268, 282))	('gastric cancer', 'Phenotype', 'HP:0012126', (237, 251))	('cadherin', 'molecular_function', 'GO:0008014', ('161', '169'))	('cadherin 1', 'Gene', (161, 171))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('BRCA1', 'Gene', '672', (84, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('196', '204'))	('RB1', 'Gene', (263, 266))	('BRCA2', 'Gene', '675', (94, 99))	('KIT', 'Gene', (428, 431))	('ovarian cancer', 'Phenotype', 'HP:0100615', (135, 149))	('BRCA1', 'Gene', (84, 89))	('hereditary diffuse gastric cancer syndrome', 'Disease', (218, 260))
16147	28256574	However, other genetic alterations, such as TP53 germline mutations, which cause Li-Fraumeni syndrome, are associated with a much broader spectrum of cancer types and are therefore considered a general cancer gene alteration.	('cause', 'Reg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('associated', 'Reg', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (150, 156))	('TP53', 'Gene', '7157', (44, 48))	('cancer', 'Disease', (202, 208))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (81, 101))	('germline mutations', 'Var', (49, 67))	('TP53', 'Gene', (44, 48))	('Li-Fraumeni syndrome', 'Disease', (81, 101))
16150	28256574	Other examples are BCR-ABL translocations in CML, APC mutations in CRC, or mutations in the RB1 tumour suppressor gene in small cell lung cancer (SCLC).	('translocations', 'Var', (27, 41))	('CML', 'Phenotype', 'HP:0005506', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('SCLC', 'Disease', (146, 150))	('APC', 'cellular_component', 'GO:0005680', ('50', '53'))	('BCR-ABL', 'Gene', (19, 26))	('mutations', 'Var', (54, 63))	('SCLC', 'Phenotype', 'HP:0030357', (146, 150))	('CRC', 'Gene', (67, 70))	('RB1', 'Gene', (92, 95))	('CML', 'Disease', 'MESH:D015464', (45, 48))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('small cell lung cancer', 'Disease', 'MESH:D055752', (122, 144))	('CML', 'Disease', (45, 48))	('APC', 'Phenotype', 'HP:0005227', (50, 53))	('APC', 'Disease', 'MESH:D011125', (50, 53))	('tumour', 'Disease', (96, 102))	('RB1', 'Gene', '5925', (92, 95))	('SCLC', 'Disease', 'MESH:D018288', (146, 150))	('small cell lung cancer', 'Disease', (122, 144))	('APC', 'Disease', (50, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('BCR-ABL', 'Gene', '25', (19, 26))	('mutations', 'Var', (75, 84))
16151	28256574	These examples of tissue-specific genetic events raise the question about the underlying molecular and cellular mechanisms, allowing or preventing cancer development at different anatomical locations.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('genetic', 'Var', (34, 41))	('preventing', 'NegReg', (136, 146))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
16160	28256574	Ablation of WNT signalling in mice results in a complete loss of intestinal epithelial cells, whereas constitutive WNT activation in intestinal stem cells by Apc deletion leads to stem cell-driven intestinal tumourigenesis.	('deletion', 'Var', (162, 170))	('Apc', 'cellular_component', 'GO:0005680', ('158', '161'))	('mice', 'Species', '10090', (30, 34))	('leads to', 'Reg', (171, 179))	('tumour', 'Disease', (208, 214))	('loss', 'NegReg', (57, 61))	('Apc', 'Gene', (158, 161))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('intestinal epithelial cells', 'MPA', (65, 92))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('signalling', 'biological_process', 'GO:0023052', ('16', '26'))
16163	28256574	Depending on the cell of origin in which the oncogene is initially expressed within the mouse mammary gland, identical Pik3ca mutations induce fundamentally different tumour types with different morphology, growth patterns, invasiveness and aggressiveness.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('aggressiveness', 'Phenotype', 'HP:0000718', (241, 255))	('Pik3ca', 'Gene', (119, 125))	('mouse', 'Species', '10090', (88, 93))	('Pik3ca', 'Gene', '18706', (119, 125))	('mutations', 'Var', (126, 135))	('invasiveness and aggressiveness', 'Disease', 'MESH:D001523', (224, 255))	('induce', 'Reg', (136, 142))
16164	28256574	Multiple differentiated cell types also give rise to KrasG12D-induced NSCLC and the cell of origin influences the NSCLC spectrum and its histopathological phenotype.	('influences', 'Reg', (99, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (70, 75))	('give rise', 'Reg', (40, 49))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('SCLC', 'Phenotype', 'HP:0030357', (115, 119))	('KrasG12D-induced', 'Var', (53, 69))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
16167	28256574	These data support the idea that a particular cell of origin may require a unique set of distinct mutations to be able to serve as the cell of origin of a tumour subtype.	('mutations', 'Var', (98, 107))	('tumour subtype', 'Disease', 'MESH:C535673', (155, 169))	('tumour subtype', 'Disease', (155, 169))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))
16171	28256574	In basal cell cancer, inducible expression of a constitutively active smoothened mutant in the adult mouse epidermis reprogrammed differentiated epidermal cells into embryonic hair follicle progenitor-like cells and induced cancer formation.	('cancer', 'Disease', (14, 20))	('basal cell cancer', 'Disease', 'MESH:D002280', (3, 20))	('basal cell cancer', 'Phenotype', 'HP:0002671', (3, 20))	('induced', 'PosReg', (216, 223))	('embryonic hair', 'Disease', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('formation', 'biological_process', 'GO:0009058', ('231', '240'))	('smoothened', 'Gene', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mouse', 'Species', '10090', (101, 106))	('mutant', 'Var', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('basal cell cancer', 'Disease', (3, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('embryonic hair', 'Disease', 'MESH:D000505', (166, 180))	('cancer', 'Disease', (224, 230))
16177	28256574	In contrast, ablation of Pten in mice suppresses pre-B-ALL development owing to activation of AKT and the tumour suppressor p53.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('pre', 'molecular_function', 'GO:0003904', ('49', '52'))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('ablation', 'Var', (13, 21))	('pre-B-ALL development', 'CPA', (49, 70))	('tumour', 'Disease', (106, 112))	('Pten', 'Gene', (25, 29))	('suppresses', 'NegReg', (38, 48))	('mice', 'Species', '10090', (33, 37))	('Pten', 'Gene', '19211', (25, 29))	('AKT', 'Pathway', (94, 97))	('activation', 'PosReg', (80, 90))
16178	28256574	In pre-B ALL cells, the absence of PTEN causes strong PI3K/AKT signals, which mimic the negative selection of autoreactive B cells and induce tumour cell death via AKT-mediated activation of the p53 cell cycle checkpoint.	('tumour cell death', 'Disease', 'MESH:D003643', (142, 159))	('PI3K/AKT signals', 'Pathway', (54, 70))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))	('cell death', 'biological_process', 'GO:0008219', ('149', '159'))	('induce', 'Reg', (135, 141))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('PI3K', 'molecular_function', 'GO:0016303', ('54', '58'))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('tumour cell death', 'Disease', (142, 159))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('199', '220'))	('absence', 'Var', (24, 31))
16183	28256574	As an example, oncogenic KRAS triggers the tumour suppressive p19ARF pathway extensively in mesenchymal tissues, such as the musculature, but not in epithelial cells of the lung.	('oncogenic KRAS', 'Var', (15, 29))	('p19ARF pathway', 'Pathway', (62, 76))	('tumour', 'Disease', (43, 49))	('triggers', 'Reg', (30, 38))	('p19', 'cellular_component', 'GO:0070743', ('62', '65'))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('KRAS', 'Var', (25, 29))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
16184	28256574	Thereby, KRAS-induced p19ARF expression prevents muscle-derived sarcoma formation in mice.	('mice', 'Species', '10090', (85, 89))	('p19', 'cellular_component', 'GO:0070743', ('22', '25'))	('p19ARF expression', 'Var', (22, 39))	('prevents', 'NegReg', (40, 48))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', (64, 71))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
16185	28256574	In line with this, specific deletion of p19 (which is encoded together with p16Ink4a by the cyclin-dependent kinase inhibitor 2a (Cdkn2a) gene) in mice induces a shift of the KRAS-induced tumour spectrum towards sarcomas.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('cyclin-dependent kinase inhibitor 2a', 'Gene', '12578', (92, 128))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))	('p19', 'Gene', (40, 43))	('sarcomas', 'Disease', 'MESH:D012509', (212, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('mice', 'Species', '10090', (147, 151))	('sarcomas', 'Disease', (212, 220))	('cyclin-dependent kinase inhibitor 2a', 'Gene', (92, 128))	('p19', 'Gene', '12581', (40, 43))	('p19', 'cellular_component', 'GO:0070743', ('40', '43'))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('92', '125'))	('deletion', 'Var', (28, 36))	('shift', 'Reg', (162, 167))	('p16Ink4a', 'Gene', (76, 84))	('induces', 'Reg', (152, 159))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('109', '125'))	('p16Ink4a', 'Gene', '12578', (76, 84))
16186	28256574	Mechanistically, cell type-specific epigenetic gene regulation of the Cdkn2a locus and thus context-specific expression of its gene products p19ARF and p16INK4A is the critical determinant of this tissue-specific cellular response.	('epigenetic gene regulation', 'Var', (36, 62))	('p16INK4A', 'Gene', '1029', (152, 160))	('p19ARF', 'Var', (141, 147))	('p19', 'cellular_component', 'GO:0070743', ('141', '144'))	('Cdkn2a', 'Gene', (70, 76))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))	('p16INK4A', 'Gene', (152, 160))
16189	28256574	Next-generation cancer genome sequencing and functional assays revealed that the rate of somatic mutations varies considerably across the genome of different cell types due to context-specific differences in chromatin organization, DNA accessibility, replication timing and transcription initiation.	('chromatin', 'MPA', (208, 217))	('differences', 'Reg', (193, 204))	('mutations', 'Var', (97, 106))	('transcription', 'MPA', (274, 287))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('DNA accessibility', 'MPA', (232, 249))	('transcription', 'biological_process', 'GO:0006351', ('274', '287'))	('cancer', 'Disease', (16, 22))	('DNA', 'cellular_component', 'GO:0005574', ('232', '235'))	('chromatin organization', 'biological_process', 'GO:0006325', ('208', '230'))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('chromatin', 'cellular_component', 'GO:0000785', ('208', '217'))
16191	28256574	This leads to an increased rate of context-specific DNA mutations in active gene promoter regions of distinct tumours, such as melanoma and lung cancer, that depend on NER for repair of e.g.	('NER', 'biological_process', 'GO:0006289', ('168', '171'))	('lung cancer', 'Disease', (140, 151))	('mutations', 'Var', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('tumours', 'Disease', (110, 117))
16192	28256574	In contrast, cancers that do not rely heavily on NER, such as CRC, show no such enrichment in TFBS mutations.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('mutations', 'Var', (99, 108))	('CRC', 'Disease', (62, 65))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('NER', 'biological_process', 'GO:0006289', ('49', '52'))	('cancers', 'Disease', (13, 20))	('TFBS', 'Gene', (94, 98))
16193	28256574	In adult stem cells of the colon, which are the cells of origin of CRC, context-specific mutation signatures correspond to spontaneous deamination of methylated cytosine (C) residues into thymine (T) at CpG sites, which are strongly associated with replication timing and might reflect the high division rate of colonic stem cells.	('deamination', 'MPA', (135, 146))	('mutation', 'Var', (89, 97))	('cytosine', 'Chemical', 'MESH:D003596', (161, 169))
16194	28256574	Because many point-mutations in CRC driver genes, such as APC, CTNNB1 (encoding beta-catenin), TP53 and SMAD family member 4 (SMAD4) are similarly C:G to T:A transitions at CpG dinucleotides, deamination-induced C to T mutagenesis might be a relevant tissue-specific cancer driver and determinant of point-mutation load in this tumour entity.	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('SMAD4', 'Gene', (126, 131))	('SMAD family member 4', 'Gene', (104, 124))	('mutagenesis', 'Var', (219, 230))	('point-mutations', 'Var', (13, 28))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('TP53', 'Gene', '7157', (95, 99))	('SMAD4', 'Gene', '4089', (126, 131))	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('CTNNB1', 'Gene', '1499', (63, 69))	('cancer', 'Disease', (267, 273))	('APC', 'Phenotype', 'HP:0005227', (58, 61))	('tumour', 'Disease', 'MESH:D009369', (328, 334))	('SMAD family member 4', 'Gene', '4089', (104, 124))	('APC', 'Disease', 'MESH:D011125', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('APC', 'Disease', (58, 61))	('tumour', 'Disease', (328, 334))	('APC', 'cellular_component', 'GO:0005680', ('58', '61'))	('CRC driver genes', 'Gene', (32, 48))	('CTNNB1', 'Gene', (63, 69))	('mutagenesis', 'biological_process', 'GO:0006280', ('219', '230'))	('TP53', 'Gene', (95, 99))
16195	28256574	Consequently, chromatin and epigenomic features of the cell of origin are the best predictors of local somatic mutation densities in a cancer cell and the cell of origin of a cancer can be determined based on the distribution of mutations along its genome.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('chromatin', 'cellular_component', 'GO:0000785', ('14', '23'))	('mutation', 'Var', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
16199	28256574	Using an elegant knock-in strategy to express wild-type HRAS from the endogenous Kras locus in mice, it was shown that Hras codon 61 mutations occurred in NSCLC only in the Hras knock-in allele expressed from the Kras locus, but never from the endogenous Hras locus.	('Hras', 'Gene', (173, 177))	('mice', 'Species', '10090', (95, 99))	('Hras', 'Gene', (119, 123))	('NSCLC', 'Disease', (155, 160))	('SCLC', 'Phenotype', 'HP:0030357', (156, 160))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('mutations', 'Var', (133, 142))	('occurred', 'Reg', (143, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))
16200	28256574	These data show that the tissue-specific mechanisms underlying Kras mutations in NSCLC, and Hras mutations in skin cancer involve tissue-specific gene regulatory elements rather than differences in the function of the encoded proteins.	('Hras', 'Gene', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('SCLC', 'Phenotype', 'HP:0030357', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('skin cancer', 'Phenotype', 'HP:0008069', (110, 121))	('skin cancer', 'Disease', 'MESH:D012878', (110, 121))	('skin cancer', 'Disease', (110, 121))	('Kras', 'Gene', (63, 67))	('mutations', 'Var', (68, 77))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
16203	28256574	Cancer cells can acquire super-enhancers at oncogenic drivers through mutation, focal amplification, chromosomal translocation, or overexpression of an oncogenic transcription factor or an epigenetic regulator that controls enhancer activity.	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('focal amplification', 'Var', (80, 99))	('Cancer', 'Disease', (0, 6))	('mutation', 'Var', (70, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('chromosomal translocation', 'Var', (101, 126))	('overexpression', 'PosReg', (131, 145))	('transcription factor', 'molecular_function', 'GO:0000981', ('162', '182'))
16205	28256574	For example, in T-ALL, a small mono-allelic insertion that creates a binding site for the haematopoietic transcription factor MYB nucleates the formation of a novel context-specific oncogenic super-enhancer upstream of the T cell acute lymphocytic leukaemia 1 (TAL1) oncogene, thereby driving its aberrant expression.	('T-ALL', 'Phenotype', 'HP:0006727', (16, 21))	('T cell acute lymphocytic leukaemia 1', 'Gene', '6886', (223, 259))	('transcription factor', 'molecular_function', 'GO:0000981', ('105', '125'))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('acute lymphocytic leukaemia', 'Phenotype', 'HP:0006721', (230, 257))	('TAL1', 'Gene', (261, 265))	('insertion', 'Var', (44, 53))	('formation', 'biological_process', 'GO:0009058', ('144', '153'))	('expression', 'MPA', (306, 316))	('transcription', 'biological_process', 'GO:0006351', ('105', '118'))	('T cell acute lymphocytic leukaemia 1', 'Gene', (223, 259))	('T cell acute lymphocytic leukaemia', 'Phenotype', 'HP:0006727', (223, 257))	('TAL1', 'Gene', '6886', (261, 265))
16206	28256574	Additionally, a polymorphism within a super-enhancer element in the first intron of the LIM domain only 1 (LMO1) gene influences specifically neuroblastoma susceptibility and oncogenic addiction to LMO1 through direct modulation of LMO1 expression.	('LMO1', 'Gene', (107, 111))	('modulation', 'Reg', (218, 228))	('neuroblastoma', 'Phenotype', 'HP:0003006', (142, 155))	('oncogenic addiction', 'CPA', (175, 194))	('LMO1', 'Gene', '4004', (107, 111))	('expression', 'MPA', (237, 247))	('polymorphism', 'Var', (16, 28))	('LMO1', 'Gene', (198, 202))	('LMO1', 'Gene', (232, 236))	('influences', 'Reg', (118, 128))	('LMO1', 'Gene', '4004', (198, 202))	('neuroblastoma', 'Disease', 'MESH:D009447', (142, 155))	('LMO1', 'Gene', '4004', (232, 236))	('LIM domain only 1', 'Gene', '4004', (88, 105))	('neuroblastoma', 'Disease', (142, 155))	('LIM domain only 1', 'Gene', (88, 105))
16211	28256574	Some tumour subtypes, such as sonic hedgehog-driven medulloblastoma with mutant TP53, always display chromothripsis.	('chromothripsis', 'MPA', (101, 115))	('medulloblastoma', 'Disease', (52, 67))	('TP53', 'Gene', '7157', (80, 84))	('tumour subtype', 'Disease', 'MESH:C535673', (5, 19))	('TP53', 'Gene', (80, 84))	('mutant', 'Var', (73, 79))	('medulloblastoma', 'Disease', 'MESH:D008527', (52, 67))	('tumour subtype', 'Disease', (5, 19))	('medulloblastoma', 'Phenotype', 'HP:0002885', (52, 67))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('display', 'Reg', (93, 100))
16214	28256574	Indeed, chromothripsis has been associated with poor prognosis in melanoma, neuroblastoma and multiple myeloma.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('neuroblastoma', 'Disease', (76, 89))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('multiple myeloma', 'Phenotype', 'HP:0006775', (94, 110))	('multiple myeloma', 'Disease', 'MESH:D009101', (94, 110))	('multiple myeloma', 'Disease', (94, 110))	('chromothripsis', 'Var', (8, 22))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
16219	28256574	In contrast, breast and lung cancers have the highest proportion of altered double-strand break repair (DSBR) genes.	('breast and lung cancers', 'Disease', 'MESH:D001943', (13, 36))	('double-strand break repair', 'Gene', (76, 102))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('lung cancers', 'Phenotype', 'HP:0100526', (24, 36))	('double-strand break repair', 'biological_process', 'GO:0006302', ('76', '102'))	('altered', 'Var', (68, 75))
16225	28256574	Recent work suggests that estrogens also play a fundamental role in tolerating otherwise lethal mutations in cancer genes such as BRCA1.	('BRCA1', 'Gene', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('BRCA1', 'Gene', '672', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (96, 105))
16228	28256574	Considering that BRCA1 mutations promote tumour formation almost exclusively in hormone-responsive tissues such as breast and ovary, the link between estrogens and the survival of BRCA1-deficient cells provides important mechanistic insights into the tissue tropism of BRCA1-deficient cancers.	('BRCA1-deficient cancers', 'Disease', 'MESH:D009369', (269, 292))	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('BRCA1-deficient', 'Disease', (180, 195))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (269, 284))	('promote', 'PosReg', (33, 40))	('breast', 'Disease', (115, 121))	('mutations', 'Var', (23, 32))	('tropism', 'biological_process', 'GO:0009606', ('258', '265'))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (180, 195))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('ovary', 'Disease', (126, 131))	('BRCA1', 'Gene', '672', (17, 22))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('BRCA1', 'Gene', (17, 22))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('BRCA1-deficient cancers', 'Disease', (269, 292))	('tumour', 'Disease', (41, 47))	('BRCA1', 'Gene', '672', (269, 274))	('BRCA1', 'Gene', '672', (180, 185))	('BRCA1-deficient', 'Disease', (269, 284))	('BRCA1', 'Gene', (180, 185))	('BRCA1', 'Gene', (269, 274))
16235	28256574	Increasing signal output is sometimes achieved by amplification of the driving oncogene in cancer types such as NSCLC, but can also be achieved by engagement of autocrine feed-forward loops or upstream signals from receptor tyrosine kinases.	('amplification', 'Var', (50, 63))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('SCLC', 'Phenotype', 'HP:0030357', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NSCLC', 'Disease', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
16237	28256574	However, deletion of Egfr in mouse models of KRAS-driven NSCLC or CRC fails to prevent tumorigenesis, unlike KRAS-driven PDAC development that requires EGFR signalling.	('signalling', 'biological_process', 'GO:0023052', ('157', '167'))	('deletion', 'Var', (9, 17))	('SCLC', 'Phenotype', 'HP:0030357', (58, 62))	('PDAC', 'Chemical', '-', (121, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('mouse', 'Species', '10090', (29, 34))	('Egfr', 'Gene', (21, 25))	('NSCLC', 'Disease', (57, 62))	('Egfr', 'molecular_function', 'GO:0005006', ('21', '25'))	('PDAC', 'Phenotype', 'HP:0006725', (121, 125))	('tumorigenesis', 'CPA', (87, 100))	('Egfr', 'Gene', '13649', (21, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
16238	28256574	In line with this, KRAS mutations are predictors of primary resistance towards EGFR inhibition in patients with NSCLC and CRC, but not PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('NSCLC', 'Disease', (112, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('KRAS', 'Gene', (19, 23))	('patients', 'Species', '9606', (98, 106))	('SCLC', 'Phenotype', 'HP:0030357', (113, 117))	('PDAC', 'Chemical', '-', (135, 139))	('CRC', 'Disease', (122, 125))	('mutations', 'Var', (24, 33))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
16241	28256574	For example, treatment of some Kras-mutant lung and pancreatic tumour models with the MEK inhibitor Trametinib uncovered a cell autonomous fibroblast growth factor receptor 1 (FGFR1)-dependent survival pathway, which is not present in Kras-mutant CRC cells.	('Trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('fibroblast growth factor receptor 1', 'Gene', (139, 174))	('MEK', 'Gene', (86, 89))	('Kras-mutant', 'Var', (31, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (52, 69))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('139', '163'))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('MEK', 'Gene', '5609', (86, 89))	('fibroblast growth factor receptor 1', 'Gene', '2260', (139, 174))	('FGFR1', 'Gene', (176, 181))	('pancreatic tumour', 'Disease', (52, 69))	('FGFR1', 'Gene', '2260', (176, 181))	('pancreatic tumour', 'Disease', 'MESH:D010190', (52, 69))
16244	28256574	The outcome of paracrine FGF signalling is also tissue specific; the pathway drives tumour development in the prostate due to the paracrine upregulation of androgen receptor signalling and AKT activation, whereas it blocks tumour progression in a patched 1 (Ptch1) mutant mouse model of medulloblastoma via inhibition of oncogenic sonic hedgehog signalling.	('tumour', 'Disease', (84, 90))	('mutant', 'Var', (265, 271))	('Ptch1', 'Gene', (258, 263))	('signalling', 'biological_process', 'GO:0023052', ('346', '356'))	('androgen receptor', 'Gene', (156, 173))	('activation', 'PosReg', (193, 203))	('Ptch1', 'Gene', '19206', (258, 263))	('signalling', 'biological_process', 'GO:0023052', ('174', '184'))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('inhibition', 'NegReg', (307, 317))	('blocks', 'NegReg', (216, 222))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('upregulation', 'PosReg', (140, 152))	('medulloblastoma', 'Phenotype', 'HP:0002885', (287, 302))	('medulloblastoma', 'Disease', 'MESH:D008527', (287, 302))	('mouse', 'Species', '10090', (272, 277))	('medulloblastoma', 'Disease', (287, 302))	('patched 1', 'Gene', (247, 256))	('signalling', 'biological_process', 'GO:0023052', ('29', '39'))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('patched 1', 'Gene', '19206', (247, 256))	('AKT', 'Pathway', (189, 192))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('androgen receptor', 'Gene', '11835', (156, 173))
16247	28256574	In other cancers, downregulation of modulators of these negative feedback programs or additional mutational hits that bypass negative feedback, such as inactivation of phosphatases (i.e.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('phosphatases', 'Enzyme', (168, 180))	('inactivation', 'Var', (152, 164))	('downregulation', 'NegReg', (18, 32))
16249	28256574	For example, in CRC, pharmacological blockade of the BRAF oncogene decreases a negative feedback loop that would otherwise block EGFR signalling.	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('pharmacological blockade', 'Var', (21, 45))	('BRAF', 'Gene', '673', (53, 57))	('CRC', 'Disease', (16, 19))	('BRAF', 'Gene', (53, 57))	('negative feedback loop', 'MPA', (79, 101))	('decreases', 'NegReg', (67, 76))	('signalling', 'biological_process', 'GO:0023052', ('134', '144'))
16250	28256574	These findings contrast with BRAF-driven melanoma, where BRAF blockade inhibits MAPK activation without impacting on EGFR signalling.	('BRAF', 'Gene', '673', (29, 33))	('activation', 'MPA', (85, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('BRAF', 'Gene', (29, 33))	('BRAF', 'Gene', '673', (57, 61))	('MAPK', 'Gene', '5595;5594;5595', (80, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('BRAF', 'Gene', (57, 61))	('MAPK activation', 'biological_process', 'GO:0000187', ('80', '95'))	('blockade', 'Var', (62, 70))	('signalling', 'biological_process', 'GO:0023052', ('122', '132'))	('MAPK', 'Gene', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('inhibits', 'NegReg', (71, 79))
16251	28256574	Therefore, tissue-specific EGFR and PI3K signalling seems to bypass BRAF inhibition and mediate primary treatment resistance in BRAF mutant CRC.	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('BRAF', 'Gene', '673', (68, 72))	('signalling', 'biological_process', 'GO:0023052', ('41', '51'))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (128, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('mutant', 'Var', (133, 139))	('BRAF', 'Gene', (128, 132))
16253	28256574	These data show that tumours of distinct tissue origin are driven by complex nonlinear signalling dynamics even if they engage an identical activating driver mutation, such as BRAFV600E.	('driven', 'Reg', (59, 65))	('BRAFV600E', 'Var', (176, 185))	('BRAFV600E', 'Mutation', 'rs113488022', (176, 185))	('nonlinear signalling', 'MPA', (77, 97))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('signalling', 'biological_process', 'GO:0023052', ('87', '97'))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('tumours', 'Disease', (21, 28))
16257	28256574	Tissue-context specific relationships between molecular alterations, such as co-occurrence or mutual exclusivity of mutations, have been observed in many cancer types, but in most cases the underlying biological principles and the therapeutic consequences are to date unclear.	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
16258	28256574	As described above, KRAS mutations have a different impact on oncogenic signalling organization in distinct tumour types such as CRC, PDAC and NSCLC.	('tumour', 'Disease', (108, 114))	('SCLC', 'Phenotype', 'HP:0030357', (144, 148))	('mutations', 'Var', (25, 34))	('PDAC', 'Chemical', '-', (134, 138))	('NSCLC', 'Disease', (143, 148))	('oncogenic signalling organization', 'MPA', (62, 95))	('signalling', 'biological_process', 'GO:0023052', ('72', '82'))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('CRC', 'Disease', (129, 132))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('impact', 'Reg', (52, 58))	('PDAC', 'Disease', (134, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('PDAC', 'Phenotype', 'HP:0006725', (134, 138))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('KRAS', 'Gene', (20, 24))
16259	28256574	The phenotype of these KRAS-driven tumour types is further modified by tissue-specific co-occurring mutations in other cancer genes, such as loss-of-function mutations in the serine-threonine kinase 11 (STK11; also known as LKB1) in NSCLC.	('modified', 'Reg', (59, 67))	('STK11', 'Gene', (203, 208))	('LKB1', 'Gene', '6794', (224, 228))	('STK11', 'molecular_function', 'GO:0033868', ('203', '208'))	('SCLC', 'Phenotype', 'HP:0030357', (234, 238))	('serine-threonine kinase 11', 'Gene', '6794', (175, 201))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('STK11', 'Gene', '6794', (203, 208))	('mutations', 'Var', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', (35, 41))	('LKB1', 'Gene', (224, 228))	('NSCLC', 'Disease', 'MESH:D002289', (233, 238))	('serine-threonine kinase 11', 'Gene', (175, 201))	('NSCLC', 'Disease', (233, 238))	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (233, 238))	('loss-of-function', 'NegReg', (141, 157))
16260	28256574	The co-occurrence of mutant KRAS and STK11 determines distinct biological features in KRAS-driven NSCLC, such as differences in pathway activation and immunogenicity, as well as therapeutic vulnerabilities.	('KRAS', 'Gene', (28, 32))	('mutant', 'Var', (21, 27))	('STK11', 'Gene', '6794', (37, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('pathway', 'MPA', (128, 135))	('NSCLC', 'Disease', (98, 103))	('STK11', 'Gene', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('STK11', 'molecular_function', 'GO:0033868', ('37', '42'))	('SCLC', 'Phenotype', 'HP:0030357', (99, 103))
16263	28256574	Thereby, epistatic interactions shape signalling pathways in cancer by permitting some and blocking others.	('permitting', 'PosReg', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('blocking', 'NegReg', (91, 99))	('signalling pathways', 'Pathway', (38, 57))	('shape', 'Reg', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('signalling', 'biological_process', 'GO:0023052', ('38', '48'))	('epistatic interactions', 'Var', (9, 31))
16267	28256574	Examples include context-specific co-occurring oncogenic mutations in KRAS and PIK3CA in CRC, EGFR amplification and O6-methylguanine-DNA methyltransferase (MGMT) methylation in NSCLC, and mutual exclusivity of EGFR amplification and isocitrate dehydrogenase 1 (IDH1) or TP53 mutation in glioblastoma.	('O6-methylguanine-DNA methyltransferase', 'Gene', (117, 155))	('KRAS', 'Gene', (70, 74))	('isocitrate dehydrogenase 1', 'Gene', (234, 260))	('mutations', 'Var', (57, 66))	('isocitrate dehydrogenase 1', 'Gene', '3417', (234, 260))	('SCLC', 'Phenotype', 'HP:0030357', (179, 183))	('IDH1', 'Gene', (262, 266))	('glioblastoma', 'Disease', 'MESH:D005909', (288, 300))	('methylation', 'biological_process', 'GO:0032259', ('163', '174'))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('MGMT', 'Gene', '4255', (157, 161))	('PIK3CA', 'Gene', '5290', (79, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('TP53', 'Gene', (271, 275))	('glioblastoma', 'Disease', (288, 300))	('IDH1', 'Gene', '3417', (262, 266))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (288, 300))	('MGMT', 'molecular_function', 'GO:0003908', ('157', '161'))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (117, 155))	('mutation', 'Var', (276, 284))	('NSCLC', 'Disease', (178, 183))	('EGFR', 'Gene', (94, 98))	('PIK3CA', 'Gene', (79, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('MGMT', 'Gene', (157, 161))	('TP53', 'Gene', '7157', (271, 275))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
16268	28256574	Examples include amplifications of MAPK3 (also known as ERK1) in KRAS mutant PDAC (synergistic impingement on the MAPK pathway), co-occurring genetic alterations of KRAS, PIK3CA and PTEN in uterine corpus endometrial carcinoma (synergistic impingement on the PI3K signalling pathway), or EGFR mutations and PTEN deletions in glioblastoma (synergistic impingement on the PI3K pathway) (http://www.cbioportal.org).	('PI3K', 'molecular_function', 'GO:0016303', ('370', '374'))	('PTEN', 'Gene', (307, 311))	('PIK3CA', 'Gene', (171, 177))	('PI3K', 'molecular_function', 'GO:0016303', ('259', '263'))	('MAPK', 'Gene', '5595;5594;5595', (35, 39))	('ERK1', 'Gene', '5595', (56, 60))	('MAPK', 'Gene', '5595;5594;5595', (114, 118))	('PDAC', 'Chemical', '-', (77, 81))	('EGFR', 'Gene', (288, 292))	('PTEN', 'Gene', '5728', (182, 186))	('deletions', 'Var', (312, 321))	('PTEN', 'Gene', '5728', (307, 311))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('corpus endometrial carcinoma', 'Disease', (198, 226))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (198, 226))	('MAPK', 'Gene', (35, 39))	('MAPK', 'molecular_function', 'GO:0004707', ('114', '118'))	('MAPK3', 'Gene', (35, 40))	('MAPK', 'Gene', (114, 118))	('MAPK3', 'Gene', '5595', (35, 40))	('KRAS', 'Gene', (65, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (325, 337))	('PIK3CA', 'Gene', '5290', (171, 177))	('mutant', 'Var', (70, 76))	('mutations', 'Var', (293, 302))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('glioblastoma', 'Disease', (325, 337))	('glioblastoma', 'Phenotype', 'HP:0012174', (325, 337))	('signalling pathway', 'biological_process', 'GO:0007165', ('264', '282'))	('EGFR', 'molecular_function', 'GO:0005006', ('288', '292'))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (205, 226))	('PTEN', 'Gene', (182, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('ERK1', 'molecular_function', 'GO:0004707', ('56', '60'))	('ERK1', 'Gene', (56, 60))
16269	28256574	In line with this, epistatic interactions are not only associated with the cell of origin of a tumour, but also affect the context-specific biological functions of the epistatically linked genes and the survival of a cancer patient.	('epistatic interactions', 'Var', (19, 41))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('associated', 'Reg', (55, 65))	('context-specific biological functions', 'MPA', (123, 160))	('patient', 'Species', '9606', (224, 231))	('survival', 'CPA', (203, 211))	('tumour', 'Disease', (95, 101))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('affect', 'Reg', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
16272	28256574	The order in which alterations in cancer genes occur might also be an important determinant of signalling organization and output, as has been shown in a model of BRAFV600E-driven serrated intestinal cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BRAFV600E-driven', 'Var', (163, 179))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('serrated intestinal', 'Phenotype', 'HP:0032222', (180, 199))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('BRAFV600E', 'Mutation', 'rs113488022', (163, 172))	('signalling', 'biological_process', 'GO:0023052', ('95', '105'))	('intestinal cancer', 'Disease', 'MESH:D007414', (189, 206))	('cancer', 'Disease', (34, 40))	('serrated intestinal cancer', 'Phenotype', 'HP:0032222', (180, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('intestinal cancer', 'Disease', (189, 206))	('cancer', 'Disease', (200, 206))
16275	28256574	This "inverted" sequence of MAPK-WNT pathway activation has not only important consequences for oncogenic signalling outputs, such as the specific activation of the p16INK4A and/or p19ARF tumour suppressors in BRAF-driven serrated intestinal carcinogenesis, but might also influence the pathomorphologic (serrated histology), genetic (MSI and DNA hypermethylation of CpG islands) and clinical (poor prognosis) characteristics of this CRC subtype.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('signalling', 'biological_process', 'GO:0023052', ('104', '114'))	('p19ARF', 'Var', (181, 187))	('p19', 'cellular_component', 'GO:0070743', ('179', '182'))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('MAPK', 'Gene', (28, 32))	('tumour', 'Disease', (188, 194))	('activation', 'PosReg', (147, 157))	('carcinogenesis', 'Disease', (242, 256))	('MSI', 'Disease', 'None', (335, 338))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))	('MSI', 'Disease', (335, 338))	('p16INK4A', 'Gene', (165, 173))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('DNA', 'cellular_component', 'GO:0005574', ('341', '344'))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('p16INK4A', 'Gene', '1029', (165, 173))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('341', '361'))	('influence', 'Reg', (273, 282))	('MAPK', 'Gene', '5595;5594;5595', (28, 32))	('serrated intestinal', 'Phenotype', 'HP:0032222', (222, 241))
16278	28256574	Mechanistically, historical contingency is exemplified by the tissue-specific interplay between genetic alterations in MYC and BCL-2.	('genetic alterations', 'Var', (96, 115))	('BCL-2', 'Gene', '596', (127, 132))	('BCL-2', 'Gene', (127, 132))	('MYC', 'Gene', '4609', (119, 122))	('MYC', 'Gene', (119, 122))	('BCL-2', 'molecular_function', 'GO:0015283', ('127', '132'))
16279	28256574	The anti-apoptotic proto-oncogene BCL-2 is activated by translocation in a variety of B-cell lymphomas.	('B-cell lymphomas', 'Disease', (86, 102))	('BCL-2', 'Gene', '596', (34, 39))	('activated', 'PosReg', (43, 52))	('translocation', 'Var', (56, 69))	('BCL-2', 'Gene', (34, 39))	('lymphomas', 'Phenotype', 'HP:0002665', (93, 102))	('BCL-2', 'molecular_function', 'GO:0015283', ('34', '39'))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (86, 102))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (86, 102))
16280	28256574	MYC hyperactivation induces apoptosis of B-lineage cells, but BCL2 overexpression represents one possibility to block this effect and permit oncogenic MYC to drive the tumour.	('MYC', 'Gene', (0, 3))	('MYC', 'Gene', (151, 154))	('BCL2', 'molecular_function', 'GO:0015283', ('62', '66'))	('BCL2', 'Gene', '596', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('BCL2', 'Gene', (62, 66))	('B-lineage cells', 'CPA', (41, 56))	('apoptosis', 'CPA', (28, 37))	('MYC', 'Gene', '4609', (151, 154))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('MYC', 'Gene', '4609', (0, 3))	('tumour', 'Disease', (168, 174))	('hyperactivation', 'Var', (4, 19))
16314	28256574	Cell-type specific metabolic alterations can make tumour cells selectively dependent upon certain nutrients and metabolic pathways, leading to tissue of origin specific therapeutic vulnerabilities.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('leading to', 'Reg', (132, 142))	('dependent', 'Reg', (75, 84))	('tumour', 'Disease', (50, 56))	('alterations', 'Var', (29, 40))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
16323	28256574	Recent work demonstrates that simultaneous DNA damage and cell division during inflammation leads to cancer because dividing cells are more vulnerable to mutations caused by DNA damage.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('mutations', 'Var', (154, 163))	('cell division', 'biological_process', 'GO:0051301', ('58', '71'))	('inflammation', 'biological_process', 'GO:0006954', ('79', '91'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('leads to', 'Reg', (92, 100))	('inflammation', 'Disease', (79, 91))
16324	28256574	smoke) can induce an extraordinary high rate of mutations resulting in the activation of diverse cancer drivers.	('cancer', 'Disease', (97, 103))	('activation', 'PosReg', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
16325	28256574	Although the developing tumours are subsequently genetically very heterogeneous, they do however, harbour mutational signatures that are associated with the cancer aetiology.	('tumours', 'Disease', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('harbour', 'Reg', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('cancer', 'Disease', (157, 163))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('mutational', 'Var', (106, 116))
16326	28256574	Treatment response to immune checkpoint inhibitors such as cytotoxic T lymphocyte associated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) and PD1 ligand 1 (PD-L1) antibodies strongly correlates with mutational load, which is the highest in UV-induced melanomas and smoke-induced NSCLC.	('mutational', 'Var', (212, 222))	('PD-L1', 'Gene', (169, 174))	('PD1 ligand 1', 'Gene', '29126', (155, 167))	('PD1 ligand 1', 'Gene', (155, 167))	('PD-L1', 'Gene', '29126', (169, 174))	('correlates', 'Reg', (196, 206))	('NSCLC', 'Disease', 'MESH:D002289', (292, 297))	('CTLA4', 'Gene', (104, 109))	('melanomas', 'Disease', 'MESH:D008545', (264, 273))	('NSCLC', 'Disease', (292, 297))	('melanomas', 'Disease', (264, 273))	('PD-1', 'Gene', (145, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (292, 297))	('PD-1', 'Gene', '5133', (145, 149))	('programmed cell death protein 1', 'Gene', (112, 143))	('ligand', 'molecular_function', 'GO:0005488', ('159', '165'))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('programmed cell death', 'biological_process', 'GO:0012501', ('112', '133'))	('melanomas', 'Phenotype', 'HP:0002861', (264, 273))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', (59, 102))	('SCLC', 'Phenotype', 'HP:0030357', (293, 297))	('CTLA4', 'Gene', '1493', (104, 109))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', '1493', (59, 102))	('programmed cell death protein 1', 'Gene', '5133', (112, 143))	('highest', 'Reg', (242, 249))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))
16334	28256574	In addition, there is an increasing body of evidence that differences in the 'estrobolome', the aggregate of enteric bacterial proteins capable of metabolizing estrogens, can substantially affect ER-positive breast cancer development.	('differences', 'Var', (58, 69))	('affect', 'Reg', (189, 195))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
16345	28256574	Cross-species comparative tumour analyses and computational approaches defining co-occurring genetic alterations and synergistic epistatic interactions, as well as mutual exclusivity will help us to model these specific molecular cancer subtypes in tissue context.	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('genetic alterations', 'Var', (93, 112))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumour', 'Disease', (26, 32))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
16346	28256574	A strategy might be to introduce a number of mutations into the appropriate target cell in vitro or in vivo in order to reproduce most of the features that are unique for the particular tumour subtype (Figure 5a).	('mutations', 'Var', (45, 54))	('particular tumour subtype', 'Disease', 'MESH:C535673', (175, 200))	('particular tumour subtype', 'Disease', (175, 200))	('introduce', 'Reg', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))
16347	28256574	This permits us to answer the question how individual mutations contribute to the tumour phenotype and how they influence intervention strategies.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('influence', 'Reg', (112, 121))	('mutations', 'Var', (54, 63))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))
16371	29275424	Overexpression of PCAT7 resulted in the promotion of tumor cell proliferation, inhibition of cells apoptosis, facilitation of cells metastasis, and formation of EMT phenotype, while PCAT7 expression deletion remarkably prohibited cell proliferation, accelerated their apoptosis, weakened metastasis, and reversed EMT to MET.	('PCAT7', 'Gene', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('230', '248'))	('si', 'Chemical', 'MESH:D012825', (295, 297))	('si', 'Chemical', 'MESH:D012825', (194, 196))	('tumor', 'Disease', (53, 58))	('EMT', 'biological_process', 'GO:0001837', ('161', '164'))	('deletion', 'Var', (199, 207))	('apoptosis', 'CPA', (268, 277))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('cell proliferation', 'CPA', (230, 248))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('promotion', 'PosReg', (40, 49))	('PCAT7', 'Gene', '101928099', (182, 187))	('PCAT7', 'Gene', (18, 23))	('accelerated', 'PosReg', (250, 261))	('cells metastasis', 'CPA', (126, 142))	('EMT', 'CPA', (313, 316))	('EMT', 'biological_process', 'GO:0001837', ('313', '316'))	('prohibited', 'NegReg', (219, 229))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('cells apoptosis', 'CPA', (93, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('268', '277'))	('apoptosis', 'biological_process', 'GO:0006915', ('268', '277'))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('si', 'Chemical', 'MESH:D012825', (274, 276))	('PCAT7', 'Gene', '101928099', (18, 23))	('metastasis', 'CPA', (288, 298))	('weakened', 'NegReg', (279, 287))
16381	29275424	There has been ample evidence suggesting that dysregulated lncRNAs are closely related to carcinogenesis.	('dysregulated', 'Var', (46, 58))	('lncRNAs', 'Protein', (59, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('related', 'Reg', (79, 86))	('carcinogenesis', 'Disease', (90, 104))
16402	29275424	After being separated by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), cell protein lysates were first transferred to polyvinylidene fluoride membranes (Roche) and then incubated with specific rabbit anti-human antibodies, including E-cadherin (1: 5000 dilution), N-cadherin (1: 5000 dilution), Vimentin (1: 5000 dilution), caspase-3 (1: 5000 dilution), caspase-9 (1: 5000 dilution), and GAPDH (1: 3000 dilution).	('E-cadherin', 'Gene', '999', (261, 271))	('GAPDH', 'Gene', '2597', (416, 421))	('caspase-3', 'Gene', (352, 361))	('human', 'Species', '9606', (233, 238))	('cadherin', 'molecular_function', 'GO:0008014', ('263', '271'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('cadherin', 'molecular_function', 'GO:0008014', ('294', '302'))	('GAPDH', 'Gene', (416, 421))	('1: 5000 dilution', 'Var', (304, 320))	('Vimentin', 'Gene', '7431', (323, 331))	('1: 5000 dilution', 'Var', (273, 289))	('caspase-9', 'Gene', '842', (382, 391))	('Vimentin', 'cellular_component', 'GO:0045099', ('323', '331'))	('Vimentin', 'Gene', (323, 331))	('1: 5000 dilution', 'Var', (333, 349))	('1: 3000', 'Var', (423, 430))	('caspase-9', 'Gene', (382, 391))	('rabbit', 'Species', '9986', (221, 227))	('N-cadherin', 'Gene', (292, 302))	('Vimentin', 'cellular_component', 'GO:0045098', ('323', '331'))	('1: 5000', 'Var', (393, 400))	('1: 5000 dilution', 'Var', (363, 379))	('caspase-3', 'Gene', '836', (352, 361))	('N-cadherin', 'Gene', '1000', (292, 302))	('E-cadherin', 'Gene', (261, 271))	('si', 'Chemical', 'MESH:D012825', (83, 85))
16459	29275424	Aberrant expression of PCAT7 was closely associated with TNM stage (p=0.035), histological grade (P=0.009), and lymph node metastasis (p=0.03), and high PCAT7 expression was an adverse prognostic factor (P=0.002).	('TNM', 'Gene', '10178', (57, 60))	('Aberrant expression', 'Var', (0, 19))	('associated', 'Reg', (41, 51))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('PCAT7', 'Gene', (153, 158))	('histological grade', 'CPA', (78, 96))	('TNM', 'Gene', (57, 60))	('PCAT7', 'Gene', (23, 28))	('lymph node metastasis', 'CPA', (112, 133))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('expression', 'MPA', (159, 169))	('high', 'Var', (148, 152))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('PCAT7', 'Gene', '101928099', (153, 158))	('PCAT7', 'Gene', '101928099', (23, 28))
16466	29275424	It also has been reported that HOTAIR can regulate downstream genes via epigenetic modification.	('HOTAIR', 'Gene', (31, 37))	('HOTAIR', 'Gene', '100124700', (31, 37))	('epigenetic modification', 'Var', (72, 95))	('regulate', 'Reg', (42, 50))
16473	29275424	Recent publications have showed that BRAF and BC087858 unequivocally augment lung cancer cell motility and invasiveness in vitro.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('lung cancer cell motility', 'Disease', 'MESH:D008175', (77, 102))	('BC087858', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('invasiveness', 'CPA', (107, 119))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('augment', 'PosReg', (69, 76))	('cell motility', 'biological_process', 'GO:0048870', ('89', '102'))	('lung cancer cell motility', 'Disease', (77, 102))
16488	28658153	In addition, high Bmi-1 expression also predicted poor OS (HR = 1.62, 95% CI = 1.14-2.3, P < .001).	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('OS', 'Chemical', '-', (55, 57))	('Bmi-1', 'Gene', (18, 23))	('poor OS', 'Disease', (50, 57))
16498	28658153	Bmi-1 overexpression could promote cell proliferation and induce leukemia initiation through the ink4a locus.	('ink4a', 'Gene', '1029', (97, 102))	('leukemia initiation', 'Disease', (65, 84))	('induce', 'PosReg', (58, 64))	('overexpression', 'Var', (6, 20))	('leukemia initiation', 'Disease', 'MESH:D007938', (65, 84))	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('promote', 'PosReg', (27, 34))	('cell proliferation', 'CPA', (35, 53))	('Bmi-1', 'Gene', (0, 5))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('ink4a', 'Gene', (97, 102))
16519	28658153	These findings suggested that high Bmi-1 expression was an indicator of aggressive biological behavior and distant dissemination of the disease.	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (72, 102))	('dissemination of the disease', 'Disease', 'MESH:D009103', (115, 143))	('expression', 'MPA', (41, 51))	('high', 'Var', (30, 34))	('dissemination of the disease', 'Disease', (115, 143))	('aggressive biological behavior', 'CPA', (72, 102))	('Bmi-1', 'Gene', (35, 40))
16526	28658153	In addition, high Bmi-1 expression also could predict worse OS in patients with NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('worse OS', 'Disease', (54, 62))	('Bmi-1', 'Gene', (18, 23))	('OS', 'Chemical', '-', (60, 62))	('patients', 'Species', '9606', (66, 74))
16530	28658153	The capability of self-renewal and multilineage differentiation in tumorigenesis, which was activated and promoted by Bmi-1 expression, could be the potential mechanisms underlying the correlation between Bmi-1 and poor differentiation in NSCLC.	('activated', 'PosReg', (92, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('Bmi-1', 'Gene', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promoted', 'PosReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('self-renewal', 'CPA', (18, 30))	('NSCLC', 'Disease', (239, 244))	('tumor', 'Disease', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))	('multilineage differentiation', 'CPA', (35, 63))	('expression', 'Var', (124, 134))
16546	27980999	Two emerging aspects considered are establishing research on the controlling delivery effect of SiO2@LDH combined with anti-cancer medicine from a new perspective.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SiO2', 'Chemical', 'MESH:D012822', (96, 100))	('SiO2@LDH', 'Var', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
16547	27980999	The fine properties synthetic SiO2@LDH-VP16 (VP16: etoposide) are practiced to exhibit the nanoparticle's suppression on migration and invasion of non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('migration', 'CPA', (121, 130))	('etoposide', 'Chemical', 'MESH:D005047', (51, 60))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (147, 173))	('VP16', 'Chemical', 'MESH:D005047', (45, 49))	('non-small cell lung cancer', 'Disease', (147, 173))	('SiO2', 'Chemical', 'MESH:D012822', (30, 34))	('LDH-VP16', 'Gene', (35, 43))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (147, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('SiO2@', 'Var', (30, 35))	('suppression', 'NegReg', (106, 117))	('NSCLC', 'Disease', (175, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (151, 173))	('VP16', 'Chemical', 'MESH:D005047', (39, 43))	('invasion', 'CPA', (135, 143))
16548	27980999	Both in vitro and in vivo inspection shows that SiO2@LDH can help VP16 better function as an anti-metastasis agent.	('SiO2', 'Chemical', 'MESH:D012822', (48, 52))	('VP16', 'Gene', (66, 70))	('SiO2@LDH', 'Var', (48, 56))	('VP16', 'Chemical', 'MESH:D005047', (66, 70))
16564	27980999	This study focuses on exploring the potential and mechanism of SiO2@LDH as a drug carrier in anti-metastases, both in vitro and in vivo.	('metastases', 'Disease', (98, 108))	('SiO2', 'Chemical', 'MESH:D012822', (63, 67))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('carrier', 'molecular_function', 'GO:0005215', ('82', '89'))	('SiO2@LDH', 'Var', (63, 71))
16570	27980999	SiO2@LDH-VP16 has better quality of dispersion, and according to the animal study, it is suitable for in vivo injection to the mice.	('mice', 'Species', '10090', (127, 131))	('dispersion', 'MPA', (36, 46))	('SiO2', 'Chemical', 'MESH:D012822', (0, 4))	('VP16', 'Chemical', 'MESH:D005047', (9, 13))	('SiO2@LDH-VP16', 'Var', (0, 13))
16571	27980999	As shown in Figure 1b, the zeta potential of SiO2 was -15 +- 1.2 mV and SiO2@LDH was -3.31 +- 0.2 mV.	('zeta potential', 'MPA', (27, 41))	('SiO2', 'Chemical', 'MESH:D012822', (45, 49))	('SiO2', 'Chemical', 'MESH:D012822', (72, 76))	('SiO2', 'Var', (72, 76))
16572	27980999	In this case, SiO2@LDH revealed properties more closely related to electrical neutrality, and can reduce nonspecific impurities in combination in vivo and can raise the delivery efficiency.	('raise', 'PosReg', (159, 164))	('nonspecific impurities in combination', 'MPA', (105, 142))	('reduce', 'NegReg', (98, 104))	('SiO2', 'Chemical', 'MESH:D012822', (14, 18))	('delivery efficiency', 'MPA', (169, 188))	('SiO2@LDH', 'Var', (14, 22))
16576	27980999	The Barrett-Joyner-Halenda pore size distribution curves are also showed in Figure 1c, all of the three samples appeared a pore size range below 50 nm, and as listed in Table  1 , the mean diameter of SiO2, SiO2@LDH, and SiO2@LDH-VP16 was 14.27, 10.73, and 3.11 nm, respectively.	('pore', 'cellular_component', 'GO:0046930', ('27', '31'))	('SiO2@LDH', 'Var', (207, 215))	('VP16', 'Chemical', 'MESH:D005047', (230, 234))	('SiO2@LDH-VP16', 'Var', (221, 234))	('SiO2', 'Chemical', 'MESH:D012822', (207, 211))	('pore', 'MPA', (123, 127))	('pore', 'cellular_component', 'GO:0046930', ('123', '127'))	('SiO2', 'Chemical', 'MESH:D012822', (201, 205))	('SiO2', 'Chemical', 'MESH:D012822', (221, 225))	('SiO2', 'Var', (201, 205))
16581	27980999	The noticeable decrease in pore size of SiO2@LDH-VP16 was considered due to the existence of drug.	('decrease', 'NegReg', (15, 23))	('SiO2', 'Chemical', 'MESH:D012822', (40, 44))	('VP16', 'Chemical', 'MESH:D005047', (49, 53))	('SiO2@LDH-VP16', 'Var', (40, 53))	('pore size', 'MPA', (27, 36))	('pore', 'cellular_component', 'GO:0046930', ('27', '31'))
16582	27980999	According to the measurement, the drug-loading rate of SiO2@LDH was about 39%, while SiO2 and LDH were 17% and 25%, respectively.	('drug-loading', 'MPA', (34, 46))	('SiO2@LDH', 'Var', (55, 63))	('SiO2', 'Chemical', 'MESH:D012822', (85, 89))	('SiO2', 'Chemical', 'MESH:D012822', (55, 59))
16584	27980999	According to the histogram, over 90% of cells survived after being treated with SiO2@LDH-VP16 for 24 h at a concentration of 2.5 and 5 mug mL-1.	('SiO2', 'Chemical', 'MESH:D012822', (80, 84))	('SiO2@LDH-VP16', 'Var', (80, 93))	('VP16', 'Chemical', 'MESH:D005047', (89, 93))	('mL-1', 'Gene', (139, 143))	('mug', 'molecular_function', 'GO:0043739', ('135', '138'))	('mL-1', 'Gene', '16728', (139, 143))
16587	27980999	As shown in Figure  3 a, the SiO2@LDH-VP16 group had a narrower migration distance and fewer migratory cells compared to free VP16 and LDH-VP16, while the SiO2@LDH group had a negligible difference from the control in both aspects.	('narrower', 'NegReg', (55, 63))	('fewer', 'NegReg', (87, 92))	('migratory cells', 'CPA', (93, 108))	('SiO2', 'Chemical', 'MESH:D012822', (29, 33))	('SiO2@LDH-VP16', 'Var', (29, 42))	('VP16', 'Chemical', 'MESH:D005047', (126, 130))	('VP16', 'Chemical', 'MESH:D005047', (38, 42))	('migration distance', 'CPA', (64, 82))	('SiO2', 'Chemical', 'MESH:D012822', (155, 159))	('VP16', 'Chemical', 'MESH:D005047', (139, 143))
16588	27980999	The metastatic mouse tumor model was chosen to explore the possible anti-cancer effect of SiO2@LDH-VP16.28 The effect on anti-metastasis of SiO2@LDH-VP16, in vivo study was carried out using the tail vein pulmonary model, as shown in Figure  4 .	('SiO2@LDH-VP16', 'Var', (140, 153))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', (21, 26))	('VP16', 'Chemical', 'MESH:D005047', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('anti-metastasis', 'CPA', (121, 136))	('SiO2', 'Chemical', 'MESH:D012822', (140, 144))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('VP16', 'Chemical', 'MESH:D005047', (149, 153))	('SiO2', 'Chemical', 'MESH:D012822', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
16589	27980999	Bioluminescence imaging showed that the mice in the SiO2@LDH-VP16 group formed relatively weak metastasis, compared to PBS group.	('SiO2@LDH-VP16', 'Var', (52, 65))	('Bioluminescence', 'biological_process', 'GO:0008218', ('0', '15'))	('VP16', 'Chemical', 'MESH:D005047', (61, 65))	('weak', 'NegReg', (90, 94))	('PBS', 'Chemical', '-', (119, 122))	('metastasis', 'CPA', (95, 105))	('mice', 'Species', '10090', (40, 44))	('SiO2', 'Chemical', 'MESH:D012822', (52, 56))
16590	27980999	In keeping with the in vitro outcome, SiO2@LDH-VP16 had a more potent inhibitory action than LDH-VP16, while neither LDH nor SiO2@LDH had a decided effect.	('SiO2@LDH-VP16', 'Var', (38, 51))	('VP16', 'Chemical', 'MESH:D005047', (47, 51))	('inhibitory action', 'MPA', (70, 87))	('SiO2', 'Chemical', 'MESH:D012822', (38, 42))	('VP16', 'Chemical', 'MESH:D005047', (97, 101))	('SiO2', 'Chemical', 'MESH:D012822', (125, 129))
16593	27980999	A visualized enhanced efficiency can be observed in the SiO2@LDH-VP16 treatment group.	('enhanced', 'PosReg', (13, 21))	('SiO2@LDH-VP16', 'Var', (56, 69))	('SiO2', 'Chemical', 'MESH:D012822', (56, 60))	('VP16', 'Chemical', 'MESH:D005047', (65, 69))
16594	27980999	In addition, SiO2@LDH may significantly increase the survivability of mice injected with tumor cells, as all the mice survived compared to other groups that had a measurable rate of death during the experiment.	('SiO2@LDH', 'Var', (13, 21))	('increase', 'PosReg', (40, 48))	('survivability', 'CPA', (53, 66))	('SiO2', 'Chemical', 'MESH:D012822', (13, 17))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
16595	27980999	As shown in Figure  5 , compared to free drug or LDH-VP16, in tube formation assay, SiO2@LDH-VP16 showed a more prominent inhibition efficiency of angiogenesis, where almost no tube-like structure can be observed.	('SiO2', 'Chemical', 'MESH:D012822', (84, 88))	('angiogenesis', 'CPA', (147, 159))	('inhibition', 'NegReg', (122, 132))	('SiO2@LDH-VP16', 'Var', (84, 97))	('VP16', 'Chemical', 'MESH:D005047', (93, 97))	('tube formation assay', 'CPA', (62, 82))	('tube formation', 'biological_process', 'GO:0035148', ('62', '76'))	('angiogenesis', 'biological_process', 'GO:0001525', ('147', '159'))	('VP16', 'Chemical', 'MESH:D005047', (53, 57))
16596	27980999	As to the chorioallantoic membrane (CAM) assay, neovascularization was significantly suppressed when treated with SiO2@LDH-VP16, in accordance with the lack of tube formation.	('neovascularization', 'CPA', (48, 66))	('SiO2', 'Chemical', 'MESH:D012822', (114, 118))	('suppressed', 'NegReg', (85, 95))	('VP16', 'Chemical', 'MESH:D005047', (123, 127))	('membrane', 'cellular_component', 'GO:0016020', ('26', '34'))	('SiO2@LDH-VP16', 'Var', (114, 127))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('tube formation', 'biological_process', 'GO:0035148', ('160', '174'))
16597	27980999	Analysis of in vivo matrigel plugs also confirmed that SiO2@LDH-VP16 reduced the degree of vascularization.	('LDH-VP16', 'Gene', (60, 68))	('SiO2@', 'Var', (55, 60))	('reduced', 'NegReg', (69, 76))	('SiO2', 'Chemical', 'MESH:D012822', (55, 59))	('VP16', 'Chemical', 'MESH:D005047', (64, 68))
16598	27980999	The hematoxylin and eosin (H&E) photos further prove the above results that SiO2@LDH-VP16 has a marked decreased infiltration, similar to that observed in the negative control.	('that SiO2@', 'Var', (71, 81))	('VP16', 'Chemical', 'MESH:D005047', (85, 89))	('H&E', 'Chemical', '-', (27, 30))	('hematoxylin', 'Chemical', 'MESH:D006416', (4, 15))	('marked', 'NegReg', (96, 102))	('decreased', 'MPA', (103, 112))	('eosin', 'Chemical', 'MESH:D004801', (20, 25))	('SiO2', 'Chemical', 'MESH:D012822', (76, 80))
16600	27980999	The cellular uptake of SiO2@LDH-VP16 is assessed by fluorescence-activated cell sorting (FACS) analysis, as evident in Figure  6 .	('uptake', 'biological_process', 'GO:0098739', ('13', '19'))	('SiO2', 'Chemical', 'MESH:D012822', (23, 27))	('SiO2@', 'Var', (23, 28))	('LDH-VP16', 'Gene', (28, 36))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('VP16', 'Chemical', 'MESH:D005047', (32, 36))	('uptake', 'biological_process', 'GO:0098657', ('13', '19'))
16604	27980999	Figure  7  clearly verified the result of FACS, since both LDH-VP16 and SiO2@LDH-VP16 revealed an increase of fluorescein isothiocyanate (FITC) fluorescence intensity, besides, SiO2@LDH, which had a notably improved efficacy of raising the uptake of VP16 in A549 cell.	('SiO2@LDH', 'Var', (177, 185))	('improved', 'PosReg', (207, 215))	('uptake', 'biological_process', 'GO:0098739', ('240', '246'))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('VP16', 'Chemical', 'MESH:D005047', (250, 254))	('uptake', 'MPA', (240, 246))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (110, 136))	('VP16', 'Chemical', 'MESH:D005047', (81, 85))	('VP16', 'Chemical', 'MESH:D005047', (63, 67))	('increase', 'PosReg', (98, 106))	('raising', 'PosReg', (228, 235))	('FITC', 'Chemical', 'MESH:D016650', (138, 142))	('SiO2', 'Chemical', 'MESH:D012822', (177, 181))	('LDH-VP16', 'Var', (59, 67))	('A549', 'CellLine', 'CVCL:0023', (258, 262))	('SiO2@LDH-VP16', 'Var', (72, 85))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('SiO2', 'Chemical', 'MESH:D012822', (72, 76))	('uptake', 'biological_process', 'GO:0098657', ('240', '246'))
16607	27980999	As evident in Figure  8 a, SiO2@LDH-VP16 remarkably weakened the band value of phospho-VEGFR-2, PI3K, phospho-mTOR, and phospho-AKT, whereas the phosph-ss-catenin signal was significant increased after SiO2@LDH-VP16 treatment.	('SiO2@LDH-VP16', 'Var', (202, 215))	('band value', 'MPA', (65, 75))	('SiO2@LDH-VP16', 'Var', (27, 40))	('increased', 'PosReg', (186, 195))	('PI3K', 'Gene', (96, 100))	('phosph-ss-catenin signal', 'MPA', (145, 169))	('VEGFR-2', 'Gene', '16542', (87, 94))	('phospho-AKT', 'Pathway', (120, 131))	('SiO2', 'Chemical', 'MESH:D012822', (202, 206))	('VEGFR-2', 'Gene', (87, 94))	('SiO2', 'Chemical', 'MESH:D012822', (27, 31))	('weakened', 'NegReg', (52, 60))	('phospho-mTOR', 'MPA', (102, 114))	('VP16', 'Chemical', 'MESH:D005047', (211, 215))	('VP16', 'Chemical', 'MESH:D005047', (36, 40))	('PI3K', 'molecular_function', 'GO:0016303', ('96', '100'))
16610	27980999	Specific surface area (SSA) is an important property of porous solid materials, which measured as the total surface area of a material per unit of mass.29 Previous researches have made clear that higher surface areas can contribute to improve loading capacity of nanoparticles.30, 31 Results show the increased SSA of SiO2@LDH compared with SiO2 (76.82-122.06 m2 g-1).	('SiO2', 'Chemical', 'MESH:D012822', (318, 322))	('SSA', 'MPA', (311, 314))	('SiO2@LDH', 'Var', (318, 326))	('increased', 'PosReg', (301, 310))	('SiO2', 'Chemical', 'MESH:D012822', (341, 345))
16611	27980999	Besides, in Figure S2 in the Supporting Information, the FTIR spectra of free VP16, SiO2@LDH, and SiO2@LDH-VP16 were shown.	('SiO2', 'Chemical', 'MESH:D012822', (84, 88))	('SiO2@LDH', 'Var', (84, 92))	('SiO2', 'Chemical', 'MESH:D012822', (98, 102))	('VP16', 'Chemical', 'MESH:D005047', (107, 111))	('SiO2@LDH-VP16', 'Var', (98, 111))	('VP16', 'Chemical', 'MESH:D005047', (78, 82))
16612	27980999	Free VP16 showed the following selected bands: 2923 cm-1 (C:H stretch), 1770 cm-1 (C=O stretch of ester bond), 1610 cm-1 (C=O stretch of carboxyl methyl), 1110 cm-1 (C:O:C stretch), and 1487 cm-1 (C=C stretching in the backbone of the aromatic phenyl ring).	('1610 cm-1', 'Var', (111, 120))	('1487 cm-1', 'Var', (186, 195))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('C', 'Chemical', 'MESH:D002244', (83, 84))	('C', 'Chemical', 'MESH:D002244', (166, 167))	('C', 'Chemical', 'MESH:D002244', (122, 123))	('C', 'Chemical', 'MESH:D002244', (197, 198))	('1110 cm-1', 'Var', (155, 164))	('2923 cm-1', 'Var', (47, 56))	('ester', 'Chemical', 'MESH:D004952', (98, 103))	('C', 'Chemical', 'MESH:D002244', (199, 200))	('VP16', 'Chemical', 'MESH:D005047', (5, 9))	('C', 'Chemical', 'MESH:D002244', (58, 59))
16613	27980999	The spectra of SiO2@LDH showed characteristic peaks: 3461.69 and 1384.12 cm-1 (:OH stretching vibration and NO3-) and 989.41 cm-1 (Si:OH bending vibration).	('SiO2', 'Chemical', 'MESH:D012822', (15, 19))	('989.41 cm-1', 'Var', (118, 129))	('SiO2@', 'Gene', (15, 20))
16616	27980999	Only about 10% of VP16 released from SiO2@LDH at 48 h when the pH value is 7.4.	('VP16', 'Protein', (18, 22))	('SiO2', 'Chemical', 'MESH:D012822', (37, 41))	('SiO2@LDH', 'Var', (37, 45))	('VP16', 'Chemical', 'MESH:D005047', (18, 22))
16619	27980999	In the case of this study, since the VP16 loading ratio of SiO2 is only 17%, to achieve the best loading ratio, LDH-VP16 and SiO2@LDH-VP16 were served as potential agent of delivery VP16, and further exploration of their comparison and difference prove that SiO2@LDH-VP16 has the advantage over LDH-VP16 in anti-metastatic efficiency.	('VP16', 'Chemical', 'MESH:D005047', (37, 41))	('SiO2@LDH-VP16', 'Var', (258, 271))	('VP16', 'Chemical', 'MESH:D005047', (116, 120))	('VP16', 'Chemical', 'MESH:D005047', (134, 138))	('anti-metastatic efficiency', 'CPA', (307, 333))	('VP16', 'Chemical', 'MESH:D005047', (182, 186))	('VP16', 'Chemical', 'MESH:D005047', (299, 303))	('SiO2', 'Chemical', 'MESH:D012822', (59, 63))	('SiO2', 'Chemical', 'MESH:D012822', (258, 262))	('SiO2', 'Chemical', 'MESH:D012822', (125, 129))	('VP16', 'Chemical', 'MESH:D005047', (267, 271))
16624	27980999	In accordance with the in vitro results, fluorescence living imaging proves the distinct enhanced anti-metastasis impact of SiO2@LDH-VP16.	('VP16', 'Chemical', 'MESH:D005047', (133, 137))	('enhanced', 'PosReg', (89, 97))	('SiO2@LDH-VP16', 'Var', (124, 137))	('anti-metastasis impact', 'CPA', (98, 120))	('SiO2', 'Chemical', 'MESH:D012822', (124, 128))
16625	27980999	In H&E staining, lung sections of SiO2@LDH-VP16 reveal less nuclear matter and highly disseminated cytoplasmic structures compared to other groups.	('VP16', 'Chemical', 'MESH:D005047', (43, 47))	('of SiO2@', 'Var', (31, 39))	('reveal', 'NegReg', (48, 54))	('H&E', 'Chemical', '-', (3, 6))	('SiO2', 'Chemical', 'MESH:D012822', (34, 38))	('less nuclear', 'CPA', (55, 67))
16626	27980999	MTT and survival curve (Figure 4d) clearly prove the biosafety of SiO2@LDH and SiO2@LDH-VP16 only has a negligible impact on cell apoptosis at the designated dose, therefore, it would not have significant influence in evaluating cancer cell migration and invasion.	('SiO2@LDH-VP16', 'Var', (79, 92))	('SiO2@LDH', 'Var', (66, 74))	('VP16', 'Chemical', 'MESH:D005047', (88, 92))	('cell migration', 'biological_process', 'GO:0016477', ('236', '250'))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('SiO2', 'Chemical', 'MESH:D012822', (79, 83))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('SiO2', 'Chemical', 'MESH:D012822', (66, 70))
16628	27980999	The mechanism of the anti-metastasis effect of SiO2@LDH must be further explained in depth.	('SiO2', 'Chemical', 'MESH:D012822', (47, 51))	('anti-metastasis effect', 'CPA', (21, 43))	('SiO2@LDH', 'Var', (47, 55))
16633	27980999	The considerable decrease of blood vessels in the SiO2@LDH-VP16 group illustrates the anti-angiogenesis effect of the drug-delivery hybrid system.	('angiogenesis', 'biological_process', 'GO:0001525', ('91', '103'))	('SiO2', 'Chemical', 'MESH:D012822', (50, 54))	('anti-angiogenesis effect', 'CPA', (86, 110))	('VP16', 'Chemical', 'MESH:D005047', (59, 63))	('decrease', 'NegReg', (17, 25))	('blood vessels', 'CPA', (29, 42))	('SiO2@LDH-VP16', 'Var', (50, 63))
16634	27980999	Consequently, SiO2@LDH-VP16 can inhibit expansion of vascularized tumors, both locally and metastasized.	('VP16', 'Chemical', 'MESH:D005047', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SiO2@LDH-VP16', 'Var', (14, 27))	('inhibit', 'NegReg', (32, 39))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('SiO2', 'Chemical', 'MESH:D012822', (14, 18))	('C', 'Chemical', 'MESH:D002244', (0, 1))
16640	27980999	Disrupting microtubule action may contribute to inhibiting tumor growth and angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('microtubule', 'Protein', (11, 22))	('tumor', 'Disease', (59, 64))	('angiogenesis', 'CPA', (76, 88))	('inhibiting', 'NegReg', (48, 58))	('Disrupting', 'Var', (0, 10))	('microtubule', 'cellular_component', 'GO:0005874', ('11', '22'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
16641	27980999	Targeting microtubule to suppress the dynamics has become a very important field in the current anti-cancer drug industry.42, 43, 44 The co-location photos indicate that SiO2@LDH-VP16 is acting on the cytomembrane and microtubules to suppress the cancer metastasis.	('cytomembrane', 'Chemical', '-', (201, 213))	('SiO2', 'Chemical', 'MESH:D012822', (170, 174))	('cancer metastasis', 'Disease', (247, 264))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('VP16', 'Chemical', 'MESH:D005047', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', (101, 107))	('SiO2@LDH-VP16', 'Var', (170, 183))	('microtubule', 'cellular_component', 'GO:0005874', ('10', '21'))	('cancer metastasis', 'Disease', 'MESH:D009362', (247, 264))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('suppress', 'NegReg', (234, 242))
16644	27980999	The findings argue that the activated receptor such as VEGF plays a role as an antigenic factor and that VEGFR-2 is necessary for tumor metastasis.46 Western blot bands demonstrated a decrease in phosphorylation of VEGFR-2 after treatment with SiO2@LDH-VP16 on A549 cells.	('SiO2@LDH-VP16', 'Var', (244, 257))	('SiO2', 'Chemical', 'MESH:D012822', (244, 248))	('VEGFR-2', 'Gene', '16542', (105, 112))	('tumor metastasis', 'Disease', 'MESH:D009362', (130, 146))	('phosphorylation', 'biological_process', 'GO:0016310', ('196', '211'))	('VEGF', 'Gene', (105, 109))	('VEGF', 'Gene', '22339', (105, 109))	('VEGFR-2', 'Gene', '16542', (215, 222))	('tumor metastasis', 'Disease', (130, 146))	('A549', 'CellLine', 'CVCL:0023', (261, 265))	('VEGF', 'Gene', (215, 219))	('phosphorylation', 'MPA', (196, 211))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('VEGF', 'Gene', '22339', (215, 219))	('decrease', 'NegReg', (184, 192))	('VEGFR-2', 'Gene', (105, 112))	('VEGF', 'Gene', (55, 59))	('VP16', 'Chemical', 'MESH:D005047', (253, 257))	('ester', 'Chemical', 'MESH:D004952', (151, 156))	('VEGF', 'Gene', '22339', (55, 59))	('VEGFR-2', 'Gene', (215, 222))
16649	27980999	Results show that SiO2@LDH-VP16 has a decent drug loading capability, which efficiently inhibited the cell migration and invasion on A549 cell and reduced metastasis in mice models.	('inhibited', 'NegReg', (88, 97))	('LDH-VP16', 'Gene', (23, 31))	('SiO2@', 'Var', (18, 23))	('VP16', 'Chemical', 'MESH:D005047', (27, 31))	('drug loading capability', 'MPA', (45, 68))	('metastasis in mice models', 'CPA', (155, 180))	('mice', 'Species', '10090', (169, 173))	('SiO2', 'Chemical', 'MESH:D012822', (18, 22))	('reduced', 'NegReg', (147, 154))	('A549', 'CellLine', 'CVCL:0023', (133, 137))	('cell migration', 'biological_process', 'GO:0016477', ('102', '116'))
16650	27980999	Better still, SiO2@LDH-VP16 shows a significant effect in elevating the mice survival rates.	('VP16', 'Chemical', 'MESH:D005047', (23, 27))	('mice survival rates', 'CPA', (72, 91))	('elevating', 'PosReg', (58, 67))	('SiO2@LDH-VP16', 'Var', (14, 27))	('mice', 'Species', '10090', (72, 76))	('SiO2', 'Chemical', 'MESH:D012822', (14, 18))
16652	27980999	To sum up, this work provides a fire-new perspective of using SiO2@LDH nanoparticles combined with anti-cancer medicine.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('SiO2', 'Chemical', 'MESH:D012822', (62, 66))	('SiO2', 'Var', (62, 66))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
16684	27980999	Next, the cells were divided into two groups treated with SiO2@LDH, VP16, LDH-VP16, and SiO2@LDH-VP16 in the two concentrations (2.5 and 5 mug mL-1), respectively.	('VP16', 'Chemical', 'MESH:D005047', (68, 72))	('mL-1', 'Gene', '16728', (143, 147))	('SiO2', 'Chemical', 'MESH:D012822', (88, 92))	('mug', 'molecular_function', 'GO:0043739', ('139', '142'))	('SiO2@LDH-VP16', 'Var', (88, 101))	('mL-1', 'Gene', (143, 147))	('VP16', 'Chemical', 'MESH:D005047', (97, 101))	('SiO2', 'Chemical', 'MESH:D012822', (58, 62))	('VP16', 'Chemical', 'MESH:D005047', (78, 82))
16687	27980999	Cell Culture and In Vitro Analysis:Transwell Migration Assay: A549 cells were pre-cultured with serum-free media for 4 h and then suspended at density of 1 x 105 per well in serum-free media (200 muL) containing VP16, LDH-VP16, SiO2@LDH, or SiO2@LDH-VP16 at two concentrations (2.5 and 5 mug mL-1), the suspended cells were seeded to upper chamber of 24-well transwell plates (BD Biosciences) with filters with an 8.0 mum pore size (Costar).	('VP16', 'Chemical', 'MESH:D005047', (250, 254))	('VP16', 'Chemical', 'MESH:D005047', (222, 226))	('VP16', 'Chemical', 'MESH:D005047', (212, 216))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('pre', 'molecular_function', 'GO:0003904', ('78', '81'))	('SiO2@LDH-VP16', 'Var', (241, 254))	('SiO2', 'Chemical', 'MESH:D012822', (228, 232))	('mL-1', 'Gene', '16728', (292, 296))	('pore', 'cellular_component', 'GO:0046930', ('422', '426'))	('VP16', 'Var', (212, 216))	('SiO2@LDH', 'Var', (228, 236))	('mug', 'molecular_function', 'GO:0043739', ('288', '291'))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('C', 'Chemical', 'MESH:D002244', (433, 434))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('SiO2', 'Chemical', 'MESH:D012822', (241, 245))	('LDH-VP16', 'Var', (218, 226))	('mL-1', 'Gene', (292, 296))
16691	27980999	In Vitro and In Vivo Angiogenes is Assays:Matrigel Tube Formation Assay: Tube formation was determined as a classical in vitro angiogenesis assay following reported protocol.56 The starving human umbilical vein endothelial cells were seeded onto Matrigel-coated 96-well at a concentration of 1 x 104 per well and cultured for 24 h in media (5% FBS, 10 ng mL-1 VEGF) with VP16, LDH, SiO2@LDH, LDH-VP16, or SiO2@LDH-VP16 (5 mug mL-1).	('Tube formation', 'biological_process', 'GO:0035148', ('73', '87'))	('FBS', 'Disease', (344, 347))	('FBS', 'Disease', 'MESH:D005198', (344, 347))	('mug', 'molecular_function', 'GO:0043739', ('422', '425'))	('mL-1', 'Gene', '16728', (426, 430))	('mL-1', 'Gene', '16728', (355, 359))	('VP16', 'Chemical', 'MESH:D005047', (414, 418))	('human', 'Species', '9606', (190, 195))	('VEGF', 'Gene', (360, 364))	('Tube Formation', 'biological_process', 'GO:0035148', ('51', '65'))	('VEGF', 'Gene', '22339', (360, 364))	('VP16', 'Chemical', 'MESH:D005047', (396, 400))	('mL-1', 'Gene', (426, 430))	('SiO2@LDH-VP16', 'Var', (405, 418))	('SiO2', 'Chemical', 'MESH:D012822', (382, 386))	('mL-1', 'Gene', (355, 359))	('VP16', 'Chemical', 'MESH:D005047', (371, 375))	('angiogenesis', 'biological_process', 'GO:0001525', ('127', '139'))	('SiO2', 'Chemical', 'MESH:D012822', (405, 409))
16693	27980999	The eggs were divided into different groups treated with VP16, LDH, SiO2@LDH, LDH-VP16, or SiO2@LDH-VP16 (5 mug mL-1) for a week in the incubator.	('mL-1', 'Gene', '16728', (112, 116))	('VP16', 'Chemical', 'MESH:D005047', (57, 61))	('VP16', 'Chemical', 'MESH:D005047', (82, 86))	('VP16', 'Chemical', 'MESH:D005047', (100, 104))	('SiO2', 'Chemical', 'MESH:D012822', (68, 72))	('SiO2', 'Chemical', 'MESH:D012822', (91, 95))	('mL-1', 'Gene', (112, 116))	('mug', 'molecular_function', 'GO:0043739', ('108', '111'))	('SiO2@LDH-VP16', 'Var', (91, 104))
16710	27980999	Co-Localization Assay: To further explore the cellular uptake of SiO2@LDH-VP16 nanoparticles, traditional markers were utilized for co-localization.	('VP16', 'Chemical', 'MESH:D005047', (74, 78))	('Localization', 'biological_process', 'GO:0051179', ('3', '15'))	('uptake', 'biological_process', 'GO:0098657', ('55', '61'))	('uptake', 'biological_process', 'GO:0098739', ('55', '61'))	('SiO2', 'Chemical', 'MESH:D012822', (65, 69))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('LDH-VP16', 'Gene', (70, 78))	('SiO2@', 'Var', (65, 70))	('localization', 'biological_process', 'GO:0051179', ('135', '147'))
16711	27980999	While DAPI (blue) was used to marked the cell nucleus.60, 61 A549 cells were incubated with VP16-FITC, LDH-VP16-FITC, or SiO2@LDH-VP16-FITC (10 mug mL-1, green) for 24 h, washed twice with PBS and then stained with Dil, Tubulin or DAPI for a certain time according to the description of kits (KeyGen BioTECH, Nanjing, China).	('cell nucleus', 'cellular_component', 'GO:0005634', ('41', '53'))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('C', 'Chemical', 'MESH:D002244', (100, 101))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('VP16-FITC', 'Chemical', '-', (92, 101))	('C', 'Chemical', 'MESH:D002244', (305, 306))	('PBS', 'Chemical', '-', (189, 192))	('VP16-FITC', 'Chemical', '-', (107, 116))	('VP16-FITC', 'Var', (92, 101))	('VP16-FITC', 'Chemical', '-', (130, 139))	('C', 'Chemical', 'MESH:D002244', (318, 319))	('mL-1', 'Gene', '16728', (148, 152))	('DAPI', 'Chemical', 'MESH:C007293', (231, 235))	('LDH-VP16-FITC', 'Var', (103, 116))	('A549', 'CellLine', 'CVCL:0023', (61, 65))	('SiO2', 'Chemical', 'MESH:D012822', (121, 125))	('mL-1', 'Gene', (148, 152))	('DAPI', 'Chemical', 'MESH:C007293', (6, 10))	('mug', 'molecular_function', 'GO:0043739', ('144', '147'))
16713	27980999	Western Blot Assay: A549 cells were seeded onto a 6-well plate and treated with VP16, LDH-VP16, SiO2@LDH-VP16, LDH, or SiO2@LDH at a two concentrations (5 and 10 mug mL-1).	('mug', 'molecular_function', 'GO:0043739', ('162', '165'))	('A549', 'CellLine', 'CVCL:0023', (20, 24))	('SiO2@LDH-VP16', 'Var', (96, 109))	('mL-1', 'Gene', (166, 170))	('LDH-VP16', 'Var', (86, 94))	('SiO2@LDH', 'Var', (119, 127))	('SiO2', 'Chemical', 'MESH:D012822', (119, 123))	('SiO2', 'Chemical', 'MESH:D012822', (96, 100))	('VP16', 'Chemical', 'MESH:D005047', (90, 94))	('ester', 'Chemical', 'MESH:D004952', (1, 6))	('VP16', 'Chemical', 'MESH:D005047', (80, 84))	('mL-1', 'Gene', '16728', (166, 170))	('VP16', 'Chemical', 'MESH:D005047', (105, 109))
16715	27980999	Membranes were probed for ss-actin, phospho-ss-catenin (Ser33/37/Thr41), PI3 Kinase p110alpha (PI3K), phospho-mTOR (Ser2448), phospho-AKT (Ser 473, phospho-VEGFR-2, FAK (D2R2E), and Paxillin (D9G12) using specific antibodies (Cell Signaling Technology, Danvers, MA, USA).	('Ser', 'cellular_component', 'GO:0005790', ('56', '59'))	('Ser', 'cellular_component', 'GO:0005790', ('139', '142'))	('FAK', 'Gene', '14083', (165, 168))	('Ser33', 'Chemical', '-', (56, 61))	('FAK', 'molecular_function', 'GO:0004717', ('165', '168'))	('Ser', 'Chemical', 'MESH:D012694', (116, 119))	('Paxillin', 'Gene', (182, 190))	('Ser', 'Chemical', 'MESH:D012694', (139, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('VEGFR-2', 'Gene', (156, 163))	('Paxillin', 'Gene', '19303', (182, 190))	('Ser2448', 'Chemical', '-', (116, 123))	('Signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('Ser', 'Chemical', 'MESH:D012694', (56, 59))	('FAK', 'Gene', (165, 168))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('Thr41', 'Chemical', '-', (65, 70))	('VEGFR-2', 'Gene', '16542', (156, 163))	('Ser', 'cellular_component', 'GO:0005790', ('116', '119'))	('Ser33/37/Thr41', 'Var', (56, 70))
16749	27796371	We show that modulation in receptor binding efficiency has no effect on virulence, supporting observations from others on the lack of connection between H3N2 IAV binding and virulence in humans.	('H3N2', 'Species', '119210', (153, 157))	('virulence', 'biological_process', 'GO:0009405', ('72', '81'))	('virulence', 'MPA', (72, 81))	('humans', 'Species', '9606', (187, 193))	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('receptor binding', 'molecular_function', 'GO:0005102', ('27', '43'))	('virulence', 'biological_process', 'GO:0016032', ('174', '183'))	('virulence', 'biological_process', 'GO:0009405', ('174', '183'))	('virulence', 'biological_process', 'GO:0009406', ('174', '183'))	('virulence', 'biological_process', 'GO:0016032', ('72', '81'))	('virulence', 'biological_process', 'GO:0009406', ('72', '81'))	('binding', 'Interaction', (36, 43))	('modulation', 'Var', (13, 23))
16750	27796371	The binding of H3N2 variants with different levels of glycosylation was analyzed using the Consortium for Functional Glycomics (CFG) v5.1 glycan array.	('v5.1', 'Gene', (133, 137))	('H3N2', 'Species', '119210', (15, 19))	('variants', 'Var', (20, 28))	('v5.1', 'Gene', '28786', (133, 137))	('glycosylation', 'biological_process', 'GO:0070085', ('54', '67'))	('binding', 'Interaction', (4, 11))	('glycan', 'Chemical', 'MESH:D011134', (138, 144))	('H3N2', 'Gene', (15, 19))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
16751	27796371	Three viruses, constructed by reverse genetics (rg), were used, containing unmodified HA from wild-type HK68 (rgHK68), or HK68 HA with two (residues 63 and 126: rgHK68 + 2) or four (residues 63, 126, 133, and 246: rgHK68 + 4) additional glycosylation sites.	('glycosylation', 'biological_process', 'GO:0070085', ('237', '250'))	('residues 63', 'Var', (182, 193))	('residues 63 and 126: rgHK68 + 2', 'Var', (140, 171))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))
16755	27796371	Eighteen glycans were recognized by rgHK68 and rgHK68 + 4 only, and twenty-three and nine glycans were recognized only by rgHK68 or rgHK68 + 4, respectively.	('glycans', 'Chemical', 'MESH:D011134', (90, 97))	('glycans', 'Chemical', 'MESH:D011134', (9, 16))	('rgHK68', 'Var', (132, 138))	('rgHK68', 'Var', (36, 42))	('rgHK68 + 4', 'Var', (47, 57))
16757	27796371	As expected, rgHK68 showed higher binding than did its glycosylation variants, based on both the number of glycans bound and the total level of fluorescent intensity (Fig.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('glycans', 'Chemical', 'MESH:D011134', (107, 114))	('glycosylation', 'biological_process', 'GO:0070085', ('55', '68'))	('binding', 'Interaction', (34, 41))	('higher', 'PosReg', (27, 33))	('rgHK68', 'Var', (13, 19))
16761	27796371	Structurally, the rgHK68 recognized multiantennary glycans (such as glycans 57, 464, 466, 481, 482, and 606; the glycan numbering corresponds to those of the CFG v5.1 glycan array) with LacNAc substitutions or LacNAc repeats (short poly LacNAc; glycans 606 and 608) as major components at the highest affinity.	('glycan', 'Chemical', 'MESH:D011134', (167, 173))	('glycan', 'Chemical', 'MESH:D011134', (68, 74))	('glycan', 'Chemical', 'MESH:D011134', (113, 119))	('LacNAc', 'Chemical', 'MESH:C000458', (237, 243))	('LacNAc', 'Chemical', 'MESH:C000458', (210, 216))	('LacNAc', 'Chemical', 'MESH:C000458', (186, 192))	('substitutions', 'Var', (193, 206))	('glycans', 'Chemical', 'MESH:D011134', (245, 252))	('v5.1', 'Gene', (162, 166))	('glycan', 'Chemical', 'MESH:D011134', (51, 57))	('glycans', 'Chemical', 'MESH:D011134', (68, 75))	('rgHK68', 'Gene', (18, 24))	('v5.1', 'Gene', '28786', (162, 166))	('glycan', 'Chemical', 'MESH:D011134', (245, 251))	('poly LacNAc', 'Chemical', '-', (232, 243))	('glycans', 'Chemical', 'MESH:D011134', (51, 58))
16762	27796371	In terms of antennary substructures, the Neu5Acalpha2-6Galbeta1-4GlcNAcbeta1-2Mana1,3- arm of the N-linked glycan (glycans 319, 346, and 348) appears to be a stronger requirement for high affinity binding than the equivalent Neu5Acalpha2-6Galbeta1-4GlcNAcbeta1-2Mana1,6- arm (glycans 308, 345, and 347).	('N-linked glycan', 'Chemical', '-', (98, 113))	('Mana1', 'Gene', (78, 83))	('348', 'Var', (137, 140))	('Mana1', 'Gene', '4123', (78, 83))	('glycans', 'Chemical', 'MESH:D011134', (115, 122))	('glycans', 'Chemical', 'MESH:D011134', (276, 283))	('Neu5Acalpha2-6Galbeta1-4GlcNAcbeta1', 'Chemical', '-', (41, 76))	('Mana1', 'Gene', '4123', (262, 267))	('binding', 'Interaction', (197, 204))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))	('Mana1', 'Gene', (262, 267))	('Neu5Acalpha2-6Galbeta1-4GlcNAcbeta1', 'Chemical', '-', (225, 260))
16763	27796371	The glycans containing terminal alpha2,3-linked SA (including those with a LacNAc motif such as glycans 237, 266, 325, 462, 483, and 600) were also bound by rgHK68, however, at lower overall affinity (8,323 +- 1,046 RFU; Fig.	('SA', 'Chemical', 'MESH:D019158', (48, 50))	('rgHK68', 'Gene', (157, 163))	('glycans', 'Chemical', 'MESH:D011134', (4, 11))	('bound', 'Interaction', (148, 153))	('462', 'Var', (119, 122))	('LacNAc', 'Chemical', 'MESH:C000458', (75, 81))	('glycans', 'Chemical', 'MESH:D011134', (96, 103))
16765	27796371	Consistent with findings from others, key structural motifs required for efficient rgHK68 binding were Neu5Acalpha2,6-LacNAc and poly LacNAc.	('poly LacNAc', 'Chemical', '-', (129, 140))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('Neu5Ac', 'Chemical', 'MESH:D019158', (103, 109))	('6-LacNAc', 'Chemical', '-', (116, 124))	('rgHK68', 'Gene', (83, 89))	('poly LacNAc', 'Var', (129, 140))
16769	27796371	2A), and had the lowest total fluorescence intensities of the three viruses (1,049 +- 94 RFU for alpha2,3- and 2,825 +- 301 RFU for alpha2,6-linked SAs; Fig.	('1,049', 'Var', (77, 82))	('alpha2,6-linked SA', 'Chemical', '-', (132, 150))	('fluorescence intensities', 'MPA', (30, 54))	('lowest', 'NegReg', (17, 23))
16770	27796371	Among the glycans that bound both rgHK68 and rgHK68 + 2, signal was diminished ~20 to 80% in the rgHK68 + 2 virus analysis.	('signal', 'MPA', (57, 63))	('glycans', 'Chemical', 'MESH:D011134', (10, 17))	('rgHK68', 'Var', (97, 103))	('diminished', 'NegReg', (68, 78))	('rgHK68', 'Var', (34, 40))	('rgHK68 + 2', 'Var', (45, 55))
16772	27796371	Unexpectedly, adding two further glycans to positions 133 and 246 of rgHK68 + 2 HA, to create rgHK68 + 4, restored much of the binding.	('restored', 'PosReg', (106, 114))	('binding', 'Interaction', (127, 134))	('glycans', 'Chemical', 'MESH:D011134', (33, 40))	('rgHK68 + 4', 'Var', (94, 104))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))
16773	27796371	The rgHK68 + 4 bound to 21 alpha2,6-, 15 alpha2,3-and two dual-linked SAs with total binding intensities of 25,956 +- 3,009 RFU, 6,610 +- 649 RFU, and 1,724 +- 160 RFU, respectively (Table 1 and Fig.	('SA', 'Chemical', 'MESH:D019158', (70, 72))	('rgHK68 + 4', 'Var', (4, 14))	('bound', 'Interaction', (15, 20))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('binding', 'Interaction', (85, 92))
16776	27796371	As seen for the rgHK68 virus, the rgHK68 + 4 showed strong binding signals to glycans containing both LacNAc and poly LacNAc units.	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('poly LacNAc', 'Chemical', '-', (113, 124))	('binding', 'Interaction', (59, 66))	('glycans', 'Protein', (78, 85))	('LacNAc', 'Chemical', 'MESH:C000458', (118, 124))	('glycans', 'Chemical', 'MESH:D011134', (78, 85))	('LacNAc', 'Chemical', 'MESH:C000458', (102, 108))	('poly LacNAc', 'Var', (113, 124))
16781	27796371	In the case of rgHK+4, the preference is for glycan 318 where the Neu5Acalpha2-6 is present on the Mana1,6 arm and Neu5Acalpha2,3 is present on the Man1,3 arm.	('Neu5Acalpha2-6', 'Var', (66, 80))	('glycan', 'Chemical', 'MESH:D011134', (45, 51))	('Man', 'Species', '9606', (99, 102))	('Mana1', 'Gene', '4123', (99, 104))	('Neu5Ac', 'Chemical', 'MESH:D019158', (66, 72))	('Neu5Ac', 'Chemical', 'MESH:D019158', (115, 121))	('Mana1', 'Gene', (99, 104))	('Man', 'Species', '9606', (148, 151))
16782	27796371	More striking, binding of rgHK68 + 4 to Neu5Acalpha2,6 capped chitobiose and chitotriose (glycans 366 and 367) was nearly five times higher than that of rgHK68.	('rgHK68 + 4', 'Var', (26, 36))	('glycans', 'Chemical', 'MESH:D011134', (90, 97))	('chitotriose', 'Chemical', 'MESH:C041161', (77, 88))	('binding', 'molecular_function', 'GO:0005488', ('15', '22'))	('higher', 'PosReg', (133, 139))	('binding', 'Interaction', (15, 22))	('Neu5Ac', 'Chemical', 'MESH:D019158', (40, 46))
16783	27796371	Similarly to rgHK68, both glycosylation variants (rgHK68 + 2 and rgHK68 + 4) preferentially bound to Neu5Acalpha2,6-linked glycans, but also retained substantial recognition of Neu5Acalpha2,3-linked glycans, with the proportion of alpha2,3- and alpha2,6-linked SAs being similar for all viruses (31% to 39% for alpha2-3-linkage, and of 55% to 63% for alpha2,6-linkage; Table 1 and Fig.	('alpha2,6-linked SA', 'Chemical', '-', (245, 263))	('recognition', 'MPA', (162, 173))	('preferentially', 'PosReg', (77, 91))	('Neu5Ac', 'Chemical', 'MESH:D019158', (177, 183))	('rgHK68 +', 'Var', (65, 73))	('Neu5Ac', 'Chemical', 'MESH:D019158', (101, 107))	('bound', 'Interaction', (92, 97))	('glycosylation', 'biological_process', 'GO:0070085', ('26', '39'))	('glycans', 'Chemical', 'MESH:D011134', (123, 130))	('glycans', 'Chemical', 'MESH:D011134', (199, 206))
16788	27796371	Binding to the SAs within this subset was comparable for the rgHK68 and rgHK68 + 4 viruses, while binding of rgHK68 + 2 was less than 50% or 20% (based on the number of glycans bound and the level of total binding intensity, respectively) of that determined for rgHK68 or rgHK68 + 4.	('binding', 'molecular_function', 'GO:0005488', ('206', '213'))	('glycans', 'Chemical', 'MESH:D011134', (169, 176))	('SA', 'Chemical', 'MESH:D019158', (15, 17))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('rgHK68', 'Var', (61, 67))	('less', 'NegReg', (124, 128))
16790	27796371	Similar to rgHK68, both glycosylation variants (rgHK68 + 2 and rgHK68 + 4) preferentially bound to alpha2,6-linked SAs, but also retained substantial recognition of alpha2,3-linked SA.	('rgHK68', 'Var', (48, 54))	('SA', 'Chemical', 'MESH:D019158', (181, 183))	('glycosylation', 'biological_process', 'GO:0070085', ('24', '37'))	('bound', 'Interaction', (90, 95))	('rgHK68 + 4', 'Var', (63, 73))	('SA', 'Chemical', 'MESH:D019158', (115, 117))	('preferentially', 'PosReg', (75, 89))	('alpha2,6-linked SA', 'Chemical', '-', (99, 117))	('recognition', 'MPA', (150, 161))
16799	27796371	Our data therefore suggest that the avidity of rgHK68 + 2 virus to SA receptors present on chicken, human and guinea RBC (as determined at 37  C) is much lower than that of rgHK68 or rgHK68 + 4.	('lower', 'NegReg', (154, 159))	('rgHK68 + 2', 'Var', (47, 57))	('human', 'Species', '9606', (100, 105))	('SA', 'Chemical', 'MESH:D019158', (67, 69))	('avidity', 'MPA', (36, 43))	('SA receptors', 'Protein', (67, 79))	('chicken', 'Species', '9031', (91, 98))
16800	27796371	In contrast to chicken, human, and guinea pig RBC, none of the rgHK68 viruses eluted from turkey RBC even after 20 hours of incubation at elevated temperature of 37  C. Importantly, even though rgHK68 + 2 bound to a limited number of sialylated structures with relatively low affinity, it remained attached to the TRBC for the full 20-hour experiment.	('chicken', 'Species', '9031', (15, 22))	('human', 'Species', '9606', (24, 29))	('turkey', 'Species', '9103', (90, 96))	('guinea pig', 'Species', '10141', (35, 45))	('sialylated structures', 'Protein', (234, 255))	('bound', 'Interaction', (205, 210))	('rgHK68 + 2', 'Var', (194, 204))
16801	27796371	Although each of the rgHK68 viruses contained NAs with identical sequences, it remained possible that different amounts of NA could incorporate into each virion (which might affect the catalytic activity of the virus and therefore the elution rate), or that the changes in HA might indirectly alter NA activity.	('NA', 'Gene', '4758', (299, 301))	('virion', 'cellular_component', 'GO:0019012', ('154', '160'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('185', '203'))	('NA', 'Gene', '4758', (46, 48))	('NA', 'Gene', '4758', (123, 125))	('catalytic activity', 'MPA', (185, 203))	('rgHK68', 'Gene', (21, 27))	('affect', 'Reg', (174, 180))	('changes', 'Var', (262, 269))	('alter', 'Reg', (293, 298))
16804	27796371	The rgHK68 + 4 showed slightly higher catalytic activity than did rgHK68 and rgHK68 + 2; however, this effect would increase elution rates while rgHK68 + 4 eluted from chicken, human, and guinea pig RBC much more slowly than did rgHK68 + 2 and, similar to rgHK68 and rgHK68 + 2, did not elute from turkey RBC.	('guinea pig', 'Species', '10141', (188, 198))	('catalytic activity', 'molecular_function', 'GO:0003824', ('38', '56'))	('slowly', 'NegReg', (213, 219))	('chicken', 'Species', '9031', (168, 175))	('catalytic activity', 'MPA', (38, 56))	('rgHK68 + 4', 'Var', (145, 155))	('elution rates', 'MPA', (125, 138))	('increase', 'PosReg', (116, 124))	('turkey', 'Species', '9103', (298, 304))	('higher', 'PosReg', (31, 37))	('human', 'Species', '9606', (177, 182))
16822	27796371	Thus, when mice were challenged with 105.0 PFU the mean mouse lung titers of rgHK68 + 4 were up to 1,000-fold lower than titers of rgHK68 (which bound similar levels of SA), while rgHK68 + 2 (which bound much lower levels of SA than either rgHK68 or rgHK68 + 4) produced up to 500-fold higher titers than did rgHK68 + 4 (p < 0.05; Fig.	('mouse', 'Species', '10090', (56, 61))	('SA', 'Chemical', 'MESH:D019158', (169, 171))	('mice', 'Species', '10090', (11, 15))	('lower', 'NegReg', (110, 115))	('SA', 'Chemical', 'MESH:D019158', (225, 227))	('rgHK68', 'Var', (77, 83))
16824	27796371	7B) of mice infected with rgHK68 was significantly higher than that of mice infected with rgHK68 + 4 (p < 0.05), and mice infected with rgHK68 + 2 lost a similar amount of weight as rgHK68 + 4-infected mice.	('mice', 'Species', '10090', (71, 75))	('mice', 'Species', '10090', (202, 206))	('mice', 'Species', '10090', (7, 11))	('mice', 'Species', '10090', (117, 121))	('rgHK68', 'Var', (26, 32))	('higher', 'PosReg', (51, 57))
16832	27796371	In the case of rgHK68 + 4, additional glycans at sites 133 and 246, essentially inside the RBS, being primarily substituted with high mannose glycans could favorably interact sterically in the region which would facilitate restoration of receptor function.	('glycans', 'Chemical', 'MESH:D011134', (38, 45))	('facilitate', 'PosReg', (212, 222))	('glycans', 'Chemical', 'MESH:D011134', (142, 149))	('interact', 'Interaction', (166, 174))	('mannose glycans', 'Chemical', '-', (134, 149))	('high mannose glycans', 'Phenotype', 'HP:0410357', (129, 149))	('restoration', 'MPA', (223, 234))	('rgHK68', 'Var', (15, 21))	('receptor function', 'MPA', (238, 255))
16835	27796371	Consistent with the latter and our previous observation that variations in SA binding by H3N2 IAVs isolated from 1968 to 2012 does not correlate with disease severity or spread, modulation in receptor binding of rgHK68 viruses had no effect on such viral characteristics as elution from turkey RBC, growth in epithelial cell cultures, cytopathology, or virulence in mice.	('receptor binding', 'molecular_function', 'GO:0005102', ('192', '208'))	('H3N2', 'Gene', (89, 93))	('elution', 'MPA', (274, 281))	('turkey', 'Species', '9103', (287, 293))	('rgHK68', 'Gene', (212, 218))	('H3N2', 'Species', '119210', (89, 93))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('virulence', 'biological_process', 'GO:0016032', ('353', '362'))	('SA', 'Chemical', 'MESH:D019158', (75, 77))	('virulence', 'biological_process', 'GO:0009406', ('353', '362'))	('variations', 'Var', (61, 71))	('modulation', 'Var', (178, 188))	('virulence', 'biological_process', 'GO:0009405', ('353', '362'))	('mice', 'Species', '10090', (366, 370))
16990	27574400	One of these genes is p66Shc, the deletion of which results in a 30% increase in the lifespan.	('p66Shc', 'Gene', '20416', (22, 28))	('increase', 'PosReg', (69, 77))	('p66Shc', 'Gene', (22, 28))	('deletion', 'Var', (34, 42))	('lifespan', 'CPA', (85, 93))
17017	27535324	However, misregulated cell migration can contribute to pathology as in autoimmune diseases and, most notably, metastatic cancer.	('cell migration', 'biological_process', 'GO:0016477', ('22', '36'))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (71, 90))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('autoimmune diseases', 'Disease', (71, 90))	('autoimmune diseases', 'Disease', 'MESH:D001327', (71, 90))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('contribute', 'Reg', (41, 51))	('misregulated', 'Var', (9, 21))	('cell migration', 'CPA', (22, 36))
17039	27535324	In our standard set of epithelial and fibroblast cell lines, we observed that, as expected, cytochalasin D treatment significantly decreased migration in all cell lines (Fig.	('cytochalasin D', 'Chemical', 'MESH:D015638', (92, 106))	('migration', 'CPA', (141, 150))	('decreased', 'NegReg', (131, 140))	('cytochalasin', 'Var', (92, 104))
17045	27535324	At the standard concentration of 1 mug/mL, cytochalasin D inhibited migration in all breast cell lines with the exception of MCF7.	('mug', 'molecular_function', 'GO:0043739', ('35', '38'))	('MCF7', 'CellLine', 'CVCL:0031', (125, 129))	('inhibited', 'NegReg', (58, 67))	('cytochalasin D', 'Var', (43, 57))	('migration', 'CPA', (68, 77))	('cytochalasin D', 'Chemical', 'MESH:D015638', (43, 57))
17048	27535324	Lung tissue samples were collected from K-ras G12D mutant mice from either lung nodules (cancer) or normal tissue from the same animal.	('G12D', 'Mutation', 'rs121913529', (46, 50))	('G12D mutant', 'Var', (46, 57))	('mutant', 'Var', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('K-ras', 'Gene', '16653', (40, 45))	('mice', 'Species', '10090', (58, 62))	('K-ras', 'Gene', (40, 45))	('cancer', 'Disease', (89, 95))	('lung nodules', 'Disease', 'MESH:D016606', (75, 87))	('lung nodules', 'Disease', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
17078	27535324	CellTrace Far Red (C34572), CellTrace Violet (C34557), and SYTO 24 Green Fluorescent Nucleic Acid Stain (SYTO 24) (S7559) were purchased from ThermoFisher Scientific (Waltham, MA).	('CellTrace', 'Chemical', '-', (0, 9))	('Nucleic Acid', 'cellular_component', 'GO:0005561', ('85', '97'))	('C34557', 'Var', (46, 52))	('SYTO 24 Green', 'Chemical', '-', (59, 72))	('CellTrace', 'Chemical', '-', (28, 37))	('SYTO 24', 'Chemical', '-', (59, 66))	('CellTrace Violet', 'Chemical', '-', (28, 44))	('C34572', 'Var', (19, 25))	('SYTO 24', 'Chemical', '-', (105, 112))
17102	27366094	1p/19q codeletion and RET rearrangements in small-cell lung cancer The prognosis of small-cell lung cancer (SCLC) is poor despite reports suggesting modest improvement in survival.	('RET', 'Gene', (22, 25))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (44, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (44, 66))	('SCLC', 'Gene', '7864', (108, 112))	('SCLC', 'Phenotype', 'HP:0030357', (108, 112))	('SCLC', 'Gene', (108, 112))	('small-cell lung cancer', 'Disease', (44, 66))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (84, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('RET', 'Gene', '5979', (22, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (84, 106))	('rearrangements', 'Var', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('small-cell lung cancer', 'Disease', (84, 106))
17104	27366094	For instance, the therapeutic effect of temozolomide, recommended for patients with relapsed SCLC, is linked to 1p/19q codeletion in anaplastic oligodendroglial tumors.	('patients', 'Species', '9606', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('SCLC', 'Gene', '7864', (93, 97))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('SCLC', 'Gene', (93, 97))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (144, 167))	('oligodendroglial tumors', 'Disease', (144, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('1p/19q codeletion', 'Var', (112, 129))	('temozolomide', 'Chemical', 'MESH:D000077204', (40, 52))
17107	27366094	Fluorescence in situ hybridization was used to detect 1p/19q codeletion and RET rearrangement in the specimens.	('RET', 'Gene', '5979', (76, 79))	('RET', 'Gene', (76, 79))	('1p/19q codeletion', 'Var', (54, 71))
17110	27366094	There was a trend toward prolonged overall survival for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (P=0.113, 0.168, 0.116, and 0.122, respectively).	('overall survival', 'MPA', (35, 51))	('prolonged', 'PosReg', (25, 34))	('19q single deletion', 'Var', (132, 151))	('patients', 'Species', '9606', (60, 68))
17112	27366094	Instead, 1p/19q codeletion is a promising marker for a good prognosis and treatment with temozolomide in SCLC.	('temozolomide', 'Chemical', 'MESH:D000077204', (89, 101))	('1p/19q codeletion', 'Var', (9, 26))	('SCLC', 'Gene', '7864', (105, 109))	('SCLC', 'Phenotype', 'HP:0030357', (105, 109))	('SCLC', 'Gene', (105, 109))
17122	27366094	The 1p/19q codeletion is an important predictive and prognostic factor in anaplastic and recurrent oligodendrogliomas treated with temozolomide and was significantly correlated with response rate (P=0.04), time-to-progression (P=0.003), and overall survival (P=0.0001).	('correlated', 'Reg', (166, 176))	('oligodendrogliomas', 'Disease', (99, 117))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('temozolomide', 'Chemical', 'MESH:D000077204', (131, 143))	('1p/19q codeletion', 'Var', (4, 21))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (99, 117))
17123	27366094	However, it is unknown whether 1p/19q codeletion exists in SCLC and whether it can be used as a predictive and prognostic factor for SCLC.	('SCLC', 'Gene', '7864', (59, 63))	('SCLC', 'Phenotype', 'HP:0030357', (59, 63))	('1p/19q codeletion', 'Var', (31, 48))	('SCLC', 'Gene', (133, 137))	('SCLC', 'Gene', '7864', (133, 137))	('SCLC', 'Phenotype', 'HP:0030357', (133, 137))	('SCLC', 'Gene', (59, 63))
17124	27366094	RET rearrangements are found in 1%-2% of NSCLC patients and are drivers of tumor growth in vitro and in vivo.	('RET', 'Gene', '5979', (0, 3))	('NSCLC', 'Disease', (41, 46))	('rearrangements', 'Var', (4, 18))	('SCLC', 'Phenotype', 'HP:0030357', (42, 46))	('patients', 'Species', '9606', (47, 55))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('RET', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('tumor', 'Disease', (75, 80))
17128	27366094	Confirmed partial responses were observed in two patients, including one harboring a novel TRIM33-RET fusion, and stable disease for at least 8 months was noted in a third patient with a KIF5B-RET.	('KIF5B', 'Gene', '3799', (187, 192))	('fusion', 'Var', (102, 108))	('patient', 'Species', '9606', (172, 179))	('RET', 'Gene', (98, 101))	('RET', 'Gene', '5979', (193, 196))	('patient', 'Species', '9606', (49, 56))	('patients', 'Species', '9606', (49, 57))	('KIF5B', 'Gene', (187, 192))	('TRIM33', 'Gene', '51592', (91, 97))	('RET', 'Gene', '5979', (98, 101))	('TRIM33', 'Gene', (91, 97))	('RET', 'Gene', (193, 196))
17129	27366094	A study by Dabir et al suggests that tyrosine kinase inhibitors targeting RET may be a beneficial treatment for a subpopulation of SCLC patients.	('RET', 'Gene', (74, 77))	('SCLC', 'Gene', '7864', (131, 135))	('SCLC', 'Phenotype', 'HP:0030357', (131, 135))	('SCLC', 'Gene', (131, 135))	('RET', 'Gene', '5979', (74, 77))	('patients', 'Species', '9606', (136, 144))	('tyrosine', 'Var', (37, 45))
17147	27366094	Deletions of 1p and 19q were defined as 20% of tumor nuclei containing the ratio<0.87 as recommended by guidelines.	('tumor', 'Disease', (47, 52))	('Deletions', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
17151	27366094	Only three specimens had a 1p/19q codeletion and no patients had RET rearrangements (Figures 1 and S1).	('RET', 'Gene', (65, 68))	('RET', 'Gene', '5979', (65, 68))	('1p/19q codeletion', 'Var', (27, 44))	('patients', 'Species', '9606', (52, 60))
17152	27366094	There was no difference between the clinical characteristics (including age, sex, smoking history, stage, and cycles of chemotherapy) for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (Table 1).	('patients', 'Species', '9606', (142, 150))	('1p single deletion', 'Var', (194, 212))	('19q single deletion', 'Var', (214, 233))
17153	27366094	There was a trend toward prolonged overall survival for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (P=0.113, 0.168, 0.116, and 0.122, respectively) (Figures 2-5).	('overall survival', 'MPA', (35, 51))	('prolonged', 'PosReg', (25, 34))	('19q single deletion', 'Var', (132, 151))	('patients', 'Species', '9606', (60, 68))
17158	27366094	The size of the resected tumor was 5x4x 3.5 cm, and his pathological TNM stage was T2aN2M0 (IIIA).	('IIA', 'Disease', 'MESH:C536042', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('T2aN2M0', 'Var', (83, 90))	('TNM', 'Gene', '10178', (69, 72))	('tumor', 'Disease', (25, 30))	('IIA', 'Disease', (93, 96))	('TNM', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
17172	27366094	His pathological TNM stage was T2aN0M0 (IB).	('TNM', 'Gene', (17, 20))	('TNM', 'Gene', '10178', (17, 20))	('T2aN0M0', 'Var', (31, 38))
17176	27366094	The codeletion of the 1p and 19q chromosomal arms is a characteristic and early genetic event in oligodendroglial tumors, which is associated with a better prognosis and enhanced response to therapy.	('codeletion', 'Var', (4, 14))	('oligodendroglial tumors', 'Disease', (97, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (97, 120))
17179	27366094	Due to a trend toward prolonged overall survival for the patients with 1p/19q codeletion, 1p/19q codeletion may be a promising marker for a good prognosis of SCLC and needs to be validated in a larger number of patients.	('SCLC', 'Phenotype', 'HP:0030357', (158, 162))	('SCLC', 'Gene', (158, 162))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (57, 65))	('overall survival', 'MPA', (32, 48))	('1p/19q codeletion', 'Var', (90, 107))	('1p/19q codeletion', 'Var', (71, 88))	('prolonged', 'PosReg', (22, 31))	('SCLC', 'Gene', '7864', (158, 162))
17180	27366094	FISH is the most commonly used method for the detection of 1p/19q codeletion in glioma specimens.	('glioma', 'Disease', (80, 86))	('1p/19q codeletion', 'Var', (59, 76))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (80, 86))
17181	27366094	FISH was used to detect 1p/19q codeletion and RET rearrangement for SCLC specimens in our study.	('1p/19q codeletion', 'Var', (24, 41))	('RET', 'Gene', '5979', (46, 49))	('SCLC', 'Gene', (68, 72))	('SCLC', 'Gene', '7864', (68, 72))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('RET', 'Gene', (46, 49))
17184	27366094	Using the combined analysis of massively parallel whole-genome and transcriptome sequencing for cancer and paired normal tissue, Ju et al reported a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21 in a 33-year-old lung adenocarcinoma patient who was a never-smoker with no familial cancer history.	('RET', 'Gene', '5979', (189, 192))	('lung adenocarcinoma', 'Disease', (278, 297))	('KIF5B', 'Gene', (175, 180))	('patient', 'Species', '9606', (298, 305))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (278, 297))	('cancer', 'Disease', (346, 352))	('familial cancer', 'Disease', 'MESH:D009369', (337, 352))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('KIF5B', 'Gene', '3799', (175, 180))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (278, 297))	('RET', 'Gene', (189, 192))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('familial cancer', 'Disease', (337, 352))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('cancer', 'Disease', (96, 102))	('fusion gene', 'Var', (155, 166))
17185	27366094	This fusion gene overexpressed chimeric RET receptor tyrosine kinase, which spontaneously induced cellular transformation.	('RET', 'Gene', (40, 43))	('RET', 'Gene', '5979', (40, 43))	('cellular transformation', 'CPA', (98, 121))	('chimeric', 'Var', (31, 39))	('induced', 'Reg', (90, 97))
17186	27366094	Of 936 patients with NSCLC, the RET fusion gene was detected in 13 patients of whom nine patients had a KIF5B-RET fusion, three patients had a CCDC6-RET fusion, and one patient had a novel NCOA4-RET fusion.	('patient', 'Species', '9606', (89, 96))	('RET', 'Gene', (195, 198))	('RET', 'Gene', '5979', (32, 35))	('patient', 'Species', '9606', (128, 135))	('SCLC', 'Phenotype', 'HP:0030357', (22, 26))	('patients', 'Species', '9606', (7, 15))	('RET', 'Gene', '5979', (110, 113))	('RET', 'Gene', '5979', (149, 152))	('patient', 'Species', '9606', (7, 14))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('fusion', 'Var', (114, 120))	('KIF5B', 'Gene', '3799', (104, 109))	('RET', 'Gene', (32, 35))	('NSCLC', 'Disease', (21, 26))	('patients', 'Species', '9606', (67, 75))	('NCOA4', 'Gene', (189, 194))	('NCOA4', 'Gene', '8031', (189, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('CCDC6', 'Gene', (143, 148))	('patients', 'Species', '9606', (128, 136))	('RET', 'Gene', (110, 113))	('CCDC6', 'Gene', '8030', (143, 148))	('RET', 'Gene', (149, 152))	('patient', 'Species', '9606', (67, 74))	('RET', 'Gene', '5979', (195, 198))	('patients', 'Species', '9606', (89, 97))	('KIF5B', 'Gene', (104, 109))	('patient', 'Species', '9606', (169, 176))
17187	27366094	An activating M918T RET somatic mutation in a metastatic SCLC tumor specimen was identified.	('RET', 'Gene', '5979', (20, 23))	('M918T', 'Var', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('SCLC tumor', 'Disease', 'MESH:D018288', (57, 67))	('SCLC tumor', 'Disease', (57, 67))	('activating', 'PosReg', (3, 13))	('RET', 'Gene', (20, 23))	('SCLC', 'Phenotype', 'HP:0030357', (57, 61))	('M918T', 'Mutation', 'rs74799832', (14, 19))
17192	27366094	However, 1p/19q codeletion is a promising marker for a good prognosis and treatment with temozolomide in SCLC.	('temozolomide', 'Chemical', 'MESH:D000077204', (89, 101))	('1p/19q codeletion', 'Var', (9, 26))	('SCLC', 'Gene', '7864', (105, 109))	('SCLC', 'Phenotype', 'HP:0030357', (105, 109))	('SCLC', 'Gene', (105, 109))
17257	33564267	Dual-luciferase reporter assay was utilized to explore the target relationship among HOXA11-AS, miR-152-3p and ITGA9.	('HOXA11-AS', 'Gene', (85, 94))	('ITGA9', 'Gene', '3680', (111, 116))	('miR-152-3p', 'Chemical', '-', (96, 106))	('ITGA9', 'Gene', (111, 116))	('miR-152-3p', 'Var', (96, 106))
17259	33564267	HOXA11-AS and ITGA9 were up-regulated while miR-152-3p was down-regulated in melanoma.	('up-regulated', 'PosReg', (25, 37))	('HOXA11-AS', 'Gene', (0, 9))	('ITGA9', 'Gene', '3680', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('down-regulated', 'NegReg', (59, 73))	('ITGA9', 'Gene', (14, 19))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('miR-152-3p', 'Var', (44, 54))	('miR-152-3p', 'Chemical', '-', (44, 54))
17260	33564267	Knockdown of HOXA11-AS refrained cell proliferation, metastasis and epithelial-mesenchymal transition (EMT) but induced apoptosis in melanoma cells.	('HOXA11-AS', 'Var', (13, 22))	('epithelial-mesenchymal transition', 'CPA', (68, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('induced', 'Reg', (112, 119))	('apoptosis', 'CPA', (120, 129))	('metastasis', 'CPA', (53, 63))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('melanoma', 'Disease', (133, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('EMT', 'biological_process', 'GO:0001837', ('103', '106'))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('68', '101'))	('cell proliferation', 'CPA', (33, 51))
17266	33564267	HOXA11-AS could promote melanoma development and be used as a promising biomarker in the diagnosis and treatment for cutaneous melanoma.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('promote', 'PosReg', (16, 23))	('cutaneous melanoma', 'Disease', (117, 135))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (24, 32))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('HOXA11-AS', 'Var', (0, 9))
17322	33564267	The sequences of wild-type (WT) and mutant-type (MUT) HOXA11-AS were cloned into the pGL3 vector (Promega, Madison, WI, USA) and the positive plasmids were named as HOXA11-AS WT and HOXA11-AS MUT.	('si', 'Chemical', 'MESH:D012825', (135, 137))	('pGL3', 'Gene', '6391', (85, 89))	('pGL', 'molecular_function', 'GO:0004598', ('85', '88'))	('mutant-type', 'Var', (36, 47))	('pGL3', 'Gene', (85, 89))	('HOXA11-AS', 'Gene', (54, 63))
17332	33564267	The linear relationship among HOXA11-AS, miR-152-3p and ITGA9 in melanoma tissues was analyzed by Spearman correlation coefficient.	('miR-152-3p', 'Var', (41, 51))	('miR-152-3p', 'Chemical', '-', (41, 51))	('ITGA9', 'Gene', '3680', (56, 61))	('ITGA9', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
17336	33564267	In comparison to normal tissues, the expression of HOXA11-AS was overtly increased in melanoma tissues (Figure 1A).	('increased', 'PosReg', (73, 82))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('HOXA11-AS', 'Var', (51, 60))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('expression', 'MPA', (37, 47))
17337	33564267	There was a lower 5-year overall survival of melanoma patients with high expression of HOXA11-AS by contrast to those patients with low expression of HOXA11-AS (Figure 1B).	('si', 'Chemical', 'MESH:D012825', (79, 81))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('patients', 'Species', '9606', (54, 62))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('high expression', 'Var', (68, 83))	('HOXA11-AS', 'Protein', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('patients', 'Species', '9606', (118, 126))	('overall survival', 'MPA', (25, 41))	('lower', 'NegReg', (12, 17))
17338	33564267	Also, HOXA11-AS was markedly up-regulated in melanoma cell lines A875 and M14 compared to normal melanocytes HEMa-LP (Figure 1C).	('HOXA11-AS', 'Var', (6, 15))	('up-regulated', 'PosReg', (29, 41))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
17339	33564267	On the contrary, miR-152-3p expression was notably decreased in melanoma tissues (Figure 1D) than that in normal tissues.	('miR-152-3p', 'Chemical', '-', (17, 27))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('decreased', 'NegReg', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('miR-152-3p', 'Var', (17, 27))
17340	33564267	It was also inverse that overall survival was noticeably declined in patients with low miR-152-3p level (Figure 1E).	('declined', 'NegReg', (57, 65))	('miR-152-3p', 'Chemical', '-', (87, 97))	('miR-152-3p level', 'Var', (87, 103))	('patients', 'Species', '9606', (69, 77))	('low', 'NegReg', (83, 86))	('overall survival', 'CPA', (25, 41))
17343	33564267	The dysregulation of HOXA11-AS and miR-152-3p demonstrated that they might play crucial roles in melanoma.	('miR-152-3p', 'Var', (35, 45))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('roles', 'Reg', (88, 93))	('melanoma', 'Disease', (97, 105))	('dysregulation', 'Var', (4, 17))	('play', 'Reg', (75, 79))	('miR-152-3p', 'Chemical', '-', (35, 45))	('HOXA11-AS', 'Protein', (21, 30))
17344	33564267	To investigate the role of HOXA11-AS in melanoma, A875 and M14 cells were transfected with si-HOXA11-AS or si-NC.	('si', 'Chemical', 'MESH:D012825', (91, 93))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('si-NC', 'Var', (107, 112))	('si-HOXA11-AS', 'Var', (91, 103))	('si-HOXA11-AS', 'Chemical', '-', (91, 103))	('si', 'Chemical', 'MESH:D012825', (107, 109))
17345	33564267	The qRT-PCR indicated that HOXA11-AS expression was distinctly decreased in si-HOXA11-AS group compared with si-NC group in A875 and M14 cells (Figure 2A and B).	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('decreased', 'NegReg', (63, 72))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('si-HOXA11-AS', 'Var', (76, 88))	('si-HOXA11-AS', 'Chemical', '-', (76, 88))	('HOXA11-AS expression', 'MPA', (27, 47))
17346	33564267	Then, MTT assay revealed that cell proliferation was strikingly declined in A875 and M14 cells transfected with si-HOXA11-AS (Figure 2C and D).	('cell proliferation', 'CPA', (30, 48))	('si-HOXA11-AS', 'Chemical', '-', (112, 124))	('declined', 'NegReg', (64, 72))	('MTT', 'Chemical', 'MESH:C070243', (6, 9))	('si-HOXA11-AS', 'Var', (112, 124))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
17347	33564267	Flow cytometry manifested that the apoptotic rate was increased after transfection with si-HOXA11-AS in A875 cells (Figure 2E) and M14 cells (Figure 2F).	('si-HOXA11-AS', 'Chemical', '-', (88, 100))	('si-HOXA11-AS', 'Var', (88, 100))	('apoptotic rate', 'CPA', (35, 49))	('increased', 'PosReg', (54, 63))
17349	33564267	As shown in Figure 2G and H, the numbers of migrated and invaded cells were significantly fewer in si-HOXA11-AS group than these in si-NC group.	('si-HOXA11-AS', 'Chemical', '-', (99, 111))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('fewer', 'NegReg', (90, 95))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('si-HOXA11-AS', 'Var', (99, 111))
17350	33564267	The level of E-cadherin (anti-EMT marker) was signally enhanced but N-cadherin and Vimentin (pro-EMT markers) were reduced (Figure 2I and J) in A875 and M14 cells transfected with si-HOXA11-AS, implying the EMT process was blocked after downregulation of HOXA11-AS.	('EMT', 'biological_process', 'GO:0001837', ('30', '33'))	('reduced', 'NegReg', (115, 122))	('EMT', 'biological_process', 'GO:0001837', ('207', '210'))	('E-cadherin', 'Gene', (13, 23))	('si-HOXA11-AS', 'Var', (180, 192))	('E-cadherin', 'Gene', '999', (13, 23))	('Vimentin', 'cellular_component', 'GO:0045099', ('83', '91'))	('N-cadherin', 'Gene', (68, 78))	('enhanced', 'PosReg', (55, 63))	('N-cadherin', 'Gene', '1000', (68, 78))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('Vimentin', 'Gene', '7431', (83, 91))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('Vimentin', 'cellular_component', 'GO:0045098', ('83', '91'))	('Vimentin', 'Gene', (83, 91))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('si-HOXA11-AS', 'Chemical', '-', (180, 192))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))
17351	33564267	Thus, knockdown of HOXA11-AS generated the inhibitory effects on cellular proliferation, metastasis, EMT and the stimulative effect on apoptosis.	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('EMT', 'CPA', (101, 104))	('knockdown', 'Var', (6, 15))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('EMT', 'biological_process', 'GO:0001837', ('101', '104'))	('inhibitory effects', 'NegReg', (43, 61))	('metastasis', 'CPA', (89, 99))	('HOXA11-AS', 'Gene', (19, 28))	('cellular proliferation', 'CPA', (65, 87))
17352	33564267	As shown in Figure 3A, HOXA11-AS WT contained the binding sites with miR-152-3p.	('miR-152-3p', 'Var', (69, 79))	('miR-152-3p', 'Chemical', '-', (69, 79))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('binding', 'Interaction', (50, 57))
17353	33564267	Dual-luciferase reporter assay presented that miR-152-3p prominently decreased the luciferase activity of HOXA11-AS WT group, contrasted to the HOXA11-AS MUT group in both A875 and M14 cells (Figure 3B and C).	('luciferase activity', 'molecular_function', 'GO:0047077', ('83', '102'))	('decreased', 'NegReg', (69, 78))	('miR-152-3p', 'Var', (46, 56))	('luciferase activity', 'molecular_function', 'GO:0045289', ('83', '102'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('83', '102'))	('activity', 'MPA', (94, 102))	('luciferase activity', 'molecular_function', 'GO:0050248', ('83', '102'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('83', '102'))	('miR-152-3p', 'Chemical', '-', (46, 56))	('luciferase', 'Enzyme', (83, 93))
17354	33564267	Additionally, miR-152-3p expression was obviously elevated by knockdown of HOXA11-AS and lessened by overexpression of HOXA11-AS in A875 and M14 cells (Figure 3D and E).	('miR-152-3p', 'Gene', (14, 24))	('HOXA11-AS', 'Gene', (75, 84))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('elevated', 'PosReg', (50, 58))	('miR-152-3p', 'Chemical', '-', (14, 24))	('lessened', 'NegReg', (89, 97))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('knockdown', 'Var', (62, 71))
17356	33564267	To explore the regulatory mechanism of HOXA11-AS in melanoma, A875 and M14 cells were transfected with miR-152-3p, miR-152-3p+HOXA11-AS or the relative controls.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('miR-152-3p', 'Chemical', '-', (103, 113))	('miR-152-3p', 'Chemical', '-', (115, 125))	('miR-152-3p', 'Var', (103, 113))	('miR-152-3p+HOXA11-AS', 'Var', (115, 135))
17358	33564267	Cell proliferation was inhibited by transfection of miR-152-3p, whereas overexpression of HOXA11-AS alleviated this inhibitory effect (Figure 4C and D).	('miR-152-3p', 'Var', (52, 62))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('inhibited', 'NegReg', (23, 32))	('miR-152-3p', 'Chemical', '-', (52, 62))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('transfection', 'Var', (36, 48))	('Cell proliferation', 'CPA', (0, 18))
17359	33564267	Flow cytometry exhibited that miR-152-3p clearly increased the apoptotic rate in A875 and M14 cells, but the promoted effect was partly prevented by HOXA11-AS up-regulation (Figure 4E and F).	('increased', 'PosReg', (49, 58))	('up-regulation', 'PosReg', (159, 172))	('apoptotic rate', 'CPA', (63, 77))	('regulation', 'biological_process', 'GO:0065007', ('162', '172'))	('miR-152-3p', 'Var', (30, 40))	('miR-152-3p', 'Chemical', '-', (30, 40))
17361	33564267	Moreover, the E-cadherin upregulation and N-cadherin/Vimentin downregulation caused by miR-152-3p were partially relieved by HOXA11-AS in A875 cells (Figure 4I) and M14 cells (Figure 4J).	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('miR-152-3p', 'Var', (87, 97))	('Vimentin', 'cellular_component', 'GO:0045099', ('53', '61'))	('N-cadherin', 'Gene', (42, 52))	('miR-152-3p', 'Chemical', '-', (87, 97))	('Vimentin', 'Gene', (53, 61))	('downregulation', 'NegReg', (62, 76))	('N-cadherin', 'Gene', '1000', (42, 52))	('Vimentin', 'cellular_component', 'GO:0045098', ('53', '61'))	('E-cadherin', 'Gene', (14, 24))	('Vimentin', 'Gene', '7431', (53, 61))	('upregulation', 'PosReg', (25, 37))
17363	33564267	Meanwhile, the rescued experiment was performed to notarize whether the function of HOXA11-AS knockdown was attributed to miR-152-3p up-regulation.	('miR-152-3p', 'Chemical', '-', (122, 132))	('regulation', 'biological_process', 'GO:0065007', ('136', '146'))	('miR-152-3p', 'Var', (122, 132))	('up-regulation', 'PosReg', (133, 146))	('HOXA11-AS', 'Gene', (84, 93))
17364	33564267	After the qRT-PCR analysis, miR-152-3p inhibition was showed to weaken the increase of miR-152-3p level caused by si-HOXA11-AS in A875 and M14 cells (Supplemental Figure 1A and B).	('si', 'Chemical', 'MESH:D012825', (114, 116))	('si-HOXA11-AS', 'Var', (114, 126))	('weaken', 'NegReg', (64, 70))	('miR-152-3p', 'Chemical', '-', (28, 38))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si-HOXA11-AS', 'Chemical', '-', (114, 126))	('miR-152-3p', 'Chemical', '-', (87, 97))	('increase', 'PosReg', (75, 83))	('miR-152-3p level', 'MPA', (87, 103))
17365	33564267	The si-HOXA11-AS-induced repression of cell proliferation (Supplemental Figure 1C and D) and the promotion of cell apoptosis (Supplemental Figure 1E and F) were countervailed following the down-regulation of miR-152-3p.	('regulation', 'biological_process', 'GO:0065007', ('194', '204'))	('promotion', 'PosReg', (97, 106))	('si-HOXA11-AS-induced', 'Var', (4, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('si-HOXA11-AS', 'Chemical', '-', (4, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('miR-152-3p', 'Chemical', '-', (208, 218))	('repression', 'NegReg', (25, 35))	('cell proliferation', 'CPA', (39, 57))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('cell apoptosis', 'CPA', (110, 124))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('down-regulation', 'NegReg', (189, 204))
17366	33564267	Similarly, miR-152-3p inhibitor returned the inhibitory regulation of si-HOXA11-AS on cell migration (Supplemental Figure 1G), invasion (Supplemental Figure 1H) and EMT process (Supplemental Figure 1I and J).	('si', 'Chemical', 'MESH:D012825', (131, 133))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('inhibitory regulation', 'MPA', (45, 66))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('miR-152-3p', 'Chemical', '-', (11, 21))	('invasion', 'CPA', (127, 135))	('EMT process', 'CPA', (165, 176))	('cell migration', 'CPA', (86, 100))	('si-HOXA11-AS', 'Gene', (70, 82))	('si-HOXA11-AS', 'Chemical', '-', (70, 82))	('miR-152-3p', 'Var', (11, 21))	('EMT', 'biological_process', 'GO:0001837', ('165', '168'))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))
17367	33564267	This revert of anti-miR-152-3p to si-HOXA11-AS suggested that the knockdown of HOXA11-AS retarded the development of melanoma via promoting miR-152-3p.	('miR-152-3p', 'MPA', (140, 150))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('miR-152-3p', 'Chemical', '-', (20, 30))	('si-HOXA11-AS', 'Chemical', '-', (34, 46))	('development of', 'CPA', (102, 116))	('HOXA11-AS', 'Var', (79, 88))	('promoting', 'PosReg', (130, 139))	('retarded', 'NegReg', (89, 97))	('knockdown', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('miR-152-3p', 'Chemical', '-', (140, 150))	('melanoma', 'Disease', (117, 125))
17368	33564267	Through the prediction of TargetScan, we found that the 3'-UTR of wild-type ITGA9 contained the binding sites of miR-152-3p (Figure 5A).	('miR-152-3p', 'Chemical', '-', (113, 123))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('binding', 'Interaction', (96, 103))	('ITGA9', 'Gene', '3680', (76, 81))	('miR-152-3p', 'Var', (113, 123))	('ITGA9', 'Gene', (76, 81))	('si', 'Chemical', 'MESH:D012825', (104, 106))
17369	33564267	The results of dual-luciferase reporter assay showed that the luciferase activity of ITGA9 3'UTR WT group was significantly declined by miR-152-3p, while this phenomenon was not found in ITGA9 3'UTR MUT group (Figure 5B and C).	('miR-152-3p', 'Chemical', '-', (136, 146))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('luciferase activity', 'molecular_function', 'GO:0047077', ('62', '81'))	('activity', 'MPA', (73, 81))	('ITGA9', 'Gene', (85, 90))	('luciferase activity', 'molecular_function', 'GO:0045289', ('62', '81'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('62', '81'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('62', '81'))	('ITGA9', 'Gene', '3680', (187, 192))	('miR-152-3p', 'Var', (136, 146))	('luciferase activity', 'molecular_function', 'GO:0050397', ('62', '81'))	('declined', 'NegReg', (124, 132))	('luciferase', 'Enzyme', (62, 72))	('ITGA9', 'Gene', '3680', (85, 90))	('ITGA9', 'Gene', (187, 192))
17372	33564267	The relation between the levels of miR-152-3p and ITGA9 was notably negative (R2=0.711, P< 0.0001) (Figure 5G).	('miR-152-3p', 'Var', (35, 45))	('ITGA9', 'Gene', (50, 55))	('negative', 'NegReg', (68, 76))	('miR-152-3p', 'Chemical', '-', (35, 45))	('ITGA9', 'Gene', '3680', (50, 55))
17374	33564267	Furthermore, the mRNA expression of ITGA9 was observably inhibited by miR-152-3p and increased by anti-miR-152-3p transfection (Figure 5J).	('si', 'Chemical', 'MESH:D012825', (28, 30))	('miR-152-3p', 'Var', (70, 80))	('ITGA9', 'Gene', (36, 41))	('inhibited', 'NegReg', (57, 66))	('miR-152-3p', 'Chemical', '-', (103, 113))	('miR-152-3p', 'Chemical', '-', (70, 80))	('anti-miR-152-3p transfection', 'Var', (98, 126))	('mRNA expression', 'MPA', (17, 32))	('increased', 'PosReg', (85, 94))	('ITGA9', 'Gene', '3680', (36, 41))
17376	33564267	All above data unraveled that miR-152-3p targeted ITGA9.	('targeted', 'Reg', (41, 49))	('ITGA9', 'Gene', (50, 55))	('miR-152-3p', 'Var', (30, 40))	('ITGA9', 'Gene', '3680', (50, 55))	('miR-152-3p', 'Chemical', '-', (30, 40))
17378	33564267	Compared to the si-ITGA9 group, the mRNA and protein levels of ITGA9 were remarkably up-regulated by anti-miR-152-3p in A875 cells (Figure 6A and B) and M14 cells (Figure 6C and D).	('ITGA9', 'Gene', '3680', (63, 68))	('miR-152-3p', 'Chemical', '-', (106, 116))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('ITGA9', 'Gene', (63, 68))	('anti-miR-152-3p', 'Var', (101, 116))	('ITGA9', 'Gene', '3680', (19, 24))	('ITGA9', 'Gene', (19, 24))	('up-regulated', 'PosReg', (85, 97))
17381	33564267	Transwell assay indicated that si-ITGA9 visibly decreased cell migration and invasion, but anti-miR-152-3p averted the suppression in part (Figure 6I and J).	('si', 'Chemical', 'MESH:D012825', (31, 33))	('ITGA9', 'Gene', '3680', (34, 39))	('cell migration', 'CPA', (58, 72))	('ITGA9', 'Gene', (34, 39))	('invasion', 'CPA', (77, 85))	('decreased', 'NegReg', (48, 57))	('miR-152-3p', 'Chemical', '-', (96, 106))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('anti-miR-152-3p', 'Var', (91, 106))	('si', 'Chemical', 'MESH:D012825', (42, 44))
17382	33564267	In addition, the si-ITGA9-induced accelerative effect on E-cadherin and prohibitive effects on N-cadherin/Vimentin were abated by anti-miR-152-3p in A875 and M14 cells (Figure 6K and L).	('ITGA9', 'Gene', '3680', (20, 25))	('N-cadherin', 'Gene', (95, 105))	('Vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('Vimentin', 'Gene', '7431', (106, 114))	('N-cadherin', 'Gene', '1000', (95, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('E-cadherin', 'Gene', (57, 67))	('ITGA9', 'Gene', (20, 25))	('E-cadherin', 'Gene', '999', (57, 67))	('Vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('miR-152-3p', 'Chemical', '-', (135, 145))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('anti-miR-152-3p', 'Var', (130, 145))	('Vimentin', 'Gene', (106, 114))	('abated', 'NegReg', (120, 126))	('accelerative effect', 'PosReg', (34, 53))
17383	33564267	Taken together, miR-152-3p inhibition promoted the progression of melanoma via motivating the expression of ITGA9.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('motivating', 'Reg', (79, 89))	('miR-152-3p', 'Var', (16, 26))	('inhibition', 'Var', (27, 37))	('ITGA9', 'Gene', '3680', (108, 113))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('promoted', 'PosReg', (38, 46))	('ITGA9', 'Gene', (108, 113))	('progression', 'CPA', (51, 62))	('expression', 'MPA', (94, 104))	('miR-152-3p', 'Chemical', '-', (16, 26))	('si', 'Chemical', 'MESH:D012825', (100, 102))
17385	33564267	Moreover, qRT-PCR revealed that the mRNA level of ITGA9 was inhibited by HOXA11-AS knockdown but anti-miR-152-3p reverted the inhibitory effect on ITGA9 (Figure 7B).	('miR-152-3p', 'Chemical', '-', (102, 112))	('mRNA level', 'MPA', (36, 46))	('ITGA9', 'Gene', (50, 55))	('ITGA9', 'Gene', '3680', (147, 152))	('inhibited', 'NegReg', (60, 69))	('ITGA9', 'Gene', (147, 152))	('anti-miR-152-3p', 'Var', (97, 112))	('ITGA9', 'Gene', '3680', (50, 55))	('knockdown', 'Var', (83, 92))
17386	33564267	Also, Western blot demonstrated that the repression of miR-152-3p conspicuously ameliorated the si-HOXA11-AS-induced ITGA9 protein downregulation in both A875 and M14 cells (Figure 7C and D).	('miR-152-3p', 'Var', (55, 65))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('ITGA9', 'Gene', '3680', (117, 122))	('si-HOXA11-AS', 'Chemical', '-', (96, 108))	('miR-152-3p', 'Chemical', '-', (55, 65))	('ITGA9', 'Gene', (117, 122))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('downregulation', 'NegReg', (131, 145))	('ameliorated', 'PosReg', (80, 91))	('si', 'Chemical', 'MESH:D012825', (96, 98))
17387	33564267	These results suggested that HOXA11-AS knockdown inhibited the level of ITGA9 by promoting miR-152-3p.	('level', 'MPA', (63, 68))	('knockdown', 'Var', (39, 48))	('ITGA9', 'Gene', '3680', (72, 77))	('miR-152-3p', 'MPA', (91, 101))	('ITGA9', 'Gene', (72, 77))	('promoting', 'PosReg', (81, 90))	('miR-152-3p', 'Chemical', '-', (91, 101))	('inhibited', 'NegReg', (49, 58))
17388	33564267	To further explore the impact of HOXA11-AS in vivo, A875 cells stably expressed sh-NC or sh-HOXA11-AS were subcutaneously injected into the back flank of nude mice to establish the xenograft model of melanoma.	('sh-HOXA11-AS', 'Var', (89, 101))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('sh-HOXA11-AS', 'Chemical', '-', (89, 101))	('melanoma', 'Disease', (200, 208))	('sh-NC', 'Gene', (80, 85))	('nude mice', 'Species', '10090', (154, 163))
17389	33564267	As Figure 8A revealed, the tumor volume of sh-HOXA11-AS group was smaller than that of sh-NC group between 1 and 4 weeks.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('sh-HOXA11-AS', 'Chemical', '-', (43, 55))	('tumor', 'Disease', (27, 32))	('smaller', 'NegReg', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('sh-HOXA11-AS', 'Var', (43, 55))
17390	33564267	After 4 weeks, tumor weight was lower in sh-HOXA11-AS group by contrast to sh-NC group (Figure 8B).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('sh-HOXA11-AS', 'Var', (41, 53))	('sh-HOXA11-AS', 'Chemical', '-', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('lower', 'NegReg', (32, 37))
17392	33564267	The level of miR-152-3p was up-regulated (Figure 8D), while ITGA9 mRNA and protein levels were decreased (Figure 8E and F) in the sh-HOXA11-AS group.	('decreased', 'NegReg', (95, 104))	('miR-152-3p', 'Chemical', '-', (13, 23))	('up-regulated', 'PosReg', (28, 40))	('sh-HOXA11-AS', 'Chemical', '-', (130, 142))	('level', 'MPA', (4, 9))	('ITGA9', 'Gene', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('miR-152-3p', 'Var', (13, 23))	('ITGA9', 'Gene', '3680', (60, 65))
17393	33564267	Additionally, E-cadherin protein expression was enhanced while N-cadherin and Vimentin protein levels were reduced after knockdown of HOXA11-AS in vivo (Figure 8G).	('knockdown', 'Var', (121, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('HOXA11-AS', 'Gene', (134, 143))	('Vimentin', 'cellular_component', 'GO:0045098', ('78', '86'))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('reduced', 'NegReg', (107, 114))	('enhanced', 'PosReg', (48, 56))	('Vimentin', 'cellular_component', 'GO:0045099', ('78', '86'))	('N-cadherin', 'Gene', (63, 73))	('Vimentin', 'Gene', (78, 86))	('N-cadherin', 'Gene', '1000', (63, 73))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('E-cadherin', 'Gene', (14, 24))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('Vimentin', 'Gene', '7431', (78, 86))
17394	33564267	The down-regulation of PCNA and cyclinD1 (pro-proliferation proteins) in sh-HOXA11-AS group suggested that silencing HOXA11-AS inhibited the proliferation of melanoma in vivo (Figure 8H).	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('silencing', 'Var', (107, 116))	('PCNA', 'Gene', (23, 27))	('cyclinD1', 'Gene', (32, 40))	('inhibited', 'NegReg', (127, 136))	('HOXA11-AS', 'Gene', (117, 126))	('proliferation', 'CPA', (141, 154))	('PCNA', 'Gene', '5111', (23, 27))	('sh-HOXA11-AS', 'Chemical', '-', (73, 85))	('cyclinD1', 'Gene', '595', (32, 40))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('PCNA', 'molecular_function', 'GO:0003892', ('23', '27'))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('down-regulation', 'NegReg', (4, 19))	('melanoma', 'Disease', (158, 166))
17395	33564267	The repression of Bcl-2 (anti-apoptosis marker) and the upregulation of Bax (pro-apoptosis marker) implied that apoptosis was triggered by knockdown of HOXA11-AS in vivo (Figure 8I).	('si', 'Chemical', 'MESH:D012825', (87, 89))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('Bcl-2', 'Gene', (18, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('upregulation', 'PosReg', (56, 68))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('knockdown', 'Var', (139, 148))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('Bax', 'Gene', '581', (72, 75))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('25', '39'))	('repression', 'NegReg', (4, 14))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('77', '90'))	('Bcl-2', 'Gene', '596', (18, 23))	('Bax', 'Gene', (72, 75))
17396	33564267	At least in part, HOXA11-AS affected the melanoma progression in vivo by modulating miR-152-3p and ITGA9 expression.	('miR-152-3p', 'Protein', (84, 94))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('miR-152-3p', 'Chemical', '-', (84, 94))	('HOXA11-AS', 'Var', (18, 27))	('ITGA9', 'Gene', (99, 104))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('affected', 'Reg', (28, 36))	('modulating', 'Reg', (73, 83))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('expression', 'MPA', (105, 115))	('ITGA9', 'Gene', '3680', (99, 104))
17400	33564267	HOXA11-AS might be a satisfactory candidate biomarker of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('HOXA11-AS', 'Var', (0, 9))	('melanoma', 'Disease', (57, 65))
17402	33564267	In recent years, Li et al clarified that interfering with the expression of HOXA11-AS inhibited cell proliferation, metastasis and EMT but stimulated apoptosis in breast cancer cells.	('interfering', 'Var', (41, 52))	('apoptosis', 'CPA', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('stimulated', 'PosReg', (139, 149))	('cell proliferation', 'CPA', (96, 114))	('HOXA11-AS', 'Gene', (76, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('metastasis', 'CPA', (116, 126))	('EMT', 'CPA', (131, 134))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('EMT', 'biological_process', 'GO:0001837', ('131', '134'))	('breast cancer', 'Disease', (163, 176))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('inhibited', 'NegReg', (86, 95))
17403	33564267	Qu et al found that HOXA11-AS knockdown prominently repressed cell growth and metastasis of laryngeal squamous cell carcinoma.	('repressed', 'NegReg', (52, 61))	('squamous cell carcinoma', 'Disease', (102, 125))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('knockdown', 'Var', (30, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('metastasis', 'CPA', (78, 88))	('cell growth', 'CPA', (62, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
17404	33564267	The silence of HOXA11-AS was also showed to reduce proliferation and metastasis but expedite apoptosis of glioma cells.	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('silence', 'Var', (4, 11))	('reduce', 'NegReg', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('proliferation', 'CPA', (51, 64))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('glioma', 'Disease', (106, 112))	('HOXA11-AS', 'Gene', (15, 24))	('apoptosis', 'CPA', (93, 102))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('expedite', 'PosReg', (84, 92))
17405	33564267	Lu et al unraveled that HOXA11-AS knockdown reduced proliferation and invasion abilities, but induced apoptosis of uveal melanoma (UM) cells.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('proliferation', 'CPA', (52, 65))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('apoptosis', 'CPA', (102, 111))	('invasion abilities', 'CPA', (70, 88))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('reduced', 'NegReg', (44, 51))	('knockdown', 'Var', (34, 43))	('induced', 'Reg', (94, 101))	('si', 'Chemical', 'MESH:D012825', (108, 110))
17408	33564267	Further experiments indicated that proliferation, metastasis (migration and invasion) and EMT of melanoma cells were all repressed but apoptosis was facilitated after HOXA11-AS was knocked down, suggesting that HOXA11-AS played as an oncogenic role in cutaneous melanoma.	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('melanoma', 'Phenotype', 'HP:0002861', (262, 270))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('melanoma', 'Disease', (262, 270))	('cutaneous melanoma', 'Disease', (252, 270))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (252, 270))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (252, 270))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (262, 270))	('facilitated', 'PosReg', (149, 160))	('HOXA11-AS', 'Gene', (167, 176))	('knocked down', 'Var', (181, 193))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))
17409	33564267	MiRNAs are generally considered as tumor suppressors to regulate tumor progression, including miR-152-3p.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-152-3p', 'Var', (94, 104))	('tumor', 'Disease', (35, 40))	('miR-152-3p', 'Chemical', '-', (94, 104))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
17410	33564267	For instance, Sun et al illuminated that miR-152-3p overexpression inhibited invasion while motivated cell apoptosis in glioma.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('miR-152-3p', 'Var', (41, 51))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('inhibited', 'NegReg', (67, 76))	('miR-152-3p', 'Chemical', '-', (41, 51))	('invasion', 'CPA', (77, 85))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('glioma', 'Disease', (120, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('overexpression', 'PosReg', (52, 66))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
17411	33564267	Also, miR-152-3p was down-regulated in prostate cancer and attenuated the abilities of cell proliferation and invasion.	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR-152-3p', 'Chemical', '-', (6, 16))	('prostate cancer', 'Disease', (39, 54))	('attenuated', 'NegReg', (59, 69))	('down-regulated', 'NegReg', (21, 35))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('miR-152-3p', 'Var', (6, 16))
17412	33564267	Consistent with these studies, we found that miR-152-3p expression was overtly declined in melanoma.	('miR-152-3p', 'Var', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('miR-152-3p', 'Chemical', '-', (45, 55))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('declined', 'NegReg', (79, 87))	('si', 'Chemical', 'MESH:D012825', (62, 64))
17413	33564267	The upregulation of miR-152-3p inhibited cell proliferation, metastasis and EMT but aggravated apoptosis in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('miR-152-3p', 'Chemical', '-', (20, 30))	('EMT', 'CPA', (76, 79))	('aggravated', 'PosReg', (84, 94))	('cell proliferation', 'CPA', (41, 59))	('apoptosis', 'CPA', (95, 104))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('metastasis', 'CPA', (61, 71))	('miR-152-3p', 'Var', (20, 30))	('inhibited', 'NegReg', (31, 40))	('upregulation', 'PosReg', (4, 16))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))	('melanoma', 'Disease', (108, 116))
17415	33564267	Cui et al discovered that HOXA11-AS promoted the glioma oncogenesis by targeting miR-140-5p as a miRNA sponge, and Zhan et al declared that HOXA11-AS modulated cellular processes of hepatocellular carcinoma via sponging miR-214-3p.	('miR', 'Gene', (220, 223))	('oncogenesis', 'biological_process', 'GO:0007048', ('56', '67'))	('cellular processes', 'CPA', (160, 178))	('miR-140', 'Gene', (81, 88))	('miR', 'Gene', '220972', (81, 84))	('hepatocellular carcinoma', 'Disease', (182, 206))	('miR-140', 'Gene', '406932', (81, 88))	('3p', 'Chemical', '-', (228, 230))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('miR', 'Gene', '220972', (97, 100))	('promoted', 'PosReg', (36, 44))	('HOXA11-AS', 'Var', (140, 149))	('glioma', 'Disease', (49, 55))	('miR', 'Gene', (81, 84))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('modulated', 'Reg', (150, 159))	('miR', 'Gene', (97, 100))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (182, 206))	('miR', 'Gene', '220972', (220, 223))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (182, 206))
17416	33564267	HOXA11-AS was also reported to expedite the retinoblastoma progression through down-regulating miR-506-3p.	('down-regulating', 'NegReg', (79, 94))	('miR', 'Gene', '220972', (95, 98))	('retinoblastoma', 'Phenotype', 'HP:0009919', (44, 58))	('miR', 'Gene', (95, 98))	('3p', 'Chemical', '-', (103, 105))	('expedite', 'PosReg', (31, 39))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('retinoblastoma', 'Disease', 'MESH:D012175', (44, 58))	('retinoblastoma', 'Disease', (44, 58))	('HOXA11-AS', 'Var', (0, 9))
17417	33564267	Herein, we found a sponge effect of HOXA11-AS on miR-152-3p.	('miR-152-3p', 'Var', (49, 59))	('sponge effect', 'MPA', (19, 32))	('miR-152-3p', 'Chemical', '-', (49, 59))
17418	33564267	In addition, HOXA11-AS regulated the cellular processes of melanoma partly by acting as a sponge of miR-152-3p.	('HOXA11-AS', 'Var', (13, 22))	('regulated', 'Reg', (23, 32))	('miR-152-3p', 'Chemical', '-', (100, 110))	('cellular processes', 'CPA', (37, 55))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
17420	33564267	TargetScan software was used for seeking the target gene of miR-152-3p and the analysis revealed that 3'-UTR of ITGA9 contained the binding sites of miR-152-3p.	('miR-152-3p', 'Chemical', '-', (60, 70))	('miR-152-3p', 'Var', (149, 159))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('miR-152-3p', 'Chemical', '-', (149, 159))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('binding', 'Interaction', (132, 139))	('ITGA9', 'Gene', '3680', (112, 117))	('ITGA9', 'Gene', (112, 117))
17421	33564267	Subsequent assays proved that ITGA9 was a downstream target of miR-152-3p.	('miR-152-3p', 'Var', (63, 73))	('ITGA9', 'Gene', (30, 35))	('miR-152-3p', 'Chemical', '-', (63, 73))	('ITGA9', 'Gene', '3680', (30, 35))
17422	33564267	Furthermore, the tumor inhibitor role of miR-152-3p in melanoma was partially achieved by targeting ITGA9.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('miR-152-3p', 'Var', (41, 51))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('tumor', 'Disease', (17, 22))	('miR-152-3p', 'Chemical', '-', (41, 51))	('ITGA9', 'Gene', '3680', (100, 105))	('ITGA9', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
17424	33564267	Yang et al asserted that HOXA11-AS increased cell viability and invasion ability in renal cancer through regulating miR-146b-5p/matrix metallopeptidase 16 (MMP16) axis.	('renal cancer', 'Disease', 'MESH:D007680', (84, 96))	('increased', 'PosReg', (35, 44))	('HOXA11-AS', 'Var', (25, 34))	('regulating', 'Reg', (105, 115))	('MMP16', 'Gene', '4325', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell viability', 'CPA', (45, 59))	('miR-146b-5p/matrix metallopeptidase 16', 'Gene', (116, 154))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('renal cancer', 'Disease', (84, 96))	('MMP16', 'Gene', (156, 161))	('MMP', 'molecular_function', 'GO:0004235', ('156', '159'))	('renal cancer', 'Phenotype', 'HP:0009726', (84, 96))	('miR-146b-5p/matrix metallopeptidase 16', 'Gene', '4325', (116, 154))	('invasion ability', 'CPA', (64, 80))
17425	33564267	Wang et al claimed that HOXA11-AS promoted liver cancer progression via modulating miR-15a-3p/signal transducer and activator of transcription 3 (STAT3) axis.	('HOXA11-AS', 'Var', (24, 33))	('signal transducer and activator of transcription 3', 'Gene', '6774', (94, 144))	('liver cancer', 'Disease', (43, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (43, 55))	('STAT3', 'Gene', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('modulating', 'Reg', (72, 82))	('promoted', 'PosReg', (34, 42))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('3p', 'Chemical', '-', (91, 93))	('STAT3', 'Gene', '6774', (146, 151))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('liver cancer', 'Disease', 'MESH:D006528', (43, 55))
17430	33564267	Zhang et al reported that repression of HOXA11-AS refrained the tumorigenesis of non-small cell lung cancer in vivo, and Li et al purported that overexpression of HOXA11-AS stimulated tumor growth of oral squamous cell carcinoma by decreasing miR-518a-3p expression and promoting PDK1 expression in vivo.	('stimulated', 'PosReg', (173, 183))	('miR', 'Gene', '220972', (243, 246))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (81, 107))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 228))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('si', 'Chemical', 'MESH:D012825', (238, 240))	('oral squamous cell carcinoma', 'Disease', (200, 228))	('miR', 'Gene', (243, 246))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('tumor', 'Disease', (184, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('3p', 'Chemical', '-', (252, 254))	('non-small cell lung cancer', 'Disease', (81, 107))	('PDK1', 'Gene', (280, 284))	('si', 'Chemical', 'MESH:D012825', (261, 263))	('decreasing', 'NegReg', (232, 242))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('PDK1', 'molecular_function', 'GO:0004740', ('280', '284'))	('si', 'Chemical', 'MESH:D012825', (291, 293))	('HOXA11-AS', 'Var', (163, 172))	('expression', 'MPA', (285, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('promoting', 'PosReg', (270, 279))	('PDK1', 'Gene', '5163', (280, 284))
17434	33564267	HOXA11-AS might be a useful biomarker for the therapy of cutaneous melanoma, which needs further confirmation through clinical exploration.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('cutaneous melanoma', 'Disease', (57, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))	('HOXA11-AS', 'Var', (0, 9))
17476	32823876	Aberrant regulation of the molecular pathways involved in inflammation displays a close association with cancer.	('inflammation', 'biological_process', 'GO:0006954', ('58', '70'))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('inflammation', 'Disease', (58, 70))
17488	32823876	Oxidative stress, resulting from an imbalance between ROS production and elimination by enzymatic/non-enzymatic antioxidants including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH), promotes tumor cell proliferation, angiogenesis, and metastasis.	('superoxide dismutase', 'Gene', '6647', (135, 155))	('glutathione', 'Chemical', 'MESH:D005978', (179, 190))	('imbalance', 'Var', (36, 45))	('CAT', 'molecular_function', 'GO:0004096', ('173', '176'))	('metastasis', 'CPA', (285, 295))	('CAT', 'Gene', '847', (173, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('247', '265'))	('tumor', 'Disease', (241, 246))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('catalase', 'Gene', (163, 171))	('catalase', 'Gene', '847', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))	('GSH', 'Chemical', 'MESH:D005978', (226, 229))	('glutathione', 'Chemical', 'MESH:D005978', (213, 224))	('rat', 'Species', '10116', (259, 262))	('superoxide dismutase', 'Gene', (135, 155))	('SOD', 'Gene', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('CAT', 'Gene', (173, 176))	('promotes', 'PosReg', (232, 240))	('SOD', 'Gene', '6647', (157, 160))	('angiogenesis', 'biological_process', 'GO:0001525', ('267', '279'))	('angiogenesis', 'CPA', (267, 279))	('imbalance', 'Phenotype', 'HP:0002172', (36, 45))	('SOD', 'molecular_function', 'GO:0004784', ('157', '160'))
17493	32823876	As a hallmark of cancer, apoptosis resistance leads to uncontrolled proliferation, cancer cells survival under hypoxic conditions, and resistance to chemotherapeutic drugs.	('hypoxic conditions', 'Disease', 'MESH:D000071069', (111, 129))	('apoptosis', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('uncontrolled', 'MPA', (55, 67))	('rat', 'Species', '10116', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('hypoxic conditions', 'Disease', (111, 129))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('cancer', 'Disease', (17, 23))	('leads to', 'Reg', (46, 54))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
17506	32823876	PARP inhibitors expedite ROS production, DNA damage, and programmed cell death.	('expedite', 'PosReg', (16, 24))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('PARP', 'Gene', (0, 4))	('DNA damage', 'CPA', (41, 51))	('programmed cell death', 'CPA', (57, 78))	('inhibitors', 'Var', (5, 15))	('ROS production', 'MPA', (25, 39))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('programmed cell death', 'biological_process', 'GO:0012501', ('57', '78'))	('PARP', 'Gene', '142', (0, 4))
17510	32823876	Aberrant regulation of autophagy contributes toward tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('regulation', 'MPA', (9, 19))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (52, 57))	('autophagy', 'CPA', (23, 32))	('regulation of autophagy', 'biological_process', 'GO:0010506', ('9', '32'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
17544	32823876	Rutin has been found to counteract several types of cancer through various mechanisms, e.g., inhibition of malignant cell growth, induction of cell cycle arrest and apoptosis, and modulation of angiogenesis, inflammation, and oxidative stress, all of which are mediated by regulating multiple cellular signaling pathways.	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('angiogenesis', 'CPA', (194, 206))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('143', '160'))	('apoptosis', 'CPA', (165, 174))	('angiogenesis', 'biological_process', 'GO:0001525', ('194', '206'))	('inflammation', 'biological_process', 'GO:0006954', ('208', '220'))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('malignant cell growth', 'CPA', (107, 128))	('cell growth', 'biological_process', 'GO:0016049', ('117', '128'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (143, 160))	('inhibition', 'NegReg', (93, 103))	('arrest', 'Disease', (154, 160))	('oxidative stress', 'Phenotype', 'HP:0025464', (226, 242))	('inflammation', 'Disease', 'MESH:D007249', (208, 220))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('signaling', 'biological_process', 'GO:0023052', ('302', '311'))	('modulation', 'Var', (180, 190))	('Rutin', 'Chemical', 'MESH:D012431', (0, 5))	('inflammation', 'Disease', (208, 220))	('arrest', 'Disease', 'MESH:D006323', (154, 160))
17568	32823876	Therefore, abrogation of chemoresistance can mitigate the relapsed tumor.	('mitigate', 'NegReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('abrogation', 'Var', (11, 21))	('chemoresistance', 'CPA', (25, 40))
17611	32823876	Therapeutic intervention involving the inhibition of VEGF has become an innovative strategy for abrogating tumor metastasis.	('inhibition', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rat', 'Species', '10116', (85, 88))	('tumor metastasis', 'Disease', 'MESH:D009362', (107, 123))	('tumor metastasis', 'Disease', (107, 123))	('VEGF', 'Protein', (53, 57))
17641	32823876	ERK plays a key role in TNF-induced autophagy, inhibition of which enhances cellular sensitivity to TNF-induced apoptosis.	('TNF', 'Gene', (24, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('TNF', 'Gene', (100, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('inhibition', 'Var', (47, 57))	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))	('enhances', 'PosReg', (67, 75))	('TNF', 'Gene', '7124', (24, 27))	('TNF', 'Gene', '7124', (100, 103))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))	('ERK', 'molecular_function', 'GO:0004707', ('0', '3'))	('cellular sensitivity', 'CPA', (76, 96))
17666	32823876	In another in vivo study, rutin reduces liver/spleen weight, abolishes proliferation, and augments the activity of macrophage phagocytosis, thereby inducing an immune response in WEHI-3-induced leukemia model in BALB/c mice.	('rutin', 'Var', (26, 31))	('immune response', 'CPA', (160, 175))	('rutin', 'Chemical', 'MESH:D012431', (26, 31))	('mice', 'Species', '10090', (219, 223))	('abolishes', 'NegReg', (61, 70))	('men', 'Species', '9606', (93, 96))	('activity of macrophage phagocytosis', 'CPA', (103, 138))	('phagocytosis', 'biological_process', 'GO:0006909', ('126', '138'))	('immune response', 'biological_process', 'GO:0006955', ('160', '175'))	('rat', 'Species', '10116', (78, 81))	('inducing', 'Reg', (148, 156))	('reduces', 'NegReg', (32, 39))	('augments', 'NegReg', (90, 98))	('proliferation', 'CPA', (71, 84))	('liver/spleen weight', 'MPA', (40, 59))	('leukemia', 'Disease', 'MESH:D007938', (194, 202))	('leukemia', 'Phenotype', 'HP:0001909', (194, 202))	('leukemia', 'Disease', (194, 202))
17699	32823876	Na+/K+, Ca2+, and Mg2+ ATPases play a key role in the transportation of the electrolytes sodium, potassium, calcium, and magnesium across membranes.	('sodium', 'Chemical', 'MESH:D012964', (89, 95))	('Mg2+', 'Chemical', '-', (18, 22))	('transportation of the electrolytes sodium', 'MPA', (54, 95))	('magnesium', 'Chemical', 'MESH:D008274', (121, 130))	('Ca2+', 'Chemical', 'MESH:D000069285', (8, 12))	('potassium', 'Chemical', 'MESH:D011188', (97, 106))	('Mg2+', 'Var', (18, 22))	('Na+/K+', 'Var', (0, 6))	('calcium', 'Chemical', 'MESH:D002118', (108, 115))
17703	32823876	Modulation of these parameters is a promising way of controlling cancer.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
17720	32823876	Overactivation of Bcl-2 proto-oncogene plays a critical role in abrogating cell apoptosis and tumor suppressor protein p53 activity.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Bcl-2', 'Gene', (18, 23))	('cell apoptosis', 'CPA', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('tumor', 'Disease', (94, 99))	('abrogating', 'NegReg', (64, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('activity', 'MPA', (123, 131))	('Overactivation', 'Var', (0, 14))
17732	32823876	Rutin also demonstrated antiangiogenic effects against B16F-10 melanoma cell-induced capillary formation in an animal model.	('rat', 'Species', '10116', (18, 21))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('B16F', 'SUBSTITUTION', 'None', (55, 59))	('Rutin', 'Chemical', 'MESH:D012431', (0, 5))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('antiangiogenic effects', 'CPA', (24, 46))	('B16F', 'Var', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
17803	27601591	Cytidine Deaminase Deficiency Reveals New Therapeutic Opportunities against Cancer One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment.	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cytidine Deaminase', 'Gene', '978', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (113, 119))	('Cytidine Deaminase', 'Gene', (0, 18))	('Cancer', 'Disease', (76, 82))	('Deficiency', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
17809	27601591	We demonstrate that DNA methylation is a prevalent mechanism of CDA silencing in tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('CDA', 'Gene', '978', (64, 67))	('silencing', 'NegReg', (68, 77))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DNA methylation', 'biological_process', 'GO:0006306', ('20', '35'))	('DNA methylation', 'Var', (20, 35))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('CDA', 'Gene', (64, 67))
17810	27601591	Finally, we show that CDA-deficient tumor cells can be specifically targeted with epigenetic treatments and with the anticancer drug aminoflavone.	('epigenetic treatments', 'Var', (82, 103))	('CDA-deficient tumor', 'Disease', (22, 41))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CDA-deficient tumor', 'Disease', 'MESH:C535474', (22, 41))	('aminoflavone', 'Chemical', 'MESH:C413760', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
17814	27601591	Two families of cytidine deaminases exhibit different biological functions, deaminating either the free cytidines, as performed by cytidine deaminase (CDA or CDD; EC3.5.4.5), or deaminating the cytidines incorporated within the DNA or RNA polymers, as performed by the AID/APOBECs (activation-induced deaminase/apolipoprotein B mRNA editing catalytic polypeptide like) proteins.	('CDD', 'Gene', (158, 161))	('AID', 'Gene', '57379', (269, 272))	('cytidines', 'Chemical', 'MESH:D003562', (194, 203))	('DNA', 'cellular_component', 'GO:0005574', ('228', '231'))	('apolipoprotein B', 'Gene', '338', (311, 327))	('RNA', 'cellular_component', 'GO:0005562', ('235', '238'))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('311', '325'))	('cytidine deaminase', 'Gene', (131, 149))	('deaminating', 'Var', (76, 87))	('AID', 'Gene', (269, 272))	('mRNA editing', 'biological_process', 'GO:0016556', ('328', '340'))	('deaminating', 'Var', (178, 189))	('cytidine deaminase', 'Gene', '978', (16, 34))	('cytidines', 'Chemical', 'MESH:D003562', (104, 113))	('CDA', 'Gene', (151, 154))	('apolipoprotein B', 'Gene', (311, 327))	('CDA', 'Gene', '978', (151, 154))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('311', '325'))	('cytidine deaminase', 'Gene', (16, 34))	('CDD', 'Gene', '4878', (158, 161))	('cytidine deaminase', 'Gene', '978', (131, 149))
17817	27601591	In addition to native nucleotides, CDA also deaminates and inactivates nucleoside analogues, such as gemcitabine and cytosine arabinoside (Ara-C), agents widely used to treat cancer.	('nucleoside', 'Chemical', 'MESH:D009705', (71, 81))	('Ara-C', 'Chemical', 'MESH:D003561', (139, 144))	('cytosine arabinoside', 'Chemical', 'MESH:D003561', (117, 137))	('CDA', 'Gene', (35, 38))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('CDA', 'Gene', '978', (35, 38))	('gemcitabine', 'Chemical', 'MESH:C056507', (101, 112))	('deaminates', 'Var', (44, 54))	('inactivates', 'NegReg', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
17824	27601591	CDA overexpression has recently been identified as a potential targetforanticancer treatment.Indeed,CDAhasbeenshowntobe involved in the deamination of oxidized and epigenetically modified cytidine nucleosides.	('cytidine nucleosides', 'Chemical', '-', (188, 208))	('CDA', 'Gene', (100, 103))	('CDA', 'Gene', (0, 3))	('involved', 'Reg', (120, 128))	('CDA', 'Gene', '978', (100, 103))	('epigenetically', 'Var', (164, 178))	('CDA', 'Gene', '978', (0, 3))	('CDAhasbeenshowntobe', 'Chemical', '-', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('deamination', 'MPA', (136, 147))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
17880	27601591	Differences in the induction of CDA expression by 5-Aza-dC, as assessed by qRT-PCR, were evaluated in two-tailed paired t tests.	('CDA', 'Gene', (32, 35))	('5-Aza-dC', 'Var', (50, 58))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (50, 58))	('CDA', 'Gene', '978', (32, 35))
17914	27601591	We found a highly significant negative correlation between CDA transcript and methylation levels at CpG two sites, cg04087271 (TSS200) and cg00784581 (5'-UTR; Pearson r = -0.4184, P = 0.009; Fig.	('cg00784581', 'Var', (139, 149))	('methylation levels', 'MPA', (78, 96))	('CDA', 'Gene', (59, 62))	('negative', 'NegReg', (30, 38))	('CDA', 'Gene', '978', (59, 62))	('cg04087271', 'Var', (115, 125))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))
17919	27601591	We found that 5-Aza-dC induced a strong increase (up to 1,000-fold induction) in CDA mRNA levels (Fig.	('CDA', 'Gene', '978', (81, 84))	('increase', 'PosReg', (40, 48))	('5-Aza-dC', 'Var', (14, 22))	('CDA', 'Gene', (81, 84))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (14, 22))
17925	27601591	The induction of CDA protein production by 5-Aza-dC led to a significant increase in gemcitabine resistance (Fig.	('gemcitabine', 'Chemical', 'MESH:C056507', (85, 96))	('5-Aza-dC', 'Var', (43, 51))	('increase', 'PosReg', (73, 81))	('gemcitabine resistance', 'MPA', (85, 107))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (43, 51))	('CDA', 'Gene', '978', (17, 20))	('CDA', 'Gene', (17, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
17929	27601591	We found a highly significant correlation between CDA transcripts levels and CDA promoter methylation on two CpG sites (cg04087271 and cg24502330).	('CDA', 'Gene', '978', (50, 53))	('cg04087271', 'Var', (120, 130))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('CDA', 'Gene', (77, 80))	('CDA', 'Gene', (50, 53))	('cg24502330', 'Var', (135, 145))	('promoter methylation', 'MPA', (81, 101))	('CDA', 'Gene', '978', (77, 80))
17930	27601591	Methylation of the cg04087271 site was the only one correlating with CDA deficiency in both tumor tissues and NCI-60 cell lines (Fig.	('cg04087271', 'Var', (19, 29))	('Methylation', 'Var', (0, 11))	('CDA deficiency in both tumor', 'Disease', (69, 97))	('NCI-60', 'CellLine', 'CVCL:A592', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('CDA deficiency in both tumor', 'Disease', 'MESH:C535474', (69, 97))
17946	27601591	Among the selected molecules presenting a significant negative correlation with CDA expression, we choose aminoflavone because it has reached phase II clinical trials in the United States for treating solid tumors, including breast cancer (NCT01015521, NCT01233947, NCT00369200, NCT00348699; ref.	('NCT00348699', 'Var', (279, 290))	('NCT01015521', 'Var', (240, 251))	('NCT01233947', 'Var', (253, 264))	('CDA', 'Gene', '978', (80, 83))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('CDA', 'Gene', (80, 83))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('aminoflavone', 'Chemical', 'MESH:C413760', (106, 118))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))	('NCT00369200', 'Var', (266, 277))
17951	27601591	We thus evaluated the causality of the relationship between CDA downregulation and the antiproliferative activity of aminoflavone by shRNA-mediated CDA depletion in HeLa cells (Supplementary Fig.	('antiproliferative activity', 'CPA', (87, 113))	('aminoflavone', 'Chemical', 'MESH:C413760', (117, 129))	('downregulation', 'NegReg', (64, 78))	('CDA', 'Gene', '978', (148, 151))	('CDA', 'Gene', (148, 151))	('HeLa', 'CellLine', 'CVCL:0030', (165, 169))	('CDA', 'Gene', (60, 63))	('depletion', 'Var', (152, 161))	('CDA', 'Gene', '978', (60, 63))
17952	27601591	We found that CDA depletion significantly increased sensitivity to aminoflavone treatment (Fig.	('increased', 'PosReg', (42, 51))	('CDA', 'Gene', (14, 17))	('aminoflavone', 'Chemical', 'MESH:C413760', (67, 79))	('depletion', 'Var', (18, 27))	('CDA', 'Gene', '978', (14, 17))	('sensitivity to aminoflavone treatment', 'MPA', (52, 89))
17960	27601591	This is the first study, to our knowledge, to reveal the extent of CDA inactivation and its epigenetic control in cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('CDA', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('CDA', 'Gene', '978', (67, 70))	('inactivation', 'Var', (71, 83))	('cancer', 'Disease', (114, 120))
17965	27601591	Oxidized and epigenetically modified cytidine nucleosides specifically target tumors overexpressing CDA.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('CDA', 'Gene', (100, 103))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('CDA', 'Gene', '978', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('epigenetically modified', 'Var', (13, 36))	('cytidine nucleosides', 'Chemical', '-', (37, 57))
17967	27601591	These findings suggest that DNA-demethylating agents could be assessed as a possible treatment for CDA-deficient tumors to induce CDA overexpression and then sensitize these tumors to treatment with oxidized and epigenetically modified cytidine nucleosides.	('CDA', 'Gene', (130, 133))	('CDA', 'Gene', '978', (99, 102))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('overexpression', 'PosReg', (134, 148))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('CDA', 'Gene', '978', (130, 133))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('epigenetically modified', 'Var', (212, 235))	('CDA-deficient tumors', 'Disease', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CDA-deficient tumors', 'Disease', 'MESH:C535474', (99, 119))	('CDA', 'Gene', (99, 102))	('cytidine nucleosides', 'Chemical', '-', (236, 256))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
17975	27601591	This study revealed for the first time that CDA expression is lost in a large proportion of tumors, mostly due to DNA methylation and that tumors from the same classically defined groups may display differences in CDA expression status, resulting in contrasting cellular properties, such as levels of sister chromatids exchanges.	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('DNA methylation', 'Var', (114, 129))	('cellular', 'MPA', (262, 270))	('levels', 'MPA', (291, 297))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lost', 'NegReg', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('CDA', 'Gene', (214, 217))	('CDA', 'Gene', '978', (214, 217))	('due', 'Reg', (107, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('114', '129'))	('CDA', 'Gene', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('expression', 'MPA', (218, 228))	('CDA', 'Gene', '978', (44, 47))
18007	32675206	Indirect evidence for a role of CD147 in SARS-CoV-2 binding has been demonstrated in vitro with the use of an anti-CD147 intervention that prevented virus replication.	('SARS-CoV-2', 'Species', '2697049', (41, 51))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('anti-CD147', 'Var', (110, 120))	('virus replication', 'MPA', (149, 166))	('binding', 'Interaction', (52, 59))	('prevented', 'NegReg', (139, 148))
18008	32675206	Furthermore, a clinical study with an anti-CD147 intervention reduced symptoms and duration of hospital admission for COVID-19 patients.	('COVID-19', 'Disease', (118, 126))	('patients', 'Species', '9606', (127, 135))	('symptoms', 'MPA', (70, 78))	('anti-CD147', 'Var', (38, 48))	('COVID-19', 'Disease', 'MESH:C000657245', (118, 126))	('reduced', 'NegReg', (62, 69))
18023	32675206	Public microarray experiments using Affymetrix chips (HuGene-1.0-st-v1 and HG-U133 Plus 2) on airway epithelial cell samples collected from nasal (GSE19190) or bronchial (GSE11906) brushings of healthy nonsmokers were obtained from the NCBI Gene Expression Omnibus (GEO) database.	('st-v1', 'Gene', '23545', (65, 70))	('Gene Expression', 'biological_process', 'GO:0010467', ('241', '256'))	('st-v1', 'Gene', (65, 70))	('GSE19190', 'Var', (147, 155))
18026	32675206	These samples were further filtered by removing individuals with asthma or COPD, resulting in a total of 504 individual healthy samples (GSE4302, 28 samples; GSE67472, 43 samples; GSE37147, 159 samples; GSE108134, 274 samples).	('GSE37147', 'Var', (180, 188))	('COPD', 'Disease', 'MESH:D029424', (75, 79))	('GSE67472', 'Var', (158, 166))	('asthma', 'Disease', (65, 71))	('asthma', 'Disease', 'MESH:D001249', (65, 71))	('COPD', 'Disease', (75, 79))	('GSE108134', 'Var', (203, 212))	('asthma', 'Phenotype', 'HP:0002099', (65, 71))	('GSE4302', 'Var', (137, 144))
18045	32675206	The immunogen for ACE2 primary antibody is mouse myeloma cell line NS0-derived recombinant human ACE2 Gln18-Ser740 (predicted).	('Gln18', 'Chemical', '-', (102, 107))	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('Gln18-Ser740', 'Var', (102, 114))	('myeloma', 'Disease', 'MESH:D009101', (49, 56))	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('ACE2', 'Gene', (97, 101))	('Ser740', 'Chemical', '-', (108, 114))	('myeloma', 'Disease', (49, 56))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))	('Ser', 'cellular_component', 'GO:0005790', ('108', '111'))	('mouse', 'Species', '10090', (43, 48))	('human', 'Species', '9606', (91, 96))
18138	32344689	Similarly, knockdown of ALK caused M phase delay, which was rescued by re-expression of ALK.	('ALK', 'Gene', (88, 91))	('ALK', 'Gene', '238', (24, 27))	('M phase', 'biological_process', 'GO:0000279', ('35', '42'))	('ALK', 'Gene', (24, 27))	('ALK', 'Gene', '238', (88, 91))	('knockdown', 'Var', (11, 20))	('M phase delay', 'CPA', (35, 48))
18139	32344689	The monopolar spindle 1 (MPS1) inhibitor, AZ3146, and MAD2 knockdown led to a release from inhibitor-induced M phase delay, suggesting that spindle assembly checkpoint may be activated in ALK-inhibited cells.	('MAD2', 'Gene', (54, 58))	('spindle assembly checkpoint', 'biological_process', 'GO:0071173', ('140', '167'))	('inhibitor-induced M phase delay', 'MPA', (91, 122))	('M phase', 'biological_process', 'GO:0000279', ('109', '116'))	('AZ3146', 'Chemical', '-', (42, 48))	('monopolar spindle 1', 'Gene', '7272', (4, 23))	('spindle', 'cellular_component', 'GO:0005819', ('14', '21'))	('MAD2', 'Gene', '4085', (54, 58))	('ALK', 'Gene', (188, 191))	('release', 'MPA', (78, 85))	('MPS1', 'Gene', '7272', (25, 29))	('MAD', 'biological_process', 'GO:0072671', ('54', '57'))	('MPS1', 'Gene', (25, 29))	('spindle', 'cellular_component', 'GO:0005819', ('140', '147'))	('monopolar spindle 1', 'Gene', (4, 23))	('knockdown', 'Var', (59, 68))	('ALK', 'Gene', '238', (188, 191))	('AZ3146', 'Var', (42, 48))
18149	32344689	Genetic alteration of ALK, including gene amplification, gene fusion, and mutation with gain of function, has been identified in different cancers.	('mutation', 'Var', (74, 82))	('gain of function', 'PosReg', (88, 104))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('ALK', 'Gene', '238', (22, 25))	('gene fusion', 'Var', (57, 68))	('ALK', 'Gene', (22, 25))
18150	32344689	Activating mutations at R1275, F1174, and F1245 positions, and gene amplification are reported in pediatric cancer neuroblastoma.	('cancer neuroblastoma', 'Disease', 'MESH:D009369', (108, 128))	('neuroblastoma', 'Phenotype', 'HP:0003006', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('F1245', 'Var', (42, 47))	('cancer neuroblastoma', 'Disease', (108, 128))	('F1174', 'Var', (31, 36))
18151	32344689	ALK-NPM1 fusion was first identified in anaplastic large-cell lymphoma (ALCL) cell line.	('ALCL', 'Disease', (72, 76))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (40, 70))	('lymphoma', 'Disease', (62, 70))	('NPM1', 'Gene', (4, 8))	('ALK', 'Gene', (0, 3))	('ALCL', 'Phenotype', 'HP:0012193', (72, 76))	('cell lymphoma', 'Phenotype', 'HP:0012191', (57, 70))	('lymphoma', 'Disease', 'MESH:D008223', (62, 70))	('ALCL', 'Disease', 'None', (72, 76))	('fusion', 'Var', (9, 15))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))	('NPM1', 'Gene', '4869', (4, 8))	('ALK', 'Gene', '238', (0, 3))
18153	32344689	Gene fusion is found widely in inflammatory myofibroblastic tumors, diffuse large B-cell lymphoma, and esophageal squamous cell, colorectal, breast, and non-small cell lung carcinomas (NSCLC).	('non-small cell lung carcinomas', 'Disease', (153, 183))	('breast', 'Disease', (141, 147))	('colorectal', 'Disease', (129, 139))	('cell lymphoma', 'Phenotype', 'HP:0012191', (84, 97))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (44, 66))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (44, 66))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (157, 183))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (82, 97))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('found', 'Reg', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (153, 183))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('myofibroblastic tumors', 'Disease', (44, 66))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (82, 97))	('Gene fusion', 'Var', (0, 11))	('NSCLC', 'Disease', (185, 190))	('esophageal squamous cell', 'Disease', (103, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (153, 183))	('B-cell lymphoma', 'Disease', (82, 97))
18154	32344689	Genetically altered ALKs are commonly activated by dimerization of their fusion partners or by activating mutations in full-length ALK.	('ALK', 'Gene', '238', (20, 23))	('Genetically altered', 'Var', (0, 19))	('ALK', 'Gene', '238', (131, 134))	('ALK', 'Gene', (20, 23))	('mutations', 'Var', (106, 115))	('activated', 'PosReg', (38, 47))	('dimerization', 'MPA', (51, 63))	('activating', 'Reg', (95, 105))	('ALK', 'Gene', (131, 134))
18156	32344689	Activating mutations in ALK are correlated with greater cell proliferation, resistance to apoptosis, and enhanced DNA synthesis, which contribute to oncogenesis.	('DNA synthesis', 'biological_process', 'GO:0071897', ('114', '127'))	('ALK', 'Gene', '238', (24, 27))	('oncogenesis', 'biological_process', 'GO:0007048', ('149', '160'))	('DNA synthesis', 'MPA', (114, 127))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('Activating mutations', 'Var', (0, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('greater', 'PosReg', (48, 55))	('cell proliferation', 'CPA', (56, 74))	('ALK', 'Gene', (24, 27))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('enhanced', 'PosReg', (105, 113))	('resistance to apoptosis', 'CPA', (76, 99))
18159	32344689	Unfortunately, an acceptable success rate has not been achieved because diverse genetic alterations in ALK affect inhibitor efficacy.	('inhibitor efficacy', 'MPA', (114, 132))	('genetic alterations', 'Var', (80, 99))	('affect', 'Reg', (107, 113))	('ALK', 'Gene', '238', (103, 106))	('ALK', 'Gene', (103, 106))
18160	32344689	Furthermore, treatment with crizotinib and ceritinib causes focal amplification of ALK and KRAS genes, and have also been reported to confer resistance against ALK inhibitors in some cases.	('ALK', 'Gene', (160, 163))	('ALK', 'Gene', '238', (83, 86))	('ALK', 'Gene', '238', (160, 163))	('amplification', 'MPA', (66, 79))	('ceritinib', 'Chemical', 'MESH:C586847', (43, 52))	('ALK', 'Gene', (83, 86))	('crizotinib', 'Chemical', 'MESH:D000077547', (28, 38))	('resistance', 'MPA', (141, 151))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))	('crizotinib', 'Var', (28, 38))
18163	32344689	Our current search for compounds that affect the M phase found that crizotinib caused M phase delay.	('M phase', 'biological_process', 'GO:0000279', ('49', '56'))	('M phase', 'biological_process', 'GO:0000279', ('86', '93'))	('crizotinib', 'Chemical', 'MESH:D000077547', (68, 78))	('crizotinib', 'Var', (68, 78))	('M phase delay', 'MPA', (86, 99))
18176	32344689	Truncated ALK is frequently found in neuroblastoma cancer cell lines.	('ALK', 'Gene', '238', (10, 13))	('neuroblastoma cancer', 'Disease', 'MESH:D009369', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ALK', 'Gene', (10, 13))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('Truncated', 'Var', (0, 9))	('neuroblastoma cancer', 'Disease', (37, 57))
18179	32344689	Since the overall expression of ALK is higher in SH-SY5Y than in the other cells, SH-SY5Y cells were used in further experiments.	('SH-SY5Y', 'Var', (49, 56))	('ALK', 'Gene', (32, 35))	('higher', 'PosReg', (39, 45))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (82, 89))	('ALK', 'Gene', '238', (32, 35))	('expression', 'MPA', (18, 28))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (49, 56))
18187	32344689	Mitotic index, the percentage of M phase cells, showed no significant change in inhibitor-treated cells, suggesting that ALK inhibition delays M phase progression without affecting mitotic entry.	('M phase progression', 'CPA', (143, 162))	('delays', 'NegReg', (136, 142))	('M phase', 'biological_process', 'GO:0000279', ('143', '150'))	('ALK', 'Gene', '238', (121, 124))	('mitotic entry', 'biological_process', 'GO:0051727', ('181', '194'))	('M phase', 'biological_process', 'GO:0000279', ('33', '40'))	('inhibition', 'Var', (125, 135))	('ALK', 'Gene', (121, 124))
18195	32344689	In the crizotinib-treated cells, the average durations of P/PM and M were 74 and 83 min, respectively, suggesting that crizotinib treatment prolongs the duration of both P/PM and M. Interestingly, the cells exhibiting abnormal M phase characteristics, including misoriented spindle (23/39 cells) and misaligned chromosomes (20/39 cells), were frequently observed upon crizotinib treatment, suggesting that crizotinib causes M-phase delay by spindle misorientation and chromosome misalignment.	('chromosome', 'cellular_component', 'GO:0005694', ('468', '478'))	('M phase', 'biological_process', 'GO:0000279', ('227', '234'))	('spindle', 'cellular_component', 'GO:0005819', ('274', '281'))	('crizotinib', 'Chemical', 'MESH:D000077547', (406, 416))	('M-phase delay', 'MPA', (424, 437))	('crizotinib', 'Chemical', 'MESH:D000077547', (119, 129))	('chromosome misalignment', 'CPA', (468, 491))	('crizotinib', 'Chemical', 'MESH:D000077547', (7, 17))	('spindle misorientation', 'CPA', (441, 463))	('crizotinib', 'Var', (406, 416))	('M-phase', 'biological_process', 'GO:0000279', ('424', '431'))	('crizotinib', 'Chemical', 'MESH:D000077547', (368, 378))	('spindle', 'cellular_component', 'GO:0005819', ('441', '448'))
18199	32344689	Crizotinib caused a significant mitotic delay in prophase/prometaphase in HeLa S3 cells (Figure S2B).	('mitotic delay', 'CPA', (32, 45))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('prophase', 'biological_process', 'GO:0051324', ('49', '57'))	('Crizotinib', 'Var', (0, 10))	('prophase/prometaphase', 'CPA', (49, 70))	('HeLa S3', 'CellLine', 'CVCL:0058', (74, 81))
18205	32344689	Knockdown of ALK increased the number of cells before anaphase onset (Figure 3B, siALK #1, #2, Figure 3C, siALK #3), indicating a delay in M phase.	('increased', 'PosReg', (17, 26))	('ALK', 'Gene', '238', (83, 86))	('M phase', 'CPA', (139, 146))	('Knockdown', 'Var', (0, 9))	('delay', 'NegReg', (130, 135))	('ALK', 'Gene', '238', (108, 111))	('ALK', 'Gene', (13, 16))	('anaphase', 'biological_process', 'GO:0051322', ('54', '62'))	('M phase', 'biological_process', 'GO:0000279', ('139', '146'))	('ALK', 'Gene', (83, 86))	('ALK', 'Gene', '238', (13, 16))	('ALK', 'Gene', (108, 111))
18207	32344689	In addition, mitotic index was reduced by ALK knockdown (Figure 2B), which is in agreement with a previous study describing the prolongation of cell cycle progression in G1 phase.	('G1 phase', 'biological_process', 'GO:0051318', ('170', '178'))	('reduced', 'NegReg', (31, 38))	('ALK', 'Gene', '238', (42, 45))	('knockdown', 'Var', (46, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('144', '154'))	('ALK', 'Gene', (42, 45))	('mitotic index', 'MPA', (13, 26))
18208	32344689	Furthermore, stable cells that express HA-tagged wild-type ALK (ALK-HA) upon Dox treatment were established from SH-SY5Y cells (SH-SY5Y/ALK-HA) (Figure S4).	('ALK', 'Gene', '238', (59, 62))	('HA-tagged', 'Var', (39, 48))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (113, 120))	('ALK', 'Gene', (64, 67))	('ALK', 'Gene', (136, 139))	('Dox', 'Chemical', 'MESH:D004317', (77, 80))	('ALK', 'Gene', (59, 62))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (128, 135))	('ALK', 'Gene', '238', (64, 67))	('ALK', 'Gene', '238', (136, 139))
18214	32344689	To investigate the underlying mechanism of ALK knockdown-induced M-phase delay, time-lapse imaging was performed with SH-SY5Y cells first treated with siALK #1 and nontargeting siCtrl and then synchronized with RO-3306.	('RO-3306', 'Chemical', 'MESH:C512984', (211, 218))	('ALK', 'Gene', (153, 156))	('ALK', 'Gene', (43, 46))	('ALK', 'Gene', '238', (153, 156))	('ALK', 'Gene', '238', (43, 46))	('M-phase', 'biological_process', 'GO:0000279', ('65', '72'))	('knockdown-induced', 'Var', (47, 64))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (118, 125))
18219	32344689	These results suggest that ALK knockdown prolonged the duration of both prophase/prometaphase and metaphase.	('metaphase', 'CPA', (98, 107))	('prophase', 'biological_process', 'GO:0051324', ('72', '80'))	('metaphase', 'biological_process', 'GO:0051323', ('98', '107'))	('ALK', 'Gene', (27, 30))	('prolonged', 'PosReg', (41, 50))	('ALK', 'Gene', '238', (27, 30))	('knockdown', 'Var', (31, 40))
18220	32344689	Inhibition of ALK delayed M phase progression and increased the number of cells with misaligned chromosomes.	('ALK', 'Gene', '238', (14, 17))	('M phase', 'biological_process', 'GO:0000279', ('26', '33'))	('increased', 'PosReg', (50, 59))	('delayed', 'NegReg', (18, 25))	('ALK', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('M phase progression', 'CPA', (26, 45))
18223	32344689	Less than 30% of solvent control cells (DMSO), but most AZ3146-treated cells progressed to cytokinesis, suggesting that SAC inactivation causes immature mitotic exit.	('causes', 'Reg', (137, 143))	('mitotic exit', 'biological_process', 'GO:0010458', ('153', '165'))	('SAC', 'biological_process', 'GO:0071173', ('120', '123'))	('AZ3146', 'Chemical', '-', (56, 62))	('inactivation', 'Var', (124, 136))	('cytokinesis', 'CPA', (91, 102))	('SAC', 'cellular_component', 'GO:0035003', ('120', '123'))	('cytokinesis', 'biological_process', 'GO:0000910', ('91', '102'))	('AZ3146-treated', 'Var', (56, 70))	('DMSO', 'Chemical', 'MESH:D004121', (40, 44))
18225	32344689	This inference was supported by knockdown experiments of MAD2, which is a component of the mitotic checkpoint complex (MCC) and is necessary for SAC activation.	('MAD2', 'Gene', (57, 61))	('mitotic checkpoint', 'biological_process', 'GO:0007093', ('91', '109'))	('MCC', 'biological_process', 'GO:0120197', ('119', '122'))	('SAC', 'cellular_component', 'GO:0035003', ('145', '148'))	('MAD2', 'Gene', '4085', (57, 61))	('mitotic checkpoint complex', 'cellular_component', 'GO:0033597', ('91', '117'))	('MAD', 'biological_process', 'GO:0072671', ('57', '60'))	('knockdown', 'Var', (32, 41))	('MCC', 'cellular_component', 'GO:0033597', ('119', '122'))	('SAC', 'biological_process', 'GO:0071173', ('145', '148'))
18226	32344689	When cells were transfected with siMAD2, most MAD2 knockdown cells progressed to cytokinesis (Figure 5B, siMAD2) faster than the control cells treated with nontargeting siRNA (siCtrl), suggesting that SAC was inactivated in them.	('cytokinesis', 'biological_process', 'GO:0000910', ('81', '92'))	('MAD2', 'Gene', '4085', (46, 50))	('SAC', 'cellular_component', 'GO:0035003', ('201', '204'))	('MAD2', 'Gene', '4085', (107, 111))	('SAC', 'biological_process', 'GO:0071173', ('201', '204'))	('MAD2', 'Gene', (107, 111))	('MAD2', 'Gene', '4085', (35, 39))	('MAD', 'biological_process', 'GO:0072671', ('46', '49'))	('MAD2', 'Gene', (46, 50))	('MAD2', 'Gene', (35, 39))	('progressed', 'PosReg', (67, 77))	('knockdown', 'Var', (51, 60))
18227	32344689	In this experiment, MAD2 knockdown cells progressed to cytokinesis, even when cells were treated with crizotinib.	('cytokinesis', 'biological_process', 'GO:0000910', ('55', '66'))	('cytokinesis', 'CPA', (55, 66))	('MAD2', 'Gene', (20, 24))	('MAD', 'biological_process', 'GO:0072671', ('20', '23'))	('MAD2', 'Gene', '4085', (20, 24))	('crizotinib', 'Chemical', 'MESH:D000077547', (102, 112))	('progressed', 'PosReg', (41, 51))	('knockdown', 'Var', (25, 34))
18255	32344689	Crizotinib is known to inhibit c-Met and ROS1 tyrosine kinases in addition to ALK.	('ALK', 'Gene', (78, 81))	('c-Met', 'Gene', (31, 36))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('c-Met', 'Gene', '4233', (31, 36))	('inhibit', 'NegReg', (23, 30))	('ROS1', 'Gene', (41, 45))	('Crizotinib', 'Var', (0, 10))	('ROS1', 'Gene', '6098', (41, 45))	('ALK', 'Gene', '238', (78, 81))
18264	32344689	In addition to that, ALK inhibitors caused cell death in M phase in H2228 cells.	('M phase', 'biological_process', 'GO:0000279', ('57', '64'))	('ALK', 'Gene', (21, 24))	('M phase', 'CPA', (57, 64))	('H2228', 'CellLine', 'CVCL:1543', (68, 73))	('inhibitors', 'Var', (25, 35))	('ALK', 'Gene', '238', (21, 24))	('cell death', 'biological_process', 'GO:0008219', ('43', '53'))
18268	32344689	Elimination of ALK inhibition-caused M phase delay by MAD2 knockdown and Mps1 inhibitor implies that SAC is activated in ALK-inhibited cells.	('MAD2', 'Gene', (54, 58))	('ALK', 'Gene', (15, 18))	('SAC', 'biological_process', 'GO:0071173', ('101', '104'))	('MAD2', 'Gene', '4085', (54, 58))	('ALK', 'Gene', '238', (121, 124))	('MAD', 'biological_process', 'GO:0072671', ('54', '57'))	('SAC', 'cellular_component', 'GO:0035003', ('101', '104'))	('ALK', 'Gene', '238', (15, 18))	('M phase', 'biological_process', 'GO:0000279', ('37', '44'))	('ALK', 'Gene', (121, 124))	('Mps1', 'Gene', '7272', (73, 77))	('knockdown', 'Var', (59, 68))	('Mps1', 'Gene', (73, 77))	('M phase', 'MPA', (37, 44))
18276	32344689	Therefore, if ALK knockdown prolongs cell cycle length, it results in relatively lower mitotic index.	('knockdown', 'Var', (18, 27))	('lower', 'NegReg', (81, 86))	('ALK', 'Gene', '238', (14, 17))	('cell cycle', 'biological_process', 'GO:0007049', ('37', '47'))	('ALK', 'Gene', (14, 17))	('mitotic index', 'CPA', (87, 100))	('cell cycle length', 'CPA', (37, 54))	('prolongs', 'PosReg', (28, 36))
18278	32344689	Proliferation of cancer cells expressing EML4-ALK fusion typically depends on the downstream signaling of this oncogene, making it an attractive target for chemotherapy treatments.	('EML4', 'Gene', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('ALK', 'Gene', '238', (46, 49))	('EML4', 'Gene', '27436', (41, 45))	('cancer', 'Disease', (17, 23))	('ALK', 'Gene', (46, 49))	('fusion', 'Var', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
18279	32344689	However, durable responses from the cells are uncommon and cells usually acquire resistance to ALK inhibitors via multiple mechanisms, such as mutations in the ALK kinase domain, amplification of ALK gene and KRAS gene, activation of kinases including EGFR, IGF1R, KIT and Src, and downregulation of DUSP6.	('Src', 'Gene', '6714', (273, 276))	('DUSP6', 'Gene', (300, 305))	('ALK', 'Gene', (196, 199))	('ALK', 'Gene', '238', (196, 199))	('amplification', 'Var', (179, 192))	('KRAS', 'Gene', '3845', (209, 213))	('KIT', 'Gene', (265, 268))	('downregulation', 'NegReg', (282, 296))	('EGFR', 'Gene', '1956', (252, 256))	('KRAS', 'Gene', (209, 213))	('mutations', 'Var', (143, 152))	('ALK', 'Gene', '238', (160, 163))	('ALK', 'Gene', '238', (95, 98))	('KIT', 'Gene', '3815', (265, 268))	('IGF1R', 'Gene', '3480', (258, 263))	('KIT', 'molecular_function', 'GO:0005020', ('265', '268'))	('Src', 'Gene', (273, 276))	('ALK', 'Gene', (160, 163))	('DUSP6', 'Gene', '1848', (300, 305))	('ALK', 'Gene', (95, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('252', '256'))	('IGF1R', 'Gene', (258, 263))	('activation', 'PosReg', (220, 230))	('EGFR', 'Gene', (252, 256))
18280	32344689	All these alterations maintain the activation of ERK and promote cancerous cell growth in the presence of ALK inhibitors.	('ALK', 'Gene', '238', (106, 109))	('ERK', 'molecular_function', 'GO:0004707', ('49', '52'))	('alterations', 'Var', (10, 21))	('promote', 'PosReg', (57, 64))	('cancerous', 'Disease', 'MESH:D009369', (65, 74))	('ALK', 'Gene', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('ERK', 'Gene', '2048', (49, 52))	('cancerous', 'Disease', (65, 74))	('ERK', 'Gene', (49, 52))	('activation', 'PosReg', (35, 45))
18281	32344689	These observations are in agreement with a previous study reporting that SHP2 inhibition restores sensitivity to ALK inhibitors in resistant cancers by inactivating ERK activity.	('inactivating', 'NegReg', (152, 164))	('SHP2', 'Gene', (73, 77))	('SHP2', 'Gene', '5781', (73, 77))	('ALK', 'Gene', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('inhibition', 'Var', (78, 88))	('ERK', 'molecular_function', 'GO:0004707', ('165', '168'))	('activity', 'MPA', (169, 177))	('restores', 'PosReg', (89, 97))	('ALK', 'Gene', '238', (113, 116))	('resistant cancers', 'Disease', (131, 148))	('ERK', 'Gene', '2048', (165, 168))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('resistant cancers', 'Disease', 'MESH:D009369', (131, 148))	('ERK', 'Gene', (165, 168))
18285	32344689	Higher levels of chromosome mis-segregation will lead to cell death and suppress cancer cell growth when chromosome instability rises above a threshold level.	('cell death', 'CPA', (57, 67))	('chromosome instability', 'Phenotype', 'HP:0040012', (105, 127))	('suppress', 'NegReg', (72, 80))	('cell death', 'biological_process', 'GO:0008219', ('57', '67'))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('cancer', 'Disease', (81, 87))	('lead to', 'Reg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('chromosome', 'Var', (17, 27))
18289	32344689	Given that ALK inhibition causes aberrant chromosome segregation, it can accelerate the development of acquired resistance to ALK-inhibitor therapy by producing genetically diverse cancerous cells.	('ALK', 'Gene', '238', (126, 129))	('causes', 'Reg', (26, 32))	('cancerous', 'Disease', 'MESH:D009369', (181, 190))	('chromosome segregation', 'biological_process', 'GO:0007059', ('42', '64'))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('aberrant chromosome segregation', 'CPA', (33, 64))	('ALK', 'Gene', (126, 129))	('aberrant chromosome segregation', 'Phenotype', 'HP:0002916', (33, 64))	('ALK', 'Gene', (11, 14))	('cancerous', 'Disease', (181, 190))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('inhibition', 'Var', (15, 25))	('ALK', 'Gene', '238', (11, 14))
18295	32344689	The Mps1 inhibitor AZ3146 was obtained from Adooq Bioscience (Irvine, CA, USA), and the reversible CDK1 inhibitor RO-3306 from Selleck Chemicals.	('CDK1', 'Gene', (99, 103))	('CDK1', 'Gene', '983', (99, 103))	('Mps1', 'Gene', '7272', (4, 8))	('CDK', 'molecular_function', 'GO:0004693', ('99', '102'))	('AZ3146', 'Chemical', '-', (19, 25))	('Mps1', 'Gene', (4, 8))	('AZ3146', 'Var', (19, 25))	('RO-3306', 'Chemical', 'MESH:C512984', (114, 121))
18305	32344689	Briefly, cells were lysed in SDS sample buffer containing 2 microg/mL aprotinin (Seikagaku Kogyo, Tokyo, Japan), 0.8 microg/mL pepstain A (Wako Pure Chemicals, Osaka, Japan), 2 microg/mL leupeptin (Nacalai Tesque), 2 mM PMSF (Nacalai Tesque), 20 mM beta-glycerophosphate (MilliporeSigma), 50 mM NaF (Wako), and 10 mM Na3VO4 (Wako) and denatured at 40 and 100  C for 20 and 5 min, respectively.	('Na3VO4', 'Var', (317, 323))	('NaF', 'Gene', '3576', (295, 298))	('beta-glycerophosphate', 'MPA', (249, 270))	('SDS', 'Chemical', 'MESH:D012967', (29, 32))	('NaF', 'Gene', (295, 298))	('Pure', 'molecular_function', 'GO:0034023', ('144', '148'))
18309	32344689	Proteins were detected with Chemi-Lumi One L (07880-70, Nacalai Tesque) and Clarity (#1705061, Bio-Rad, Hercules, CA, USA) using an image analyzer ChemiDoc XRSplus (Bio-Rad).	('Rad', 'Gene', '6236', (169, 172))	('Rad', 'Gene', (169, 172))	('XRSplus', 'Disease', 'None', (156, 163))	('Rad', 'biological_process', 'GO:1990116', ('169', '172'))	('Rad', 'biological_process', 'GO:1990116', ('99', '102'))	('Rad', 'Gene', '6236', (99, 102))	('Rad', 'Gene', (99, 102))	('Proteins', 'Protein', (0, 8))	('XRSplus', 'Disease', (156, 163))	('#1705061', 'Var', (85, 93))	('07880-70', 'Var', (46, 54))
18319	32344689	SH-SY5Y cells (1 x 103 per well) were seeded in 96-well plates, and the next day were cultured with crizotinib (0.01, 0.1, 1, and 10 microM), ceritinib (0.001, 0.01, 0.1, and 1 microM), and TAE684 (0.0001, 0.001, 0.01, 0.1, and 1 microM) for 2 days.	('ceritinib', 'Chemical', 'MESH:C586847', (142, 151))	('0.01', 'Var', (112, 116))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (0, 7))	('0.001', 'Var', (153, 158))	('crizotinib', 'Chemical', 'MESH:D000077547', (100, 110))	('TAE684', 'Chemical', 'MESH:C516714', (190, 196))
18328	32344689	Inhibitors of ALK affect M phase progression in cells expressing wild-type ALK or EML4-ALK fusion via prolongation of the onset of anaphase due to defects in chromosome alignment.	('M phase progression', 'CPA', (25, 44))	('ALK', 'Gene', (75, 78))	('EML4', 'Gene', (82, 86))	('ALK', 'Gene', '238', (14, 17))	('ALK', 'Gene', '238', (87, 90))	('affect', 'Reg', (18, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('chromosome alignment', 'CPA', (158, 178))	('Inhibitors', 'Var', (0, 10))	('prolongation', 'PosReg', (102, 114))	('EML4', 'Gene', '27436', (82, 86))	('M phase', 'biological_process', 'GO:0000279', ('25', '32'))	('ALK', 'Gene', (14, 17))	('ALK', 'Gene', '238', (75, 78))	('defects', 'NegReg', (147, 154))	('ALK', 'Gene', (87, 90))	('anaphase', 'biological_process', 'GO:0051322', ('131', '139'))
18360	31570854	Similarly, knockdown of TXNDC12 by specific siRNAs repressed cell migration, invasion, and adhesion in SNU449 cells (Supplementary Fig.	('repressed', 'NegReg', (51, 60))	('SNU449', 'CellLine', 'CVCL:0454', (103, 109))	('invasion', 'CPA', (77, 85))	('TXNDC12', 'Gene', (24, 31))	('cell migration', 'biological_process', 'GO:0016477', ('61', '75'))	('adhesion', 'CPA', (91, 99))	('cell migration', 'CPA', (61, 75))	('knockdown', 'Var', (11, 20))
18361	31570854	2e, overexpression of TXNDC12 significantly promoted liver colonization of Hep3B cells, whereas depletion of TXNDC12 significantly inhibited liver colonization of HCCLM3 cells.	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('promoted', 'PosReg', (44, 52))	('liver colonization of HCCLM3 cells', 'CPA', (141, 175))	('TXNDC12', 'Gene', (109, 116))	('liver colonization', 'CPA', (53, 71))	('depletion', 'Var', (96, 105))	('inhibited', 'NegReg', (131, 140))	('Hep3B', 'CellLine', 'CVCL:0326', (75, 80))	('TXNDC12', 'Gene', (22, 29))
18363	31570854	A higher number of metastatic nodules were observed in mice injected with the Hep3B-TXNDC12 cells than in those injected with Hep3B-Vector cells, while fewer metastatic nodules were observed in mice injected with HCCLM3-shTXNDC12 cells than in those injected with HCCLM3-shNC cells (Fig.	('Hep3B-Vector', 'CellLine', 'CVCL:0326', (126, 138))	('Hep3B-TXNDC12', 'CellLine', 'CVCL:0326', (78, 91))	('mice', 'Species', '10090', (55, 59))	('Hep3B-TXNDC12 cells', 'Var', (78, 97))	('HCC', 'Phenotype', 'HP:0001402', (213, 216))	('metastatic nodules', 'CPA', (19, 37))	('mice', 'Species', '10090', (194, 198))	('HCC', 'Phenotype', 'HP:0001402', (264, 267))
18365	31570854	Overexpression of TXNDC12 decreased E-cadherin mRNA levels and increased ZEB1 (an inducer of EMT and a key transcriptional repressor of E-cadherin) mRNA levels, while knockdown of TXNDC12 increased E-cadherin and decreased ZEB1 mRNA levels (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('cadherin', 'molecular_function', 'GO:0008014', ('200', '208'))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('decreased', 'NegReg', (26, 35))	('increased', 'PosReg', (188, 197))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('ZEB1', 'MPA', (73, 77))	('decreased', 'NegReg', (213, 222))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (136, 146))	('knockdown', 'Var', (167, 176))	('TXNDC12', 'Gene', (180, 187))	('EMT', 'biological_process', 'GO:0001837', ('93', '96'))	('increased', 'PosReg', (63, 72))	('mRNA levels', 'MPA', (148, 159))	('E-cadherin', 'Gene', (198, 208))	('E-cadherin', 'Gene', '999', (198, 208))	('ZEB1 mRNA levels', 'MPA', (223, 239))
18366	31570854	We then performed immunoblot analyses to confirm that TXNDC12 could inhibit the protein expression of E-cadherin and upregulate that of ZEB1, as well as that of Vimentin, a mesenchymal cell marker (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('Vimentin', 'Gene', '7431', (161, 169))	('TXNDC12', 'Var', (54, 61))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('Vimentin', 'cellular_component', 'GO:0045099', ('161', '169'))	('inhibit', 'NegReg', (68, 75))	('protein expression', 'MPA', (80, 98))	('E-cadherin', 'Gene', (102, 112))	('E-cadherin', 'Gene', '999', (102, 112))	('upregulate', 'PosReg', (117, 127))	('Vimentin', 'Gene', (161, 169))	('Vimentin', 'cellular_component', 'GO:0045098', ('161', '169'))
18369	31570854	To verify whether TXNDC12 induced EMT in HCC cells through upregulation of ZEB1, we knocked down ZEB1 expression in TXNDC12-overexpressing cells and observed that ZEB1 knockdown eliminated the TXNDC12-mediated upregulation of Vimentin and downregulation of E-cadherin (Fig.	('ZEB1', 'Gene', (97, 101))	('Vimentin', 'Gene', '7431', (226, 234))	('Vimentin', 'cellular_component', 'GO:0045098', ('226', '234'))	('knocked', 'Var', (84, 91))	('downregulation', 'NegReg', (239, 253))	('eliminated', 'NegReg', (178, 188))	('cadherin', 'molecular_function', 'GO:0008014', ('259', '267'))	('Vimentin', 'cellular_component', 'GO:0045099', ('226', '234'))	('EMT', 'biological_process', 'GO:0001837', ('34', '37'))	('E-cadherin', 'Gene', (257, 267))	('E-cadherin', 'Gene', '999', (257, 267))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('Vimentin', 'Gene', (226, 234))	('upregulation', 'PosReg', (210, 222))
18376	31570854	To determine whether the activation of beta-catenin is essential for the TXNDC12-mediated promotion of EMT, we knocked down the expression of beta-catenin in TXNDC12-overexpressing cells and observed that knockdown of beta-catenin eliminated the TXNDC12-mediated upregulation of ZEB1 and Vimentin, as well as the TXNDC12-mediated downregulation of E-cadherin (Fig.	('eliminated', 'NegReg', (231, 241))	('E-cadherin', 'Gene', (348, 358))	('Vimentin', 'cellular_component', 'GO:0045098', ('288', '296'))	('E-cadherin', 'Gene', '999', (348, 358))	('cadherin', 'molecular_function', 'GO:0008014', ('350', '358'))	('upregulation', 'PosReg', (263, 275))	('knockdown', 'Var', (205, 214))	('Vimentin', 'Gene', (288, 296))	('Vimentin', 'cellular_component', 'GO:0045099', ('288', '296'))	('EMT', 'biological_process', 'GO:0001837', ('103', '106'))	('ZEB1', 'Protein', (279, 283))	('Vimentin', 'Gene', '7431', (288, 296))	('downregulation', 'NegReg', (330, 344))
18380	31570854	Similarly, we found that inhibition of TXNDC12 abrogated the increase in cell motility induced by TGFbeta1 (Supplementary Fig.	('TGFbeta1', 'Gene', '7040', (98, 106))	('TXNDC12', 'Gene', (39, 46))	('TGFbeta1', 'Gene', (98, 106))	('cell motility', 'biological_process', 'GO:0048870', ('73', '86'))	('cell motility', 'CPA', (73, 86))	('inhibition', 'Var', (25, 35))	('abrogated', 'NegReg', (47, 56))	('increase', 'PosReg', (61, 69))
18382	31570854	To explore the mechanism by which TXNDC12 induces beta-catenin activation, we examined the formation of the E-cadherin/beta-catenin complex by co-IP and immunofluorescence analysis.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('TXNDC12', 'Var', (34, 41))	('catenin complex', 'cellular_component', 'GO:0016342', ('124', '139'))
18383	31570854	5a, b, the amount of E-cadherin/beta-catenin complex in HCC cells with high TXNDC12 expression was lower than that in HCC cells with low TXNDC12 expression.	('catenin complex', 'cellular_component', 'GO:0016342', ('37', '52'))	('lower', 'NegReg', (99, 104))	('high', 'Var', (71, 75))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('amount of', 'MPA', (11, 20))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('TXNDC12', 'Gene', (76, 83))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))
18384	31570854	Subsequently, we mapped the binding domains of TXNDC12 by transfection of TXNDC12 truncation mutants into 293T cells.	('TXNDC12', 'Gene', (74, 81))	('293T', 'CellLine', 'CVCL:0063', (106, 110))	('truncation mutants', 'Var', (82, 100))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))
18385	31570854	To further investigate whether the PDI enzymatic activity of TXNDC12 is required for beta-catenin activation, we constructed a TXNDC12-CS mutant in which both cysteines in the active site were mutated.	('TXNDC12-CS', 'Gene', (127, 137))	('cysteines', 'Chemical', 'MESH:D003545', (159, 168))	('TXNDC12-CS', 'Chemical', '-', (127, 137))	('mutant', 'Var', (138, 144))	('PDI', 'Gene', '64714', (35, 38))	('PDI', 'Gene', (35, 38))
18386	31570854	Consistent with this result, we found that the TXNDC12-CS mutant was unable to induce the nuclear translocation of beta-catenin (Fig.	('TXNDC12-CS', 'Var', (47, 57))	('TXNDC12-CS', 'Chemical', '-', (47, 57))	('beta-catenin', 'Protein', (115, 127))	('nuclear translocation', 'MPA', (90, 111))
18387	31570854	Similarly, the transcriptional activity of beta-catenin in HCC cells transfected with the TXNDC12-CS mutant was not significantly different from that in control cells (Fig.	('TXNDC12-CS', 'Gene', (90, 100))	('mutant', 'Var', (101, 107))	('TXNDC12-CS', 'Chemical', '-', (90, 100))	('beta-catenin', 'Protein', (43, 55))	('transcriptional activity', 'MPA', (15, 39))	('HCC', 'Phenotype', 'HP:0001402', (59, 62))
18388	31570854	We also found that the TXNDC12-CS mutant did not induce either the EMT process (Fig.	('EMT', 'biological_process', 'GO:0001837', ('67', '70'))	('TXNDC12-CS', 'Var', (23, 33))	('TXNDC12-CS', 'Chemical', '-', (23, 33))	('EMT process', 'CPA', (67, 78))
18391	31570854	For both the West China Hospital (WCH) and TCGA datasets, the unadjusted survival curves showed that the high TXNDC12 expression group had worse OS (hazard ratio (HR), 3.80; 95% confidence interval (CI), 1.91-7.54) and DFS (HR, 3.54; 95% CI, 1.98-6.36) than the low TXNDC12 expression group (P < 0.05).	('DFS', 'Disease', 'None', (219, 222))	('DFS', 'Disease', (219, 222))	('high TXNDC12 expression', 'Var', (105, 128))
18392	31570854	Similarly, the 3-year DFS rate of the low TXNDC12 expression group was higher than that of the high TXNDC12 expression group (Fig.	('higher', 'PosReg', (71, 77))	('DFS', 'Disease', (22, 25))	('low TXNDC12 expression', 'Var', (38, 60))	('DFS', 'Disease', 'None', (22, 25))
18395	31570854	These results further confirmed that TXNDC12 could stimulate the nuclear translocation of beta-catenin and subsequently downregulate the expression of E-cadherin.	('nuclear translocation', 'MPA', (65, 86))	('beta-catenin', 'Protein', (90, 102))	('expression', 'MPA', (137, 147))	('TXNDC12', 'Var', (37, 44))	('downregulate', 'NegReg', (120, 132))	('stimulate', 'PosReg', (51, 60))	('E-cadherin', 'Gene', (151, 161))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))	('E-cadherin', 'Gene', '999', (151, 161))
18397	31570854	Taken together, these results indicated that the combination of TXNDC12 and nuclear beta-catenin could serve as a biomarker in HCC for evaluating the metastatic potential and predicting the prognosis of HCC patients.	('patients', 'Species', '9606', (207, 215))	('TXNDC12', 'Var', (64, 71))	('metastatic potential', 'CPA', (150, 170))	('HCC', 'Disease', (203, 206))	('nuclear beta-catenin', 'Protein', (76, 96))	('HCC', 'Phenotype', 'HP:0001402', (127, 130))	('HCC', 'Phenotype', 'HP:0001402', (203, 206))
18407	31570854	A member of the PDI family, TXNDC12 has been implicated in the tumorigenesis and metastasis of gastric cancer.	('tumor', 'Disease', (63, 68))	('PDI', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('metastasis of gastric cancer', 'Disease', (81, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('TXNDC12', 'Var', (28, 35))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (81, 109))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('implicated', 'Reg', (45, 55))	('PDI', 'Gene', '64714', (16, 19))
18408	31570854	In addition, we observed that TXNDC12 promoted intrahepatic metastasis and lung colonization of HCC cells in mouse models.	('lung colonization of HCC cells', 'CPA', (75, 105))	('TXNDC12', 'Var', (30, 37))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (47, 70))	('intrahepatic metastasis', 'Disease', (47, 70))	('promoted', 'PosReg', (38, 46))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))	('mouse', 'Species', '10090', (109, 114))
18412	31570854	In one study, pancreatic ductal adenocarcinoma (PDAC) mouse models were established with deletion of Snail or Twist, two key transcription factors responsible for EMT.	('Twist', 'Gene', (110, 115))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (14, 46))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))	('PDAC', 'Chemical', '-', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('Twist', 'Gene', '22160', (110, 115))	('deletion', 'Var', (89, 97))	('Snail', 'Gene', (101, 106))	('Snail', 'Gene', '20613', (101, 106))	('pancreatic ductal adenocarcinoma', 'Disease', (14, 46))	('mouse', 'Species', '10090', (54, 59))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (14, 46))	('EMT', 'biological_process', 'GO:0001837', ('163', '166'))
18423	31570854	Overexpression of TXNDC12 in HCC is a strong indicator of high tumor aggressiveness and correlates with poor clinical outcomes.	('high tumor aggressiveness', 'Disease', 'MESH:D001523', (58, 83))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('Overexpression', 'Var', (0, 14))	('TXNDC12', 'Gene', (18, 25))	('high tumor aggressiveness', 'Disease', (58, 83))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('aggressiveness', 'Phenotype', 'HP:0000718', (69, 83))
18441	32395124	PPARG Drives Molecular Networks as an Inhibitor for the Pathologic Development and Progression of Lung Adenocarcinoma Previous studies showed that low PPARG expression was associated with poor prognosis of lung adenocarcinoma (LA) with limited mechanisms identified.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (206, 225))	('LA', 'Phenotype', 'HP:0030078', (227, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('PPARG', 'Gene', (151, 156))	('expression', 'MPA', (157, 167))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('low', 'Var', (147, 150))	('Lung Adenocarcinoma', 'Disease', (98, 117))	('PPARG', 'Gene', (0, 5))	('PPARG', 'Gene', '5468', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (206, 225))	('PPARG', 'Gene', '5468', (151, 156))	('lung adenocarcinoma', 'Disease', (206, 225))
18527	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))
18531	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))
18532	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))
18533	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))	('CT', 'Disease', 'MESH:D013736', (141, 143))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('variants', 'Var', (64, 72))
18537	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))
18539	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))
18540	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))
18542	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))
18543	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))
18544	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))
18545	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))
18549	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))	('genetic variants', 'Var', (90, 106))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('CT', 'Disease', 'MESH:D013736', (110, 112))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
18550	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))
18551	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))
18560	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))	('rs150492976', 'Mutation', 'rs150492976', (31, 42))	('rs75932085', 'Var', (60, 70))	('rs4726004', 'Mutation', 'rs4726004', (111, 120))	('rs144031443', 'Mutation', 'rs144031443', (15, 26))	('rs4726004', 'Var', (111, 120))	('rs144031443', 'Var', (15, 26))	('rs150492976', 'Var', (31, 42))
18563	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))
18571	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))
18572	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))	('OPRM1', 'Gene', '4988', (84, 89))	('rs402969', 'Var', (296, 304))	('rs402969', 'Mutation', 'rs402969', (28, 36))	('rs402969', 'Mutation', 'rs402969', (296, 304))	('OPRM1', 'Gene', (242, 247))	('OPRM1', 'Gene', '4988', (242, 247))	('C > T', 'Var', (313, 318))	('NLRP8', 'Gene', '126205', (306, 311))	('rs6941653', 'Var', (73, 82))	('rs6941653', 'Mutation', 'rs6941653', (14, 23))
18573	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))
18575	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))	('LUAD', 'Disease', (153, 157))	('SCC', 'Disease', (69, 72))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('rs6941653', 'Var', (56, 65))	('SCC', 'Disease', 'MESH:D002294', (69, 72))
18576	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))
18577	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))
18578	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))
18580	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))	('transcription factor', 'molecular_function', 'GO:0000981', ('96', '116'))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('NFATC2', 'Gene', '4773', (117, 123))	('rs6941653', 'Var', (38, 47))	('rs6941653', 'Mutation', 'rs6941653', (38, 47))	('binding', 'Interaction', (85, 92))	('NFATC2', 'Gene', (117, 123))
18582	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))	('binding', 'molecular_function', 'GO:0005488', ('99', '106'))	('rs9397692', 'Mutation', 'rs9397692', (33, 42))	('NFATC2', 'Gene', '4773', (140, 146))	('affect', 'Reg', (88, 94))	('transcription', 'biological_process', 'GO:0006351', ('119', '132'))	('transcription factor', 'molecular_function', 'GO:0000981', ('119', '139'))	('NFATC2', 'Gene', (140, 146))	('binding', 'Interaction', (99, 106))
18583	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))	('BRCA1', 'Gene', (124, 129))	('modify', 'Reg', (98, 104))	('rs402969', 'Mutation', 'rs402969', (50, 58))	('rs402969', 'Var', (50, 58))
18584	32194810	Consistently, the Regulome DB score of rs805165 was 5 (TF binding or DNase peak).	('TF binding', 'molecular_function', 'GO:0008134', ('55', '65'))	('rs805165', 'Var', (39, 47))	('rs805165', 'Mutation', 'rs805165', (39, 47))	('DNase peak', 'MPA', (69, 79))
18587	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))
18588	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))
18600	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))	('CT', 'Disease', 'MESH:D013736', (139, 141))	('lung cancer', 'Disease', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associations', 'Interaction', (98, 110))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))
18602	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))
18604	32194810	Previous studies revealed that genetic variants in OPRM1 could modulate the dependence to multiple drugs or chemical agents, including nicotine, cocaine, alcohol.	('dependence to multiple drugs or', 'MPA', (76, 107))	('cocaine', 'Disease', (145, 152))	('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))
18609	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))
18610	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))
18612	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.	('affect', 'Reg', (123, 129))	('rs6941653', 'Mutation', 'rs6941653', (27, 36))	('rs9397692', 'Var', (74, 83))	('rs9397692', 'Mutation', 'rs9397692', (74, 83))	('NFATC2', 'Gene', (148, 154))	('binding', 'molecular_function', 'GO:0005488', ('134', '141'))	('NFATC2', 'Gene', '4773', (148, 154))	('binding', 'Interaction', (134, 141))	('rs6941653', 'Var', (27, 36))
18613	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', 'Var', (4, 12))	('NLRP8', 'Gene', '126205', (44, 49))	('rs402969', 'Mutation', 'rs402969', (4, 12))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('87', '105'))	('NLRP8', 'Gene', (44, 49))
18617	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))	('gene expression', 'biological_process', 'GO:0010467', ('149', '164'))	('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))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))
18618	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))
18621	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))
18721	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))	('EIF4', 'cellular_component', 'GO:0008304', ('27', '31'))	('EIF4EBP1', 'Gene', '1978', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('phosphorylated', 'Var', (12, 26))
18725	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))
18726	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))
18732	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))
18782	31817953	In contrast to other members of the CD28 family, PD1 transduces only signals when cross-linked together with the B cell or T cell antigen receptor thereby yielding co-inhibitory micro-clusters with the T cell receptor (TCR) and CD28.	('PD1', 'Gene', (49, 52))	('CD28', 'Gene', (228, 232))	('CD28', 'Gene', '940', (36, 40))	('TCR', 'cellular_component', 'GO:0042101', ('219', '222'))	('CD28', 'Gene', '940', (228, 232))	('yielding', 'Reg', (155, 163))	('co-inhibitory', 'MPA', (164, 177))	('TCR', 'biological_process', 'GO:0006283', ('219', '222'))	('cross-linked', 'Var', (82, 94))	('PD1', 'Gene', '5133', (49, 52))	('CD28', 'Gene', (36, 40))
18785	31817953	PD-1 ligation caused a reduced phosphorylation of CD3, ZAP70 and protein kinase C, inhibits ERK activation in T cells and the calcium mobilization and phosphorylation of Igbeta, Syk, PLC-gamma2 and ERK in B cells.	('Syk', 'Gene', (178, 181))	('ZAP70', 'Gene', (55, 60))	('ligation', 'Var', (5, 13))	('Igbeta', 'Gene', (170, 176))	('ERK', 'Gene', (92, 95))	('ZAP70', 'Gene', '7535', (55, 60))	('ERK', 'molecular_function', 'GO:0004707', ('92', '95'))	('phosphorylation', 'MPA', (151, 166))	('phosphorylation', 'MPA', (31, 46))	('phosphorylation', 'biological_process', 'GO:0016310', ('151', '166'))	('PLC', 'cellular_component', 'GO:0042824', ('183', '186'))	('protein kinase C', 'Enzyme', (65, 81))	('PD-1', 'Gene', (0, 4))	('Igbeta', 'Gene', '974', (170, 176))	('inhibits', 'NegReg', (83, 91))	('ERK', 'Gene', '5594', (198, 201))	('PLC-gamma2', 'Gene', '5336', (183, 193))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('reduced', 'NegReg', (23, 30))	('ERK', 'molecular_function', 'GO:0004707', ('198', '201'))	('calcium mobilization', 'biological_process', 'GO:0051209', ('126', '146'))	('ERK', 'Gene', '5594', (92, 95))	('calcium mobilization', 'MPA', (126, 146))	('activation', 'MPA', (96, 106))	('ERK', 'Gene', (198, 201))	('Syk', 'Gene', '6850', (178, 181))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('CD3', 'Protein', (50, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('PLC-gamma2', 'Gene', (183, 193))
18786	31817953	Thus, PD-1 ligation attenuates TCR-mediated signaling and impairs the activity of the PI3K-Akt and the Ras/MEK/ERK pathway.	('attenuates', 'NegReg', (20, 30))	('Akt', 'Gene', '207', (91, 94))	('ERK', 'Gene', '5594', (111, 114))	('activity', 'MPA', (70, 78))	('TCR', 'cellular_component', 'GO:0042101', ('31', '34'))	('PD-1', 'Gene', (6, 10))	('impairs', 'NegReg', (58, 65))	('ERK', 'Gene', (111, 114))	('Akt', 'Gene', (91, 94))	('TCR', 'biological_process', 'GO:0006283', ('31', '34'))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('MEK', 'Gene', (107, 110))	('TCR-mediated', 'Pathway', (31, 43))	('MEK', 'Gene', '5609', (107, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('ERK', 'molecular_function', 'GO:0004707', ('111', '114'))	('ligation', 'Var', (11, 19))
18791	31817953	Next to this, PD-1 ligation alters the metabolic program of activated T cells thereby generating a more oxidative microenvironment.	('generating', 'Reg', (86, 96))	('more', 'PosReg', (99, 103))	('ligation', 'Var', (19, 27))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('alters', 'Reg', (28, 34))	('PD-1', 'Gene', (14, 18))	('metabolic program', 'MPA', (39, 56))
18801	31817953	Over the last years, aberrant PD-L1 expression in tumors and immune cells could be due to structural alterations, such as DNA copy number alterations (CNA) mediated by gene deletions or gene amplifications as well as translocations.	('gene deletions', 'Var', (168, 182))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('aberrant', 'Var', (21, 29))	('N', 'Chemical', 'MESH:D009584', (152, 153))	('gene amplifications', 'Var', (186, 205))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('PD-L1', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('due', 'Reg', (83, 86))	('expression', 'MPA', (36, 46))	('translocations', 'Var', (217, 231))
18803	31817953	Interestingly, deletions of PD-L1 were more frequently found than gains and were most prominent in melanoma as well as NSCLC.	('found', 'Reg', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('prominent', 'Reg', (86, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('PD-L1', 'Gene', (28, 33))	('deletions', 'Var', (15, 24))	('NSCLC', 'Disease', (119, 124))
18804	31817953	In many cancer types, copy number gains (CNG) were found in focal regions, chromosome 9p24.1 or in the whole of chromosome 9, which correlated with increased PD-L1 expression levels and response to iCPI therapy as determined by analysis of datasets from The Cancer Genome Atlas (TCGA) of different cancer types.	('copy number', 'Var', (22, 33))	('cancer', 'Disease', (8, 14))	('increased', 'PosReg', (148, 157))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('Cancer', 'Disease', (258, 264))	('Cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (298, 304))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('Cancer', 'Disease', 'MESH:D009369', (258, 264))	('gains', 'PosReg', (34, 39))	('increased PD', 'Phenotype', 'HP:0008151', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))	('PD-L1 expression levels', 'MPA', (158, 181))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
18806	31817953	PD-L1 CNGs were in particular found in NSCLC of smokers with mutations and EML4-ALK rearrangements.	('EML4', 'Gene', (75, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('EML4', 'Gene', '27436', (75, 79))	('found', 'Reg', (30, 35))	('mutations', 'Var', (61, 70))	('PD-L1', 'Gene', (0, 5))	('ALK', 'Gene', '238', (80, 83))	('NSCLC', 'Disease', (39, 44))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('ALK', 'Gene', (80, 83))
18807	31817953	In NSCLC, CD274 amplifications associated with an increased PD-L1 expression, which co-occurred with Janus Kinase (JAK)2 amplifications.	('NSCLC', 'Disease', (3, 8))	('CD274', 'Gene', '29126', (10, 15))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('increased', 'PosReg', (50, 59))	('PD-L1', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('JAK', 'molecular_function', 'GO:0004713', ('115', '118'))	('CD274', 'Gene', (10, 15))	('JAK)2', 'Gene', '3717', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('amplifications', 'Var', (16, 30))	('increased PD', 'Phenotype', 'HP:0008151', (50, 62))
18808	31817953	In cervical, lung and squamous cell cancers, PD-L1 amplification was frequently accompanied by an amplification of the PD-L2 gene, while in triple negative breast cancer (TNBC), genomic amplification of 9p24.1 was found.	('amplification', 'MPA', (98, 111))	('accompanied by', 'Reg', (80, 94))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cervical', 'Disease', (3, 11))	('squamous cell cancers', 'Disease', 'MESH:D018307', (22, 43))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('N', 'Chemical', 'MESH:D009584', (172, 173))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('PD-L2', 'Gene', (119, 124))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (22, 43))	('squamous cell cancers', 'Disease', (22, 43))	('breast cancer', 'Disease', (156, 169))	('lung', 'Disease', (13, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('PD-L1', 'Gene', (45, 50))	('amplification', 'Var', (51, 64))
18809	31817953	It is noteworthy that PD-L1 amplification was present primary tumors and associated metastasis with a concordance rate of 73%.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PD-L1', 'Gene', (22, 27))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('metastasis', 'CPA', (84, 94))	('amplification', 'Var', (28, 41))
18810	31817953	The single nucleotide polymorphism (SNP) rs4143815C>G in the 3' UTR of PD-L1 has been associated with an increased cancer risk and might be used as biomarker to predict the susceptibility to cancer.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (191, 197))	('rs4143815C>G', 'Var', (41, 53))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('associated', 'Reg', (86, 96))	('PD-L1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
18811	31817953	In addition, a number of polymorphisms were also described in PD-1, which were associated with the risk of susceptibility of different cancers.	('associated', 'Reg', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('PD-1', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('polymorphisms', 'Var', (25, 38))
18814	31817953	Vice versa inhibition of MYC results in downregulation of PD-L1 expression.	('MYC', 'Gene', (25, 28))	('expression', 'MPA', (64, 74))	('downregulation', 'NegReg', (40, 54))	('MYC', 'Gene', '4609', (25, 28))	('inhibition', 'Var', (11, 21))	('PD-L1', 'Gene', (58, 63))
18815	31817953	Signaling via the PIK3/AKT/mTOR pathways also control immune surveillance, while PTEN loss and mutations in PIK3CA induce the activation of the AKT/mTOR pathway thereby increasing PD-L1 expression, which could be associated with immune resistance.	('PD-L1', 'Protein', (180, 185))	('loss', 'NegReg', (86, 90))	('AKT', 'Gene', (144, 147))	('mTOR', 'Gene', '2475', (148, 152))	('immune surveillance', 'MPA', (54, 73))	('PIK3', 'Gene', (108, 112))	('PIK3CA', 'Gene', (108, 114))	('AKT', 'Gene', (23, 26))	('PIK3', 'Gene', '5294', (108, 112))	('Signaling', 'biological_process', 'GO:0023052', ('0', '9'))	('mTOR', 'Gene', '2475', (27, 31))	('associated', 'Reg', (213, 223))	('control', 'Reg', (46, 53))	('mutations', 'Var', (95, 104))	('AKT', 'Gene', '207', (144, 147))	('AKT', 'Gene', '207', (23, 26))	('PIK3', 'Gene', (18, 22))	('activation', 'PosReg', (126, 136))	('PIK3', 'Gene', '5294', (18, 22))	('increasing', 'PosReg', (169, 179))	('PIK3CA', 'Gene', '5290', (108, 114))	('mTOR', 'Gene', (148, 152))	('expression', 'MPA', (186, 196))	('mTOR', 'Gene', (27, 31))
18816	31817953	The EGF-R expression is a strong independent predictive marker of PD-L1 overexpression, while inhibition of EGF-R expression using tyrosine kinase inhibitors (TKI) leads to a downregulation of PD-L1 expression.	('tyrosine', 'Chemical', 'None', (131, 139))	('EGF-R', 'Gene', '1956', (108, 113))	('PD-L1', 'Gene', (193, 198))	('EGF-R', 'Gene', (108, 113))	('expression', 'MPA', (199, 209))	('downregulation', 'NegReg', (175, 189))	('EGF-R', 'Gene', '1956', (4, 9))	('EGF', 'molecular_function', 'GO:0005154', ('4', '7'))	('EGF-R', 'Gene', (4, 9))	('inhibition', 'Var', (94, 104))	('EGF', 'molecular_function', 'GO:0005154', ('108', '111'))
18817	31817953	Thus, PD-L1 expression can be induced by EGF signaling and enhanced by activating mutations in the EGF-R gene and contributes to the EGF-R-driven immune escape.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('immune escape', 'CPA', (146, 159))	('activating mutations', 'Var', (71, 91))	('EGF', 'molecular_function', 'GO:0005154', ('41', '44'))	('EGF-R', 'Gene', '1956', (99, 104))	('EGF', 'molecular_function', 'GO:0005154', ('99', '102'))	('enhanced', 'PosReg', (59, 67))	('expression', 'MPA', (12, 22))	('EGF-R', 'Gene', (133, 138))	('PD-L1', 'Gene', (6, 11))	('mutations', 'Var', (82, 91))	('contributes', 'Reg', (114, 125))	('EGF', 'molecular_function', 'GO:0005154', ('133', '136'))	('EGF-R', 'Gene', (99, 104))	('EGF-R', 'Gene', '1956', (133, 138))
18825	31817953	Next to the transcriptional control of PD-L1 expression, epigenetic mechanisms could lead to altered expression.	('PD-L1', 'Gene', (39, 44))	('lead to altered', 'Reg', (85, 100))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('epigenetic mechanisms', 'Var', (57, 78))	('transcriptional control', 'biological_process', 'GO:0006355', ('12', '35'))	('expression', 'MPA', (101, 111))
18827	31817953	Hypermethylation of the CD274 promoter leads to a reduced/lack of PD-L1 expression, which could be reverted by the treatment of cells with the demethylating agents 5-azacytidin (5-AZA), which increased the expression of PD-L1 expression at the mRNA and protein level.	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('N', 'Chemical', 'MESH:D009584', (246, 247))	('CD274', 'Gene', '29126', (24, 29))	('5-azacytidin', 'Chemical', 'MESH:C068492', (164, 176))	('expression', 'MPA', (206, 216))	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (72, 82))	('5-AZA', 'Chemical', 'MESH:C068492', (178, 183))	('CD274', 'Gene', (24, 29))	('reduced/lack', 'NegReg', (50, 62))	('PD-L1', 'Gene', (66, 71))	('increased', 'PosReg', (192, 201))
18829	31817953	Thus, PD-L1 promoter methylation may provide a potentially more effective immunotherapeutic strategy in some tumor patients.	('patients', 'Species', '9606', (115, 123))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('methylation', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('PD-L1', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
18832	31817953	Structural alterations leading to the disruption of the 3' UTR of the PD-L1 gene have been recently described and appear to be highly common in different cancer types including T cell leukemia/lymphoma, diffuse large B cell lymphoma and stomach adenocarcinoma.	('lymphoma', 'Phenotype', 'HP:0002665', (193, 201))	('T cell leukemia/lymphoma', 'Disease', (177, 201))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (217, 232))	('disruption', 'Var', (38, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (224, 232))	('stomach adenocarcinoma', 'Disease', (237, 259))	('alterations', 'Var', (11, 22))	('large B cell', 'Phenotype', 'HP:0005404', (211, 223))	('B cell lymphoma', 'Disease', (217, 232))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('PD-L1', 'Gene', (70, 75))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (237, 259))	('T cell leukemia/lymphoma', 'Phenotype', 'HP:0005517', (177, 201))	('T cell leukemia/lymphoma', 'Disease', 'MESH:D016399', (177, 201))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	('B cell lymphoma', 'Disease', 'MESH:D016393', (217, 232))	('cancer', 'Disease', (154, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('common', 'Reg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
18833	31817953	Furthermore, disruption of the PD-L1 3' UTR in mice enables immune evasion of tumor cells with elevated PD-L1 expression, which is actively inhibited by immune checkpoint blockade.	('elevated', 'PosReg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('disruption', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('immune evasion', 'biological_process', 'GO:0051842', ('60', '74'))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', (78, 83))	('immune evasion', 'biological_process', 'GO:0042783', ('60', '74'))	('mice', 'Species', '10090', (47, 51))	('PD-L1', 'Gene', (31, 36))	('PD-L1', 'Gene', (104, 109))
18834	31817953	Abnormalities in the 3' UTR could on the one hand induce a stabilization of PD-L1 transcripts, while the 3' UTR has also potential microRNA (miRNA) binding sites, which are involved in intra-tumoral immune suppression.	('intra-tumoral immune suppression', 'Disease', 'OMIM:146850', (185, 217))	('Abnormalities', 'Var', (0, 13))	('N', 'Chemical', 'MESH:D009584', (144, 145))	('intra-tumoral immune suppression', 'Disease', (185, 217))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('miRNA) binding', 'molecular_function', 'GO:0035198', ('141', '155'))	('stabilization', 'MPA', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('binding', 'Interaction', (148, 155))	('PD-L1', 'Gene', (76, 81))
18835	31817953	Indeed, a mutation in the 3' UTR has been shown to disrupt the miR-570 binding thereby enhancing PD-L1 expression.	('PD-L1', 'Protein', (97, 102))	('miR-570', 'Gene', '693155', (63, 70))	('disrupt', 'NegReg', (51, 58))	('enhancing', 'PosReg', (87, 96))	('miR-570', 'Gene', (63, 70))	('mutation', 'Var', (10, 18))	('binding', 'Interaction', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
18844	31817953	In contrast, deregulation of PD-L1 by long-noncoding RNAs (lnRNAs) has been reported.	('PD-L1', 'Gene', (29, 34))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('deregulation', 'MPA', (13, 25))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('long-noncoding RNAs', 'Var', (38, 57))
18849	31817953	Inhibitors of N-linked, but not O-linked glycosylation alters the migratory shift of PD-L1 suggesting that PD-L1 is primarily N-glycosylated.	('glycosylation', 'biological_process', 'GO:0070085', ('41', '54'))	('Inhibitors', 'Var', (0, 10))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('alters', 'Reg', (55, 61))	('migratory shift', 'CPA', (66, 81))
18860	31817953	However, there are patients that are not benefitting from this treatment, including patients with tumors carrying EGF-R mutations.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (84, 92))	('EGF-R', 'Gene', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EGF', 'molecular_function', 'GO:0005154', ('114', '117'))	('mutations', 'Var', (120, 129))	('EGF-R', 'Gene', '1956', (114, 119))
18865	31817953	This increased knowledge might also offer novel opportunities for the treatment of tumors by targeting, e.g., respective signal pathways, PTMs or epigenetic modifications.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('signal pathways', 'Pathway', (121, 136))	('epigenetic modifications', 'Var', (146, 170))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
18884	31379585	In a study focusing on non-canonical miRNA functions, which are receptor-mediated, it was demonstrated that two sEV-delivered miRNAs, miR-21 and miR-29a, are able to bind to the murine toll-like receptor (TLR) 7 and the human TLR8 and induce cytokine expression.	('TLR8', 'Gene', (226, 230))	('miR-21', 'Var', (134, 140))	('TLR8', 'Gene', '51311', (226, 230))	('bind', 'Interaction', (166, 170))	('human', 'Species', '9606', (220, 225))	('miR-29a', 'Gene', (145, 152))	('cytokine expression', 'MPA', (242, 261))	('murine', 'Species', '10090', (178, 184))	('miR-29a', 'Gene', '387222', (145, 152))	('induce', 'PosReg', (235, 241))
18902	31379585	It was shown that deletion of mPGES-1 impairs the left ventricular contractile function after acute myocardial infarction and leads to overall remodeling of the left ventricle.	('leads to', 'Reg', (126, 134))	('left ventricular contractile function', 'CPA', (50, 87))	('myocardial infarction', 'Phenotype', 'HP:0001658', (100, 121))	('myocardial infarction', 'Disease', (100, 121))	('impairs', 'NegReg', (38, 45))	('myocardial infarction', 'Disease', 'MESH:D009203', (100, 121))	('remodeling', 'CPA', (143, 153))	('mPGES-1', 'Gene', '64292', (30, 37))	('deletion', 'Var', (18, 26))	('mPGES-1', 'Gene', (30, 37))
18913	31379585	In this respect, mPGES-1 inhibition might be of particular interest since inhibition of mPGES-1, instead of COX-2, may be associated with fewer side effects as other prostanoids would not be affected.	('mPGES-1', 'Gene', '64292', (17, 24))	('mPGES-1', 'Gene', (88, 95))	('COX-2', 'Gene', (108, 113))	('inhibition', 'Var', (74, 84))	('mPGES-1', 'Gene', (17, 24))	('prostanoids', 'Chemical', 'MESH:D011453', (166, 177))	('COX-2', 'Gene', '4513', (108, 113))	('mPGES-1', 'Gene', '64292', (88, 95))
18944	31379585	In human fibroblasts of smokers with chronic obstructive pulmonary disease, it was found that single nucleotide polymorphisms in the miR-146a precursor caused several patients to have reduced miRNA level, which significantly improved baseline lung function.	('miR-146a', 'Gene', (133, 141))	('improved baseline lung function', 'Phenotype', 'HP:0005952', (225, 256))	('human', 'Species', '9606', (3, 8))	('single nucleotide polymorphisms', 'Var', (94, 125))	('patients', 'Species', '9606', (167, 175))	('reduced', 'NegReg', (184, 191))	('improved', 'PosReg', (225, 233))	('lung function', 'MPA', (243, 256))	('miR-146a', 'Gene', '406938', (133, 141))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (45, 74))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (37, 74))	('miRNA level', 'MPA', (192, 203))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (37, 74))	('chronic obstructive pulmonary disease', 'Disease', (37, 74))
18945	31379585	Very recently, it was demonstrated that the polymorphisms of miR-146a (rs2910164) and plasmacytoma variant translocation 1 (PVT1; rs13281615) affect the prognosis of colon cancer by regulating COX-2 expression and cell apoptosis.	('affect', 'Reg', (142, 148))	('COX-2', 'Gene', '4513', (193, 198))	('colon cancer', 'Disease', (166, 178))	('polymorphisms', 'Var', (44, 57))	('regulating', 'Reg', (182, 192))	('plasmacytoma variant translocation 1', 'Gene', '5820', (86, 122))	('expression', 'MPA', (199, 209))	('rs2910164', 'Var', (71, 80))	('PVT1', 'Gene', (124, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('PVT1', 'Gene', '5820', (124, 128))	('rs13281615', 'Mutation', 'rs13281615', (130, 140))	('colon cancer', 'Phenotype', 'HP:0003003', (166, 178))	('cell apoptosis', 'CPA', (214, 228))	('miR-146a', 'Gene', (61, 69))	('rs2910164', 'Mutation', 'rs2910164', (71, 80))	('miR-146a', 'Gene', '406938', (61, 69))	('plasmacytoma', 'Phenotype', 'HP:0011857', (86, 98))	('colon cancer', 'Disease', 'MESH:D015179', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('plasmacytoma variant translocation 1', 'Gene', (86, 122))	('COX-2', 'Gene', (193, 198))
18946	31379585	The presence of PVT1 decreased the expression level of miR-146a, which in turn increased the COX-2 level.	('PVT1', 'Gene', (16, 20))	('expression level', 'MPA', (35, 51))	('increased', 'PosReg', (79, 88))	('COX-2', 'Gene', (93, 98))	('miR-146a', 'Gene', '406938', (55, 63))	('decreased', 'NegReg', (21, 30))	('PVT1', 'Gene', '5820', (16, 20))	('miR-146a', 'Gene', (55, 63))	('presence', 'Var', (4, 12))	('COX-2', 'Gene', '4513', (93, 98))
18961	31379585	Finally, 15-PDGH was identified as the canonical target of miR-146b-3p that promotes proliferation, migration, and anchorage-independent growth of cervical cancer cells.	('migration', 'CPA', (100, 109))	('cervical cancer', 'Disease', 'MESH:D002583', (147, 162))	('miR-146b-3p', 'Var', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cervical cancer', 'Disease', (147, 162))	('promotes', 'PosReg', (76, 84))	('anchorage-independent growth', 'CPA', (115, 143))	('proliferation', 'CPA', (85, 98))
18980	31379585	Furthermore, several publications demonstrated that 5-LO is a canonical target for miR-19a-3p, miR-125-5p, miR-216-3p, and miR-674-5p (see  Table 2 ).	('miR-125-5p', 'Var', (95, 105))	('miR-674-5p', 'Gene', (123, 133))	('miR-19a', 'Gene', (83, 90))	('miR-674-5p', 'Gene', '102466726', (123, 133))	('miR-216-3p', 'Var', (107, 117))	('miR-19a', 'Gene', '406979', (83, 90))	('miR-125-5p', 'Chemical', '-', (95, 105))
18981	31379585	Specifically, miR-19a-3p and miR-125-5p regulate 5-LO expression in the human myeloid cell line MonoMac 6.	('miR-125-5p', 'Var', (29, 39))	('regulate', 'Reg', (40, 48))	('human', 'Species', '9606', (72, 77))	('miR-19a', 'Gene', (14, 21))	('miR-19a', 'Gene', '406979', (14, 21))	('5-LO', 'Gene', (49, 53))	('miR-125-5p', 'Chemical', '-', (29, 39))
18983	31379585	Overall, it reveals that miR-19a-3p and miR-125b-5p target 5-LO in a cell type and stimulus-specific manner.	('miR-19a', 'Gene', '406979', (25, 32))	('miR-19a', 'Gene', (25, 32))	('target', 'Reg', (52, 58))	('miR-125', 'Chemical', '-', (40, 47))	('miR-125b-5p', 'Var', (40, 51))	('5-LO', 'Protein', (59, 63))
18992	31379585	These data indicate that miR-216-3p might represent a novel target for colorectal cancer treatment.	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('miR-216-3p', 'Var', (25, 35))
18999	31379585	Thus, LTB4 induces the expression of inflammatory miRNAs including miR-155, miR-146a and miR125b in macrophages via the LT B4 receptor-1 (BLT1) and Galpha1 signaling.	('miR-155', 'Gene', (67, 74))	('LTB4', 'Gene', (6, 10))	('miR125b', 'Var', (89, 96))	('induces', 'PosReg', (11, 18))	('miR-146a', 'Gene', '406938', (76, 84))	('BLT1', 'Gene', (138, 142))	('miR-155', 'Gene', '406947', (67, 74))	('miR-146a', 'Gene', (76, 84))	('BLT1', 'Gene', '1241', (138, 142))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('expression', 'MPA', (23, 33))
19003	31379585	This suggests that miRNAs not only regulate cellular functions in an autocrine/intracrine manner but also can affect processes such as the formation of lipid mediators in a paracrine fashion.	('affect', 'Reg', (110, 116))	('miRNAs', 'Var', (19, 25))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('lipid', 'Chemical', 'MESH:D008055', (152, 157))	('formation of lipid mediators', 'MPA', (139, 167))	('regulate', 'Reg', (35, 43))	('cellular functions', 'MPA', (44, 62))
19004	31379585	Of note, 5-LO was identified as a binding protein for Dicer, which suggests that 5-LO can modulate the Dicer function and interferes with miRNA generation.	('Dicer', 'Gene', '23405', (103, 108))	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('Dicer', 'Gene', (103, 108))	('modulate', 'Reg', (90, 98))	('5-LO', 'Var', (81, 85))	('miRNA', 'MPA', (138, 143))	('Dicer', 'Gene', '23405', (54, 59))	('Dicer', 'Gene', (54, 59))	('interferes', 'NegReg', (122, 132))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
19074	31104002	It has also been demonstrated in metastatic breast, colorectal, and prostate cancer patients that NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs.	('CTCs', 'Var', (184, 188))	('patients', 'Species', '9606', (221, 229))	('al', 'Chemical', 'MESH:D000535', (7, 9))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('decreased', 'NegReg', (129, 138))	('patients', 'Species', '9606', (84, 92))	('al', 'Chemical', 'MESH:D000535', (200, 202))	('prostate cancer', 'Disease', (68, 83))	('NK cell cytotoxic activity', 'CPA', (98, 124))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (142, 150))	('rat', 'Species', '10116', (24, 27))	('colorectal', 'Disease', (52, 62))	('al', 'Chemical', 'MESH:D000535', (60, 62))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
19160	31104002	Other positive selection antibodies include anti HER2 and anti EGFR.	('EGFR', 'Gene', '1956', (63, 67))	('anti', 'Var', (44, 48))	('EGFR', 'Gene', (63, 67))	('anti', 'Var', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))
19191	31104002	Patients with detectable CTCs are known to have shorter overall survival (OS) and progression free survival (PFS).	('progression free survival', 'CPA', (82, 107))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('overall', 'MPA', (56, 63))	('shorter', 'NegReg', (48, 55))	('Patients', 'Species', '9606', (0, 8))	('CTCs', 'Var', (25, 29))	('al', 'Chemical', 'MESH:D000535', (105, 107))	('al', 'Chemical', 'MESH:D000535', (60, 62))
19196	31104002	Patients with apoptotic CTCs or CTC clusters in blood samples after systemic therapy initiation had worse prognosis in terms of PFS and OS than patients with CTCs without these properties, indicating morphological characterization of CTCs could be an important prognostic marker during therapy in patients with >= 5 CTC per 7.5 ml blood.	('PFS', 'Disease', (128, 131))	('apoptotic', 'Var', (14, 23))	('patients', 'Species', '9606', (297, 305))	('patients', 'Species', '9606', (144, 152))	('Patients', 'Species', '9606', (0, 8))	('al', 'Chemical', 'MESH:D000535', (211, 213))
19225	31104002	In breast cancer, the presence of 5 or more CTCs per 7.5 ml of blood has been associated with a reduction in progression free survival, overall survival, as well as with higher disease progression and mortality of metastatic breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('al', 'Chemical', 'MESH:D000535', (150, 152))	('progression free survival', 'CPA', (109, 134))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('disease progression', 'CPA', (177, 196))	('al', 'Chemical', 'MESH:D000535', (205, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('al', 'Chemical', 'MESH:D000535', (140, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('al', 'Chemical', 'MESH:D000535', (132, 134))	('presence', 'Var', (22, 30))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))	('reduction', 'NegReg', (96, 105))	('higher', 'PosReg', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('patients', 'Species', '9606', (239, 247))	('overall survival', 'CPA', (136, 152))
19258	31104002	The incidence of CTCs in metastatic colorectal cancer has been shown to be higher than in non-metastatic disease, and correlates well with both progression free survival and overall survival, thus demonstrating the prognostic utility of the method.	('colorectal cancer', 'Disease', (36, 53))	('higher', 'PosReg', (75, 81))	('rat', 'Species', '10116', (204, 207))	('al', 'Chemical', 'MESH:D000535', (44, 46))	('CTCs', 'Var', (17, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('al', 'Chemical', 'MESH:D000535', (167, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('al', 'Chemical', 'MESH:D000535', (188, 190))	('al', 'Chemical', 'MESH:D000535', (178, 180))
19262	31104002	Moreover, CTC detection in the portal vein has been associated with higher rates of liver metastases after surgery in contrast to detection in peripheral blood.	('liver metastases', 'Disease', 'MESH:D009362', (84, 100))	('al', 'Chemical', 'MESH:D000535', (151, 153))	('rat', 'Species', '10116', (75, 78))	('al', 'Chemical', 'MESH:D000535', (35, 37))	('CTC detection', 'Var', (10, 23))	('liver metastases', 'Disease', (84, 100))
19320	30719213	In these trials tumor type, protein overexpression, or gene amplification are the primary selection criteria for patient inclusion.	('patient', 'Species', '9606', (113, 120))	('overexpression', 'PosReg', (36, 50))	('protein', 'Protein', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('gene amplification', 'Var', (55, 73))	('tumor', 'Disease', (16, 21))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
19337	30719213	In a small percentage of patients, c-Met is constitutively activated by a mutation resulting in the deletion of exon 14.	('c-Met', 'Protein', (35, 40))	('patients', 'Species', '9606', (25, 33))	('activated', 'PosReg', (59, 68))	('exon 14', 'Gene', (112, 119))	('deletion', 'Var', (100, 108))
19340	30719213	In our studies, we utilize BMS-777607, a small molecule ATP-competitive c-Met inhibitor evaluated in Phase I/II clinical trials in a variety of tumor types, including metastatic gastroesophageal cancer, hormone refractory prostate cancer, head and neck squamous cell carcinoma, and type 1 papillary renal cell carcinoma.	('BMS-777607', 'Var', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (253, 276))	('neck', 'cellular_component', 'GO:0044326', ('248', '252'))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (289, 319))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (239, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (289, 319))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('gastroesophageal cancer', 'Disease', (178, 201))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (178, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (239, 276))	('hormone refractory prostate cancer', 'Disease', 'MESH:D064129', (203, 237))	('1 papillary renal cell carcinoma', 'Phenotype', 'HP:0011797', (287, 319))	('ATP', 'Chemical', 'MESH:D000255', (56, 59))	('hormone refractory prostate cancer', 'Disease', (203, 237))	('papillary renal cell carcinoma', 'Disease', (289, 319))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (299, 319))
19349	30719213	The following 14 cell lines were found to secrete HGF: U87, U118, OS156, MG-63, WI-38, HL-60, RKO, KHT, RIF-1, SCCVII, EMT6, D1K2-T1, D1K2-T3, and MTAMF.	('U87', 'Gene', '641648', (55, 58))	('D1K2-T1', 'Var', (125, 132))	('EMT', 'biological_process', 'GO:0001837', ('119', '122'))	('HL-60', 'CellLine', 'CVCL:0002', (87, 92))	('D1K2-T3', 'Var', (134, 141))	('U87', 'Gene', (55, 58))
19351	30719213	Tumor cells that both secrete HGF and express c-Met are referred to in this paper as autocrine-activated tumor cells.	('c-Met', 'Var', (46, 51))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HGF', 'Protein', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
19352	30719213	Several murine carcinoma cell lines were tested for deletion of exon 14, a mutation known to cause activation of the c-Met pathway.	('c-Met pathway', 'Pathway', (117, 130))	('carcinoma', 'Disease', 'MESH:D002277', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('activation', 'PosReg', (99, 109))	('carcinoma', 'Disease', (15, 24))	('deletion', 'Var', (52, 60))	('murine', 'Species', '10090', (8, 14))
19354	30719213	Cells were assessed for their ability to migrate in the presence of BMS-777607 at low and high HGF concentrations (Figure 5).	('BMS-777607', 'Var', (68, 78))	('rat', 'Species', '10116', (44, 47))	('migrate', 'CPA', (41, 48))	('rat', 'Species', '10116', (106, 109))
19358	30719213	At 0.4 and 0.8 ng/mL HGF, the DU145 and the MDA-MB-231 cell lines did not demonstrate a significant inhibition of migration in the presence of BMS-777607.	('rat', 'Species', '10116', (117, 120))	('rat', 'Species', '10116', (81, 84))	('migration', 'CPA', (114, 123))	('DU145', 'CellLine', 'CVCL:0105', (30, 35))	('BMS-777607', 'Var', (143, 153))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (44, 54))
19370	30719213	In this model, mice were inoculated with (i) BMS-777607 pretreated (100 nM or 1 muM for 24 hours) DU145 or MDA-MB-231 tumor cells or (ii) untreated tumor cells and given daily doses of BMS-777607 (15 or 30 mg/kg) by oral gavage.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (107, 117))	('DU145', 'CellLine', 'CVCL:0105', (98, 103))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('muM', 'Gene', '56925', (80, 83))	('tumor', 'Disease', (118, 123))	('BMS-777607', 'Var', (45, 55))	('mice', 'Species', '10090', (15, 19))	('muM', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
19371	30719213	Neither pretreating the tumor cells nor treating the tumor cell bearing mice with BMS 777607 resulted in a reduction in the tumor cell initiated angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('angiogenesis', 'biological_process', 'GO:0001525', ('145', '157'))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Disease', (53, 58))	('BMS 777607', 'Var', (82, 92))	('reduction', 'NegReg', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
19373	30719213	Mice were injected intradermally with tumor cells and then received BMS-777607 daily for 3 days.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('BMS-777607', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Mice', 'Species', '10090', (0, 4))
19374	30719213	In the case of the SCCVII tumor cell line, some mice were injected with tumor cells that were pretreated with 100 nM or 1 muM BMS-777607 for 24 hours prior to injection.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('BMS-777607', 'Var', (126, 136))	('muM', 'Gene', (122, 125))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('muM', 'Gene', '56925', (122, 125))
19380	30719213	Similarly, BMS-777607 did not reduce lung metastasis formation in two independent experiments using the MDA-MB-231-4715-LM2 cell line.	('formation', 'biological_process', 'GO:0009058', ('53', '62'))	('MDA-MB-231-4715-LM2', 'CellLine', 'CVCL:0062', (104, 123))	('lung metastasis formation', 'CPA', (37, 62))	('BMS-777607', 'Var', (11, 21))
19381	30719213	Previously published work from our lab demonstrated efficacy of the BMS-777607 c-Met inhibitor in reducing experimental lung metastasis in the KHT tumor cell line (Figure 9D).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('reducing', 'NegReg', (98, 106))	('KHT tumor', 'Disease', 'MESH:D009369', (143, 152))	('rat', 'Species', '10116', (46, 49))	('c-Met', 'Protein', (79, 84))	('BMS-777607', 'Var', (68, 78))	('KHT tumor', 'Disease', (143, 152))
19383	30719213	Mice receiving 30 mg/kg BMS-777607 developed significantly fewer lung SCCVII metastases than mice receiving vehicle.	('metastases', 'Disease', (77, 87))	('BMS-777607', 'Var', (24, 34))	('mice', 'Species', '10090', (93, 97))	('Mice', 'Species', '10090', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('fewer', 'NegReg', (59, 64))
19388	30719213	C-Met inhibitors have been extensively examined in preclinical studies, where they were found to be well tolerated and effective as anti-cancer therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('C-Met', 'Gene', '4233', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('rat', 'Species', '10116', (109, 112))	('cancer', 'Disease', (137, 143))	('inhibitors', 'Var', (6, 16))	('C-Met', 'Gene', (0, 5))
19390	30719213	Clinical trials of c-Met inhibitors typically select patients on the bases of tumor type, MET amplification, or c-Met protein overexpression.	('patients', 'Species', '9606', (53, 61))	('overexpression', 'PosReg', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('c-Met protein', 'Protein', (112, 125))	('MET amplification', 'Var', (90, 107))	('tumor', 'Disease', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
19401	30719213	In our studies, the human cancer cell lines DU145 and MDA-MB-231 showed a strong reduction of c-Met phosphorylation, migration, and invasion when treated with the c-Met inhibitor BMS-777607 in the presence of commonly used concentrations of HGF (25-50 ng/mL).	('human', 'Species', '9606', (20, 25))	('migration', 'CPA', (117, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('BMS-777607', 'Var', (179, 189))	('DU145', 'CellLine', 'CVCL:0105', (44, 49))	('c-Met phosphorylation', 'MPA', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('reduction', 'NegReg', (81, 90))	('rat', 'Species', '10116', (120, 123))	('rat', 'Species', '10116', (230, 233))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (54, 64))	('invasion', 'CPA', (132, 140))
19407	30719213	While paracrine-activated tumor cells responded to c-Met inhibition only in the presence of very high concentrations of HGF, tumor cells that had a deletion of exon 14, as well as those that secreted HGF, thereby activating c-Met in an autocrine fashion, were intrinsically sensitive to c-Met inhibition.	('deletion', 'Var', (148, 156))	('activating', 'MPA', (213, 223))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (125, 130))	('exon 14', 'Gene', (160, 167))	('rat', 'Species', '10116', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
19415	30719213	While murine HGF resulted in substantially less phosphorylation than human HGF, it was interesting that 5 ng/mL murine HGF resulted in approximately as much phosphorylation as 0.5 ng/mL human HGF (a value realistic in humans).	('phosphorylation', 'biological_process', 'GO:0016310', ('157', '172'))	('humans', 'Species', '9606', (218, 224))	('murine', 'Species', '10090', (112, 118))	('phosphorylation', 'MPA', (157, 172))	('human', 'Species', '9606', (69, 74))	('less', 'NegReg', (43, 47))	('phosphorylation', 'MPA', (48, 63))	('human', 'Species', '9606', (186, 191))	('murine HGF', 'Var', (112, 122))	('human', 'Species', '9606', (218, 223))	('murine', 'Species', '10090', (6, 12))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))
19427	30719213	BMS-777607 also inhibits Ron, Axl, and Tyro3.	('Axl', 'Gene', (30, 33))	('Ron', 'Gene', '4486', (25, 28))	('Ron', 'Gene', (25, 28))	('BMS-777607', 'Var', (0, 10))	('Tyro3', 'Gene', '7301', (39, 44))	('inhibits', 'NegReg', (16, 24))	('Axl', 'Gene', '558', (30, 33))	('Tyro3', 'Gene', (39, 44))
19459	30719213	Mice received BMS-777607 via oral gavage at a concentration of 30 mg/kg daily, for five days after tumor cell injection.	('tumor', 'Disease', (99, 104))	('rat', 'Species', '10116', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('BMS-777607', 'Var', (14, 24))
19614	29849795	In addition, the present results demonstrated for the first time that high expression of GOLPH3 in the original tumor may signify better take rates in xenograft models, compared with low expression.	('better', 'PosReg', (130, 136))	('take rates', 'CPA', (137, 147))	('original tumor', 'Disease', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('xenograft models', 'CPA', (151, 167))	('high', 'Var', (70, 74))	('original tumor', 'Disease', 'MESH:D009369', (103, 117))	('GOLPH3', 'Gene', (89, 95))	('expression', 'MPA', (75, 85))
19615	29849795	According to previously published studies, high GOLPH3 expression promotes tumor cell proliferation.	('GOLPH3', 'Gene', (48, 54))	('high', 'Var', (43, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('expression', 'MPA', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('promotes', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
19623	29510676	Signaling protein signature predicts clinical outcome of non-small-cell lung cancer Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('Non-small-cell lung cancer', 'Disease', (84, 110))	('cancer', 'Disease', (104, 110))	('Signaling', 'biological_process', 'GO:0023052', ('0', '9'))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('abnormalities', 'Var', (139, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('Non-small-cell lung cancer', 'Disease', 'MESH:D002289', (84, 110))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('cancer', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('cancer', 'Disease', (211, 217))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Disease', (72, 83))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('NSCLC', 'Disease', (112, 117))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
19748	29510676	As we have identified several patients with good prognosis but high JNK1 expression, low CHK1 expression may have a dominant effect on tumor progression, possibly by promoting metastasis (Fig.	('metastasis', 'CPA', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('low', 'NegReg', (85, 88))	('JNK1', 'Gene', (68, 72))	('promoting', 'PosReg', (166, 175))	('CHK1', 'Gene', (89, 93))	('tumor', 'Disease', (135, 140))	('JNK', 'molecular_function', 'GO:0004705', ('68', '71'))	('expression', 'MPA', (73, 83))	('patients', 'Species', '9606', (30, 38))	('JNK1', 'Gene', '5599', (68, 72))	('high', 'Var', (63, 67))	('expression', 'MPA', (94, 104))	('CHK1', 'Gene', '1111', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
19775	29068423	The proteogenomic profiling of biomarker signatures in cancer biopsies could be used to monitor response to therapy and at the same time disease progression, as the outcome of a particular treatment is not uniform among affected patients due to specific genomic and epigenomic alterations.	('patients', 'Species', '9606', (229, 237))	('epigenomic alterations', 'Var', (266, 288))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
19778	29068423	Recent investigations on human colon cancer have shown that there is a poor correlation between expressed proteome and protein abundance and DNA mutation in the colon cancer genome.	('colon cancer', 'Disease', (31, 43))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('human', 'Species', '9606', (25, 30))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('colon cancer', 'Disease', 'MESH:D015179', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colon cancer', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('mutation', 'Var', (145, 153))
19779	29068423	These studies have shown that tumor-associated somatic mutations or copy number variations might be accountable for these outcomes.	('copy number variations', 'Var', (68, 90))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
19793	29068423	Genomic alterations due to somatic and inherited mutations, copy number variations, and epigenetic changes in cancer genome alter cellular function at the protein level by modulating its abundance and protein-protein interaction.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('modulating', 'Reg', (172, 182))	('abundance', 'MPA', (187, 196))	('protein-protein interaction', 'MPA', (201, 228))	('cellular function at the protein', 'MPA', (130, 162))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('copy number variations', 'Var', (60, 82))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('alter', 'Reg', (124, 129))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('epigenetic changes', 'Var', (88, 106))
19796	29068423	Furthermore, a complimentary effort using both the genomic and proteomic-based approaches can be employed to accurately identify genetic variants and their role in tumorigenesis at the protein level.	('tumor', 'Disease', (164, 169))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('variants', 'Var', (137, 145))
19798	29068423	Thus, the proteogenomic analysis of clinical samples may better delineate the functional consequences of somatic mutations and may accurately map driver mutations in significantly larger deletions and amplified regions in chromosomes.	('mutations', 'Var', (153, 162))	('mutations', 'Var', (113, 122))	('clinical samples', 'Species', '191496', (36, 52))
19802	29068423	Further, an understanding of how somatic mutations in a cancer patient's genome alter the pathways in proteome is crucial, which as a result present different clinical phenotypes and therapeutic targets.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('clinical', 'Species', '191496', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Disease', (56, 62))	('alter', 'Reg', (80, 85))	('pathways in proteome', 'Pathway', (90, 110))
19806	29068423	Recently, a comprehensive genetic analysis of multiple cancer genomes in pancreatic cancer has shown 63 genetic alterations, the majority of which are point mutations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Disease', (84, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('point mutations', 'Var', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('alterations', 'Reg', (112, 123))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('cancer', 'Disease', (55, 61))
19807	29068423	Interestingly, these alterations have been shown to affect 12 signaling pathways leading to pancreatic tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('12 signaling pathways', 'Pathway', (59, 80))	('pancreatic tumorigenesis', 'Disease', 'MESH:D010190', (92, 116))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('affect', 'Reg', (52, 58))	('leading', 'Reg', (81, 88))	('pancreatic tumorigenesis', 'Disease', (92, 116))	('alterations', 'Var', (21, 32))
19816	29068423	In another pan-cancer study, researchers found discordance between HER2 copy number variation, mRNA expression, and protein expression level in colorectal and serous endometrial cancer, which demonstrates that a simple protein-based analysis of patients' samples across tumor subtypes could highlight potential therapeutic targets.	('colorectal and serous endometrial cancer', 'Disease', 'MESH:D016889', (144, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (245, 253))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('serous endometrial cancer', 'Phenotype', 'HP:0012887', (159, 184))	('HER2', 'Gene', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('copy number variation', 'Var', (72, 93))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('mRNA expression', 'MPA', (95, 110))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('cancer', 'Disease', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('endometrial cancer', 'Phenotype', 'HP:0012114', (166, 184))	('cancer', 'Disease', (178, 184))	('HER2', 'Gene', '2064', (67, 71))	('protein expression level', 'MPA', (116, 140))
19819	29068423	In addition, HGSC is the most common subtype of ovarian cancer associated with breast cancer susceptibility gene (BRCA) germline mutation in patients.	('HGSC', 'Disease', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('subtype of ovarian cancer', 'Disease', (37, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('subtype of ovarian cancer', 'Disease', 'MESH:D010051', (37, 62))	('germline mutation', 'Var', (120, 137))	('BRCA', 'Gene', '672', (114, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('BRCA', 'Gene', (114, 118))	('patients', 'Species', '9606', (141, 149))
19823	29068423	A clinical proteogenomic analysis of 100 pancreatic ductal adenocarcinoma samples was able to precisely identify mutations in TP53, KRAS, SMAD4, CDKN2A, ARID1A, and ROBO2, including mutations in the KDM6A and PREX2 driver genes, which drive PDAC tumorigenesis.	('KRAS', 'Gene', (132, 136))	('TP53', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('mutations', 'Var', (113, 122))	('clinical', 'Species', '191496', (2, 10))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (41, 73))	('ARID1A', 'Gene', (153, 159))	('PDAC', 'Disease', (241, 245))	('CDKN2A', 'Gene', (145, 151))	('N', 'Chemical', 'MESH:D009584', (148, 149))	('ROBO2', 'Gene', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('pancreatic ductal adenocarcinoma', 'Disease', (41, 73))	('SMAD4', 'Gene', (138, 143))	('TP53', 'Gene', '7157', (126, 130))	('PDAC', 'Chemical', '-', (241, 245))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (41, 73))	('tumor', 'Disease', (246, 251))	('PDAC', 'Phenotype', 'HP:0006725', (241, 245))	('KRAS', 'Gene', '3845', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (246, 251))
19828	29068423	A proteogenomic analysis of 77 breast cancer samples has shown that 43% of PIK3CA is mutated in luminal breast cancer tumors, and 83% of TP53 is mutated in basal-like tumors (TCGA, 2012).	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutated', 'Var', (85, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('PIK3CA', 'Gene', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('breast cancer', 'Disease', (31, 44))	('tumors', 'Disease', (118, 124))	('TP53', 'Gene', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('luminal breast cancer tumors', 'Disease', 'MESH:D001943', (96, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('PIK3CA', 'Gene', '5290', (75, 81))	('luminal breast cancer tumors', 'Disease', (96, 124))	('basal-like tumors', 'Phenotype', 'HP:0002671', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('TP53', 'Gene', '7157', (137, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('tumors', 'Disease', (167, 173))
19832	29068423	It has been observed that the copy number variation (CNV) of these genes has been found in a higher percentage of CRC patients, which always alters the gene expression pattern in those patients and has promiscuous impact in treatment response.	('N', 'Chemical', 'MESH:D009584', (54, 55))	('copy number variation', 'Var', (30, 51))	('gene expression', 'biological_process', 'GO:0010467', ('152', '167'))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('alters', 'Reg', (141, 147))	('gene expression pattern', 'MPA', (152, 175))	('patients', 'Species', '9606', (185, 193))	('patients', 'Species', '9606', (118, 126))	('CRC', 'Disease', (114, 117))
19840	29068423	It is a well-established fact that cancer is triggered due to mutations and epigenetic alterations in the genome; however, the molecular impact of these changes transpire at the proteome level by dysregulating signaling pathways.	('cancer', 'Disease', (35, 41))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('mutations', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('dysregulating', 'Reg', (196, 209))	('signaling pathways', 'Pathway', (210, 228))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('changes', 'Var', (153, 160))	('epigenetic alterations', 'Var', (76, 98))
19845	29068423	During tumorigenesis, genetic alterations in signaling molecules lead to over-activated cell surface receptors, which as a consequence affect downstream signaling pathways.	('downstream signaling pathways', 'Pathway', (142, 171))	('over-activated', 'PosReg', (73, 87))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('cell surface', 'cellular_component', 'GO:0009986', ('88', '100'))	('tumor', 'Disease', (7, 12))	('affect', 'Reg', (135, 141))	('genetic alterations', 'Var', (22, 41))	('cell surface receptors', 'Protein', (88, 110))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
19847	29068423	Interestingly, post-translational modification, such as the phosphorylation of STY residues in these kinases, also transiently controls and propagates abnormal signals during tumorigenesis, and as a consequence a cell faces altered signaling pathways.	('phosphorylation', 'MPA', (60, 75))	('controls', 'Reg', (127, 135))	('tumor', 'Disease', (175, 180))	('STY', 'Protein', (79, 82))	('faces altered', 'Reg', (218, 231))	('abnormal signals', 'MPA', (151, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('post-translational', 'Var', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('post-translational modification', 'biological_process', 'GO:0043687', ('15', '46'))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('signaling pathways', 'Pathway', (232, 250))
19849	29068423	The TCGA data set analysis of 3185 genomes, which covered 12 tumor types, showed phosphorylated Single Nucleotide Polymorphism variants in 90% of tumors, which could influence cancer susceptibility by modifying the phosphorylation kinase network.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('modifying', 'Reg', (201, 210))	('phosphorylation', 'biological_process', 'GO:0016310', ('215', '230'))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Single Nucleotide Polymorphism variants', 'Var', (96, 135))	('cancer', 'Disease', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (146, 152))	('influence', 'Reg', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', (61, 66))	('phosphorylation kinase network', 'Pathway', (215, 245))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
19850	29068423	A recent study in non-small cell lung carcinoma cancer patients has shown a fourfold upregulation of phosphorylation of Akt in lung tumor samples, In addition, analogous studies have also suggested that the phosphorylated form of Akt has been associated with a poor prognosis and tumor aggression.	('tumor aggression', 'Disease', 'MESH:D001523', (280, 296))	('Akt', 'Gene', '207', (120, 123))	('Akt', 'Gene', '207', (230, 233))	('upregulation of phosphorylation', 'biological_process', 'GO:0042327', ('85', '116'))	('non-small cell lung carcinoma cancer', 'Disease', 'MESH:D002289', (18, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('lung tumor', 'Disease', (127, 137))	('aggression', 'Phenotype', 'HP:0000718', (286, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (18, 47))	('non-small cell lung carcinoma cancer', 'Disease', (18, 54))	('lung tumor', 'Phenotype', 'HP:0100526', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('aggression', 'biological_process', 'GO:0002118', ('286', '296'))	('upregulation', 'PosReg', (85, 97))	('phosphorylated', 'Var', (207, 221))	('phosphorylation', 'MPA', (101, 116))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (22, 47))	('tumor aggression', 'Disease', (280, 296))	('lung tumor', 'Disease', 'MESH:D008175', (127, 137))	('lung carcinoma cancer', 'Phenotype', 'HP:0030078', (33, 54))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('patients', 'Species', '9606', (55, 63))	('Akt', 'Gene', (120, 123))	('Akt', 'Gene', (230, 233))
19860	29068423	A recent study on the role of Ybx1 phosphorylation in colon cancer has shown that S176 phosphorylation is responsible for an aggressive form of colon cancer, and its inhibition could be an important treatment option for colon cancer.	('colon cancer', 'Disease', (54, 66))	('colon cancer', 'Disease', (220, 232))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('responsible for', 'Reg', (106, 121))	('colon cancer', 'Phenotype', 'HP:0003003', (144, 156))	('Ybx1', 'Gene', (30, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('phosphorylation', 'MPA', (87, 102))	('Ybx1', 'Gene', '4904', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('S176', 'Var', (82, 86))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('colon cancer', 'Disease', 'MESH:D015179', (144, 156))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Disease', 'MESH:D015179', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('colon cancer', 'Disease', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
19861	29068423	Aberrant alterations in glycosylation patterns have been linked with tumor aggression and tumor microenvironment heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glycosylation patterns', 'MPA', (24, 46))	('glycosylation', 'biological_process', 'GO:0070085', ('24', '37'))	('aggression', 'biological_process', 'GO:0002118', ('75', '85'))	('tumor', 'Disease', (69, 74))	('aggression', 'Phenotype', 'HP:0000718', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('linked', 'Reg', (57, 63))	('tumor aggression', 'Disease', (69, 85))	('Aberrant alterations', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor aggression', 'Disease', 'MESH:D001523', (69, 85))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
19864	29068423	In ovarian cancer, many membrane proteins have been found to be aberrantly glycosylated and modified, including CA125 and KLK6, which qualify as potential biomarkers for an early diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('KLK6', 'Gene', '5653', (122, 126))	('modified', 'Var', (92, 100))	('CA125', 'Gene', (112, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('KLK6', 'Gene', (122, 126))	('membrane proteins', 'Protein', (24, 41))	('membrane', 'cellular_component', 'GO:0016020', ('24', '32'))	('ovarian cancer', 'Disease', (3, 17))	('CA125', 'Gene', '94025', (112, 117))
19865	29068423	Further, MUC-4:a transmembrane protein:expression has been observed in pancreatic ductal adenocarcinoma, and it is aberrantly glycosylated, which is involved in cancer progression and neoplast cancer aggression.	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('aggression', 'biological_process', 'GO:0002118', ('200', '210'))	('cancer', 'Disease', (161, 167))	('aggression', 'Phenotype', 'HP:0000718', (200, 210))	('transmembrane', 'cellular_component', 'GO:0016021', ('17', '30'))	('neoplast cancer aggression', 'Disease', 'MESH:D009369', (184, 210))	('aberrantly', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('MUC-4', 'Gene', '4585', (9, 14))	('transmembrane', 'cellular_component', 'GO:0044214', ('17', '30'))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('observed', 'Reg', (59, 67))	('MUC-4', 'Gene', (9, 14))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('neoplast cancer aggression', 'Disease', (184, 210))
19871	29068423	The detection of aberrant glycosylated MUC1-specific autoantibodies correlates with colorectal cancer, which has the capability to predict cancer with 95% specificity.	('colorectal cancer', 'Disease', (84, 101))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('aberrant', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('MUC1', 'Gene', (39, 43))	('MUC1', 'Gene', '4582', (39, 43))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (139, 145))
19875	29068423	Lysine N-acetylation precisely regulates the function of histone and non-histone proteins, and, especially, histone acetyltransferase (HAT) are dysregulated as a result of numerous genetic or epigenetic alterations.	('histone', 'MPA', (108, 115))	('histone', 'Protein', (57, 64))	('Lysine N', 'Chemical', '-', (0, 8))	('function', 'MPA', (45, 53))	('epigenetic alterations', 'Var', (192, 214))	('regulates', 'Reg', (31, 40))
19877	29068423	However, abnormal acetylation could activate malignant proteins and trigger tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('abnormal', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('malignant proteins', 'Protein', (45, 63))	('activate', 'PosReg', (36, 44))	('acetylation', 'MPA', (18, 29))	('trigger', 'PosReg', (68, 75))
19880	29068423	Further, epigenetic therapy, employing histone deacetylase inhibitors and acetylation modulators, shows promise in treating some forms of cancers.	('epigenetic', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
19882	29068423	In conclusion, post-translational modifications play an extremely important role in cancer activation by altering signaling pathways controlled by kinases.	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('post-translational modifications', 'Var', (15, 47))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('altering', 'Reg', (105, 113))	('signaling pathways controlled', 'Pathway', (114, 143))
19889	29068423	Earlier studies have reported the use of a single biomarker which has shown significance in the early diagnosis of cancer, and by employing a proteogenomic approach, the APEX1 gene has been identified as biomarker which could monitor damaged DNA repair, and its deletion triggered radiosensitivity in cell lines inherently expressing radio resistance phenotypes.	('APEX', 'cellular_component', 'GO:0097683', ('170', '174'))	('cancer', 'Disease', (115, 121))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('damaged DNA repair', 'MPA', (234, 252))	('triggered', 'Reg', (271, 280))	('APEX1', 'Gene', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('DNA repair', 'biological_process', 'GO:0006281', ('242', '252'))	('deletion', 'Var', (262, 270))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('radiosensitivity', 'CPA', (281, 297))	('APEX1', 'Gene', '328', (170, 175))
19891	29068423	Additionally, a number of gene variations have also been associated with radiotoxicity.	('gene variations', 'Var', (26, 41))	('radiotoxicity', 'Disease', (73, 86))	('radiotoxicity', 'Disease', 'None', (73, 86))	('associated', 'Reg', (57, 67))
19902	29068423	In another elegant study based on Reverse Phase Protein Array (RPPA) analysis of a cohort of 118 stage II colon cancer patients, an upregulation of three components of an activated PIK3/Akt pathway, namely phospho-Akt, S6RP, and phospho-4E-BP1, served as novel biomarkers for stage II colon cancer recurrence.	('PIK3', 'Gene', (181, 185))	('Akt', 'Gene', '207', (186, 189))	('upregulation', 'PosReg', (132, 144))	('Akt', 'Gene', '207', (214, 217))	('patients', 'Species', '9606', (119, 127))	('PIK3', 'Gene', '5294', (181, 185))	('Akt', 'Gene', (186, 189))	('II colon cancer', 'Disease', (282, 297))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('S6RP', 'Gene', (219, 223))	('phospho-4E-BP1', 'Var', (229, 243))	('II colon cancer', 'Disease', (103, 118))	('Akt', 'Gene', (214, 217))	('II colon cancer', 'Disease', 'MESH:D015179', (282, 297))	('II colon cancer', 'Disease', 'MESH:D015179', (103, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (285, 297))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
19906	29068423	A large number of cancer genome sequence analyses have shown that each patient's tumor contains specific genetic alterations and that these alterations drive tumorigenesis.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('genetic alterations', 'Var', (105, 124))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('drive', 'Reg', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patient', 'Species', '9606', (71, 78))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', (81, 86))
19907	29068423	Interestingly, a clear landscape of genomic alterations in a specific cancer subtype may lead to an individualized medical treatment that is precisely based on the specific genetic alterations of an individual cancer patient.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lead to', 'Reg', (89, 96))	('patient', 'Species', '9606', (217, 224))	('alterations', 'Var', (44, 55))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (210, 216))
19911	29068423	A large-scale cancer genome atlas (TCGA) analysis has clearly established that a large number of genetic alterations and aberrations in an individual genome and epigenome accumulate over time and activate malignant transformations.	('activate', 'PosReg', (196, 204))	('aberrations', 'Var', (121, 132))	('genetic alterations', 'Var', (97, 116))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer genome atlas', 'Disease', 'MESH:D009369', (14, 33))	('malignant transformations', 'CPA', (205, 230))	('cancer genome atlas', 'Disease', (14, 33))
19914	29068423	The well-established examples of a precision medicine approach are the mutational profile of the EGFR receptor gene, which triggers uncontrolled growth and at the same time blocks apoptotic signals.	('triggers', 'PosReg', (123, 131))	('mutational profile', 'Var', (71, 89))	('EGFR', 'Gene', '1956', (97, 101))	('apoptotic signals', 'CPA', (180, 197))	('EGFR', 'Gene', (97, 101))	('blocks', 'NegReg', (173, 179))	('uncontrolled growth', 'MPA', (132, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
19915	29068423	Thus, Tarceva is designed to block mutant EGFR activity.	('EGFR', 'Gene', '1956', (42, 46))	('Tarceva', 'Chemical', 'MESH:D000069347', (6, 13))	('EGFR', 'Gene', (42, 46))	('mutant', 'Var', (35, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('activity', 'MPA', (47, 55))
19916	29068423	In a corollary finding, Cetuximab therapy in colorectal cancer patients based on a KRAS mutational profile has been quite promising.	('KRAS', 'Gene', (83, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('KRAS', 'Gene', '3845', (83, 87))	('mutational', 'Var', (88, 98))	('colorectal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (63, 71))	('Cetuximab', 'Chemical', 'MESH:D000068818', (24, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))
19919	29068423	Interestingly, the genetic profiling of tumor samples helps us to understand the link between specific genetic variants and the important clinical state of the patient, which could serve as an important step in personalized medicine (Figure 2).	('clinical', 'Species', '191496', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('variants', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patient', 'Species', '9606', (160, 167))
19932	29068423	Cancer genomic alterations, combined with cutting-edge proteomic technologies and bioinformatics tools, are beginning to reveal patients' specific cancer landscapes.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('alterations', 'Var', (15, 26))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (147, 153))	('patients', 'Species', '9606', (128, 136))
19933	29068423	Thus, an onco-proteogenomic approach can precisely identify point mutations, splice variants, copy number variation, and gene fusions in a patient's genome, which could be complimented with changes in the proteome and its post-translational modifications, which could immensely facilitate the early diagnosis, prognosis, and treatment of cancer.	('cancer', 'Disease', (338, 344))	('facilitate', 'PosReg', (278, 288))	('point mutations', 'Var', (60, 75))	('patient', 'Species', '9606', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('copy number variation', 'Var', (94, 115))
19937	29068423	Advances in Next-Gen sequencing have facilitated the RNA-Seq-based transcriptomic analysis of cancer samples, and it allows us to precisely quantify mRNA transcripts and helps us to identify the various genetic variants which might be responsible for cancer progression.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('mRNA transcripts', 'MPA', (149, 165))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('variants', 'Var', (211, 219))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
19944	28915579	Therefore, in this study we identified dysregulated miRNAs by next generation sequencing (NGS) and analyzed their prognostic value.	('miR', 'Gene', '220972', (52, 55))	('dysregulated', 'Var', (39, 51))	('miR', 'Gene', (52, 55))
19960	28915579	Additionally, microRNAs have also involved in resistance to chemotherapy and novel targeted agents in non-small cell lung cancer.	('involved', 'Reg', (34, 42))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (102, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('non-small cell lung cancer', 'Disease', (102, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('microRNAs', 'Var', (14, 23))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (102, 128))
19982	28915579	KRAS status was an independent prognostic variable for RFS according to the Cox regression model (p = 0.020) and the signature (miR-21high and miR-188high) was an independent poor prognostic biomarker for RFS (p = 0.001) and OS (p < 0.0001) (Table 4).	('miR-188', 'Gene', (143, 150))	('miR-188', 'Gene', '406964', (143, 150))	('Cox', 'Gene', '1351', (76, 79))	('miR-21high', 'Var', (128, 138))	('Cox', 'Gene', (76, 79))	('KRAS', 'Gene', (0, 4))	('RFS', 'Disease', (205, 208))	('KRAS', 'Gene', '3845', (0, 4))
19985	28915579	The analyses confirmed that both miR-21 and miR-188 were significantly overexpressed in tumor tissues (p < 0.0001).	('miR-188', 'Gene', '406964', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('overexpressed', 'PosReg', (71, 84))	('miR-188', 'Gene', (44, 51))	('miR-21', 'Var', (33, 39))	('tumor', 'Disease', (88, 93))
19999	28915579	Extensive profiling studies have connected dysregulated levels of miR-182 with several cancer types, including NSCLC.	('cancer', 'Disease', (87, 93))	('NSCLC', 'Disease', (111, 116))	('miR-182', 'Gene', (66, 73))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('dysregulated', 'Var', (43, 55))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('miR-182', 'Gene', '406958', (66, 73))
20018	28915579	The down-regulation of miR-451a, miR-144, miR-195, miR-218, miR-145, miR-30a, miR-126 and miR-139 has been found in both the training and validation set.	('miR-30a', 'Gene', '407029', (69, 76))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('miR-144', 'Gene', (33, 40))	('miR-144', 'Gene', '406936', (33, 40))	('miR-145', 'Gene', (60, 67))	('miR-126', 'Gene', (78, 85))	('miR-195', 'Gene', (42, 49))	('miR-139', 'Gene', (90, 97))	('miR-195', 'Gene', '406971', (42, 49))	('miR-218', 'Var', (51, 58))	('miR-145', 'Gene', '406937', (60, 67))	('miR-30a', 'Gene', (69, 76))	('miR-139', 'Gene', '406931', (90, 97))	('down-regulation', 'NegReg', (4, 19))	('miR-451a', 'Gene', '574411', (23, 31))	('miR-451a', 'Gene', (23, 31))	('miR-126', 'Gene', '406913', (78, 85))
20046	28915579	In line with these results, some studies have reported that high levels of miR-21 in either tumor or blood samples were associated with a negative prognosis in lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('negative', 'NegReg', (138, 146))	('tumor', 'Disease', (92, 97))	('patients', 'Species', '9606', (172, 180))	('high levels', 'Var', (60, 71))	('lung cancer', 'Disease', (160, 171))	('miR-21', 'Gene', (75, 81))
20047	28915579	described that aberrant miR-21 expression; enhanced by the activated EGFR signaling pathway, played a significant role in lung carcinogenesis in those that never-smoked.	('lung carcinogenesis', 'Disease', (122, 141))	('enhanced', 'PosReg', (43, 51))	('miR-21', 'Gene', (24, 30))	('EGFR', 'Gene', '1956', (69, 73))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (122, 141))	('EGFR', 'Gene', (69, 73))	('expression', 'MPA', (31, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('aberrant', 'Var', (15, 23))	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('69', '91'))
20050	28915579	Recently, a preclinical study in a murine lung cancer model with an anti-miR-21 molecule revealed that treated animals displayed tumor regression or no tumor growth and prolonged survival while compared with the untreated group.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('survival', 'CPA', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('lung cancer', 'Disease', (42, 53))	('anti-miR-21 molecule', 'Var', (68, 88))	('prolonged', 'PosReg', (169, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (129, 134))	('murine', 'Species', '10090', (35, 41))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
20062	28915579	In concordance with our results, in patients with acute myeloid leukemia (cytogenetically-normal), high miR-188 expression has been significantly associated with shorter OS and event-free survival.	('patients', 'Species', '9606', (36, 44))	('acute myeloid leukemia', 'Disease', (50, 72))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (50, 72))	('high', 'Var', (99, 103))	('miR-188', 'Gene', (104, 111))	('miR-188', 'Gene', '406964', (104, 111))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (50, 72))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (56, 72))	('shorter OS', 'Disease', (162, 172))
20108	28646928	Incident cases were classified by the International Classification of Diseases for Oncology (ICD-O-3) codes C34.0-C34.9, with morphology codes including M-8046, 8140, 8200, 8250, 8252-8253, 8255, 8480-8481, and 8550 which were identified through computer-assisted record linkage with state cancer registries for the years 2002-2011.	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('M-8046', 'Var', (153, 159))	('8255', 'Var', (190, 194))	('8550', 'Var', (211, 215))	('8252-8253', 'Var', (179, 188))	('8200', 'Var', (167, 171))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('8140', 'Var', (161, 165))	('Oncology', 'Phenotype', 'HP:0002664', (83, 91))	('8480-8481', 'Var', (196, 205))	('C34.0-C34.9', 'Var', (108, 119))	('8250', 'Var', (173, 177))
20210	28061425	Similarly, we previously reported that exposure to respirable CNC causes oxidative stress, tissue damage, and inflammatory responses in mice following pharyngeal aspiration .	('oxidative stress', 'MPA', (73, 89))	('mice', 'Species', '10090', (136, 140))	('exposure', 'Var', (39, 47))	('aspiration', 'Phenotype', 'HP:0002835', (162, 172))	('inflammatory responses', 'CPA', (110, 132))	('oxidative stress', 'Phenotype', 'HP:0025464', (73, 89))	('causes', 'Reg', (66, 72))	('tissue damage', 'CPA', (91, 104))	('CNC', 'Gene', '5573', (62, 65))	('CNC', 'Gene', (62, 65))
20362	28560182	Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Treatment of Metastatic Non-Small Cell Lung Cancer, with a Focus on Afatinib Somatic epidermal growth factor receptor (EGFR) mutations are present in around 50% of Asian patients and in 10-15% of Caucasian patients with metastatic non-small cell lung cancer (NSCLC) of adenocarcinoma histology.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('148', '171'))	('adenocarcinoma', 'Disease', (332, 346))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (294, 320))	('Afatinib', 'Chemical', 'MESH:D000077716', (131, 139))	('Metastatic Non-Small Cell Lung Cancer', 'Disease', (76, 113))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (298, 320))	('NSCLC', 'Disease', 'MESH:D002289', (322, 327))	('patients', 'Species', '9606', (269, 277))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('EGFR', 'Gene', '1956', (182, 186))	('cell lung cancer', 'Disease', 'MESH:D008175', (304, 320))	('adenocarcinoma', 'Disease', 'MESH:D000230', (332, 346))	('Lung Cancer', 'Phenotype', 'HP:0100526', (102, 113))	('Metastatic Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (76, 113))	('NSCLC', 'Disease', (322, 327))	('epidermal growth factor receptor', 'Gene', (148, 180))	('epidermal growth factor receptor', 'Gene', '1956', (148, 180))	('cell lung cancer', 'Disease', (304, 320))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (87, 113))	('Epidermal Growth Factor Receptor', 'Gene', (0, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (322, 327))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (91, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (309, 320))	('patients', 'Species', '9606', (233, 241))	('mutations', 'Var', (188, 197))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', (182, 186))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))
20365	28560182	Afatinib, an irreversible ErbB family blocker, has shown in two randomly controlled trials in patients with EGFR-activating mutations, a significant improvement in PFS and health-related quality of life when compared to platinum-based chemotherapy.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('mutations', 'Var', (124, 133))	('improvement', 'PosReg', (149, 160))	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('ErbB', 'Gene', (26, 30))	('ErbB', 'Gene', '1956', (26, 30))	('PFS', 'Disease', (164, 167))	('platinum', 'Chemical', 'MESH:D010984', (220, 228))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('health-related quality of life', 'CPA', (172, 202))
20366	28560182	Afatinib improved OS in patients with Del19 mutations.	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('patients', 'Species', '9606', (24, 32))	('improved', 'PosReg', (9, 17))	('Del19 mutations', 'Var', (38, 53))
20369	28560182	A phase IIb trial comparing afatinib and gefitinib in first-line EGFR positive NSCLC showed significantly improved PFS with afatinib but OS was not significantly improved.	('improved', 'PosReg', (106, 114))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('EGFR', 'Gene', '1956', (65, 69))	('gefitinib', 'Chemical', 'MESH:D000077156', (41, 50))	('EGFR', 'Gene', (65, 69))	('afatinib', 'Var', (124, 132))	('afatinib', 'Chemical', 'MESH:D000077716', (28, 36))	('afatinib', 'Chemical', 'MESH:D000077716', (124, 132))	('PFS', 'Disease', (115, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('NSCLC', 'Disease', (79, 84))
20372	28560182	The principal targets identified include rearrangements in the anaplastic lymphoma kinase gene and mutations of the epidermal growth factor receptor (EGFR).	('epidermal growth factor receptor', 'Gene', (116, 148))	('EGFR', 'Gene', (150, 154))	('lymphoma', 'Disease', 'MESH:D008223', (74, 82))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('rearrangements', 'Var', (41, 55))	('epidermal growth factor receptor', 'Gene', '1956', (116, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('150', '154'))	('mutations', 'Var', (99, 108))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (63, 82))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('116', '139'))	('EGFR', 'Gene', '1956', (150, 154))	('lymphoma', 'Disease', (74, 82))
20375	28560182	Somatic EGFR mutations are present in around 50% of patients in Asia and in 10-15% of Caucasian patients with metastatic NSCLC with adenocarcinoma histology.	('adenocarcinoma', 'Disease', 'MESH:D000230', (132, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('NSCLC', 'Disease', (121, 126))	('EGFR', 'Gene', '1956', (8, 12))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('patients', 'Species', '9606', (96, 104))	('EGFR', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('adenocarcinoma', 'Disease', (132, 146))	('patients', 'Species', '9606', (52, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
20376	28560182	Most of these mutations are caused by deletions on the exon 19 or L858R point mutations on exon 21.	('caused', 'Reg', (28, 34))	('L858R point', 'Var', (66, 77))	('deletions on', 'Var', (38, 50))	('L858R', 'Mutation', 'rs121434568', (66, 71))
20377	28560182	EGFR-activating mutations lead to aberrant constitutive signaling by EGFR and its associated cell signaling pathways.	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (0, 4))	('lead to', 'Reg', (26, 33))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (16, 25))	('aberrant', 'MPA', (34, 42))	('cell signaling pathways', 'Pathway', (93, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('constitutive signaling', 'MPA', (43, 65))	('EGFR', 'Gene', '1956', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
20379	28560182	Because of this, inhibition of EGFR interrupts proliferation and induces apoptosis.	('interrupts', 'NegReg', (36, 46))	('EGFR', 'Gene', '1956', (31, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('EGFR', 'Gene', (31, 35))	('induces', 'Reg', (65, 72))	('inhibition', 'Var', (17, 27))	('apoptosis', 'CPA', (73, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('proliferation', 'CPA', (47, 60))
20380	28560182	Epidermal growth factor receptor inhibition with oral tyrosine kinase inhibitors (TKIs) has shown proven clinical benefit in patients with NSCLC harboring activating EGFR mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('EGFR', 'Gene', '1956', (166, 170))	('activating', 'PosReg', (155, 165))	('NSCLC', 'Disease', (139, 144))	('EGFR', 'Gene', (166, 170))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('mutations', 'Var', (171, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('patients', 'Species', '9606', (125, 133))
20383	28560182	This leads to the inhibition of both mutant and, to a lesser extent, wild-type EGFR.	('inhibition', 'NegReg', (18, 28))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('mutant', 'Var', (37, 43))
20385	28560182	Several subgroup analyses of these trials in addition to smaller subsequent trials, however, showed that the presence of EGFR-activating mutations was a strong predictor of clinical benefit with gefitinib when compared with platinum-doublet chemotherapy.	('gefitinib', 'Chemical', 'MESH:D000077156', (195, 204))	('benefit', 'PosReg', (182, 189))	('EGFR', 'Gene', '1956', (121, 125))	('EGFR', 'Gene', (121, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('mutations', 'Var', (137, 146))	('presence', 'Var', (109, 117))	('platinum', 'Chemical', 'MESH:D010984', (224, 232))	('clinical', 'MPA', (173, 181))
20386	28560182	As a result, subsequent phase III trials of EGFR-TKIs included exclusively patients with activating EGFR mutations.	('EGFR', 'Gene', '1956', (100, 104))	('activating', 'PosReg', (89, 99))	('EGFR', 'Gene', (100, 104))	('patients', 'Species', '9606', (75, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('mutations', 'Var', (105, 114))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
20390	28560182	Erlotinib was associated with a significant benefit in PFS and was better tolerated than chemotherapy (Table 1).	('benefit', 'PosReg', (44, 51))	('PFS', 'Disease', (55, 58))	('Erlotinib', 'Var', (0, 9))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
20393	28560182	Erlotinib may be an option in both EGFR mutated and wild-type patients.	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('mutated', 'Var', (40, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('patients', 'Species', '9606', (62, 70))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
20399	28560182	Unfortunately, NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistances.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', (82, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('resistances', 'MPA', (111, 122))	('develop', 'Reg', (103, 110))	('NSCLC', 'Disease', (15, 20))	('EGFR', 'Gene', '1956', (26, 30))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('EGFR', 'Gene', '1956', (82, 86))	('mutations', 'Var', (42, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
20407	28560182	The largest randomized phase III trials in treatment-naive advanced NSCLC with EGFR-activating mutations were the LL3 and LL6 trials.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('mutations', 'Var', (95, 104))	('NSCLC', 'Disease', (68, 73))
20413	28560182	A preplanned analysis indicated that the PFS advantage was greater in patients with common EGFR mutations (Del19 and/or L858R).	('patients', 'Species', '9606', (70, 78))	('EGFR', 'Gene', (91, 95))	('Del19', 'Var', (107, 112))	('PFS', 'MPA', (41, 44))	('L858R', 'Mutation', 'rs121434568', (120, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('EGFR', 'Gene', '1956', (91, 95))	('L858R', 'Var', (120, 125))
20414	28560182	However, afatinib also showed activity in some patients with select uncommon EGFR-activating mutations.	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (47, 55))	('EGFR', 'Gene', '1956', (77, 81))	('afatinib', 'Chemical', 'MESH:D000077716', (9, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))	('activity', 'MPA', (30, 38))
20415	28560182	A pooled analysis of LL3, LL6, and the phase II LUX-Lung 2 trials showed a median PFS of 10.7 months in 38 patients with uncommon mutations of EGFR.	('EGFR', 'Gene', (143, 147))	('mutations', 'Var', (130, 139))	('EGFR', 'Gene', '1956', (143, 147))	('patients', 'Species', '9606', (107, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))
20416	28560182	The pooled analysis also demonstrated particularly poor outcomes with afatinib in patients with exon 20 insertions (median PFS 2.7 months, n = 23).	('exon 20 insertions', 'Var', (96, 114))	('patients', 'Species', '9606', (82, 90))	('afatinib', 'Gene', (70, 78))	('afatinib', 'Chemical', 'MESH:D000077716', (70, 78))	('insertions', 'Var', (104, 114))
20436	28560182	These reductions were shown to decrease excessive plasma concentrations of afatinib and, therefore, reduced toxicity without compromising efficacy.	('afatinib', 'Chemical', 'MESH:D000077716', (75, 83))	('excessive plasma concentrations', 'Phenotype', 'HP:0020170', (40, 71))	('reductions', 'Var', (6, 16))	('reduced', 'NegReg', (100, 107))	('decrease', 'NegReg', (31, 39))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))	('toxicity', 'Disease', (108, 116))	('decrease excessive plasma concentrations', 'Phenotype', 'HP:0020171', (31, 71))	('excessive plasma concentrations', 'MPA', (40, 71))
20454	28560182	Analysis by EGFR mutation subtype showed a median OS of 30.7 months for afatinib compared to 26.4 months for gefitinib (HR 0.83, p = 0.2841) in patients with exon 19 deletion.	('afatinib', 'Chemical', 'MESH:D000077716', (72, 80))	('exon 19 deletion', 'Var', (158, 174))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('patients', 'Species', '9606', (144, 152))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'Gene', (12, 16))	('gefitinib', 'Chemical', 'MESH:D000077156', (109, 118))
20466	28560182	Immune-checkpoint inhibitors are now the preferred second-line option or even first-line option for patients with positive PD-L1 expression.	('PD-L1', 'Gene', (123, 128))	('patients', 'Species', '9606', (100, 108))	('PD-L1', 'Gene', '29126', (123, 128))	('expression', 'Var', (129, 139))
20468	28560182	This is particularly true in patients with EGFR-activating driver mutations where three EGFR-TKIs, gefitinib, erlotinib, and afatinib were shown to have significant survival advantage over first-line platinum-based chemotherapy.	('mutations', 'Var', (66, 75))	('erlotinib', 'Chemical', 'MESH:D000069347', (110, 119))	('patients', 'Species', '9606', (29, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('platinum', 'Chemical', 'MESH:D010984', (200, 208))	('survival', 'CPA', (165, 173))	('advantage', 'PosReg', (174, 183))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', '1956', (88, 92))	('afatinib', 'Chemical', 'MESH:D000077716', (125, 133))	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', (88, 92))	('gefitinib', 'Chemical', 'MESH:D000077156', (99, 108))
20470	28560182	Afatinib remains the only EGFR-TKI to have demonstrated a significant OS advantage in comparison to chemotherapy in patients with EGFR Del19 mutations.	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (141, 150))	('patients', 'Species', '9606', (116, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('EGFR', 'Gene', '1956', (26, 30))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
20473	28560182	There continues to be significant developments in the field of EGFR mutation-positive NSCLC, a third-generation of EGFR-TKIs is already seeking to improve outcomes, especially with osimertinib in patients resistant to EGFR-TKIs due to T790M mutations.	('EGFR', 'Gene', '1956', (63, 67))	('T790M', 'Mutation', 'rs121434569', (235, 240))	('osimertinib', 'Chemical', 'MESH:C000603933', (181, 192))	('mutation-positive', 'Var', (68, 85))	('NSCLC', 'Disease', (86, 91))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('218', '222'))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('patients', 'Species', '9606', (196, 204))	('EGFR', 'Gene', '1956', (218, 222))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('T790M mutations', 'Var', (235, 250))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('EGFR', 'Gene', (218, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
20474	28002805	Expression of PSMA in tumor neovasculature of high grade sarcomas including synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma and MPNST PSMA (prostate specific membrane antigen) is physiologically expressed in normal prostate tissue.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (94, 110))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('PSMA', 'Gene', (147, 151))	('synovial sarcoma', 'Disease', 'MESH:D013584', (76, 92))	('PSMA', 'molecular_function', 'GO:0043275', ('14', '18'))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (94, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (76, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('prostate specific membrane antigen', 'molecular_function', 'GO:0043275', ('153', '187'))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (112, 136))	('undifferentiated sarcoma', 'Disease', (112, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('MPNST', 'Var', (141, 146))	('PSMA', 'Gene', '2346', (14, 18))	('rhabdomyosarcoma', 'Disease', (94, 110))	('PSMA', 'molecular_function', 'GO:0043275', ('147', '151'))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('membrane', 'cellular_component', 'GO:0016020', ('171', '179'))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('PSMA', 'Gene', (14, 18))	('tumor', 'Disease', (22, 27))	('synovial sarcoma', 'Disease', (76, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('PSMA', 'Gene', '2346', (147, 151))	('sarcomas', 'Disease', (57, 65))
20501	28002805	Analyzing only tumors with strong neovascular PSMA expression (labelling index 2), malignant tumors with a high PSMA expression were more frequent (39/599; 6.51%) compared to tumors of intermediate biological potential (3/148; 2.03%) and benign tumors (1/32; 3.13%) (p = 0.078, Fisher s exact test, malignant vs. intermediate/benign tumors).	('tumors', 'Disease', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('malignant tumors', 'Disease', 'MESH:D018198', (83, 99))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (333, 339))	('benign tumors', 'Disease', 'MESH:D009369', (326, 339))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PSMA', 'Gene', '2346', (112, 116))	('malignant tumors', 'Disease', (83, 99))	('tumors', 'Disease', (245, 251))	('PSMA', 'molecular_function', 'GO:0043275', ('46', '50'))	('tumors', 'Disease', (15, 21))	('benign tumors', 'Disease', 'MESH:D009369', (238, 251))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('PSMA', 'Gene', (112, 116))	('PSMA', 'Gene', '2346', (46, 50))	('benign tumors', 'Disease', (326, 339))	('tumors', 'Disease', (93, 99))	('high', 'Var', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('PSMA', 'Gene', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('PSMA', 'molecular_function', 'GO:0043275', ('112', '116'))	('benign tumors', 'Disease', (238, 251))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
20544	28002805	The authors concluded that high PSMA expression increases uptake of BIND-014 in certain tumors, pointing towards a potential utility of PSMA expression as a predictive biomarker for responsiveness to BIND-014.	('uptake', 'biological_process', 'GO:0098739', ('58', '64'))	('PSMA', 'molecular_function', 'GO:0043275', ('136', '140'))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('increases', 'PosReg', (48, 57))	('PSMA', 'Gene', (136, 140))	('PSMA', 'Gene', '2346', (32, 36))	('high', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('PSMA', 'molecular_function', 'GO:0043275', ('32', '36'))	('uptake', 'MPA', (58, 64))	('PSMA', 'Gene', '2346', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('uptake', 'biological_process', 'GO:0098657', ('58', '64'))	('PSMA', 'Gene', (32, 36))
20645	33888147	siRNA therapeutic potentials were recently (2018) confirmed after the FDA-approval of the first siRNA-based drug (i.e., Patisiran by Alnylam) for the treatment of nerve damage in hereditary transthyretin-mediated amyloidosis (hATTR) in adults.	('amyloidosis', 'Disease', 'MESH:D000686', (213, 224))	('hATTR', 'Gene', '7276', (226, 231))	('amyloidosis', 'Phenotype', 'HP:0011034', (213, 224))	('transthyretin', 'Gene', (190, 203))	('nerve damage', 'Disease', (163, 175))	('hATTR', 'Gene', (226, 231))	('hereditary', 'Var', (179, 189))	('N', 'Gene', '43740575', (99, 100))	('Patisiran', 'Disease', (120, 129))	('Patisiran', 'Disease', 'None', (120, 129))	('nerve damage', 'Disease', 'MESH:D010523', (163, 175))	('transthyretin', 'Gene', '7276', (190, 203))	('N', 'Gene', '43740575', (3, 4))	('amyloidosis', 'Disease', (213, 224))
20677	33888147	However, recently there has been evidence that targeting sequences within the 10 kb of the genome at 3' end would decrease siRNA's drug efficacy.	('decrease', 'NegReg', (114, 122))	('drug efficacy', 'MPA', (131, 144))	('N', 'Gene', '43740575', (126, 127))	('sequences', 'Var', (57, 66))
20701	33888147	Nonetheless, inhibition of Type 1 Angiotensin II Receptor (ATR1), which is stimulated during the virus infection, is proven to ameliorate acute lung failure in mice models.	('lung failure', 'Disease', 'MESH:D012131', (144, 156))	('virus infection', 'Disease', 'MESH:D001102', (97, 112))	('virus infection', 'Disease', (97, 112))	('inhibition', 'Var', (13, 23))	('lung failure', 'Disease', (144, 156))	('rat', 'Species', '10116', (133, 136))	('ATR1', 'Gene', (59, 63))	('N', 'Gene', '43740575', (0, 1))	('mice', 'Species', '10090', (160, 164))	('ameliorate', 'PosReg', (127, 137))	('ATR1', 'Gene', '13498', (59, 63))
20704	33888147	Inhibition of furin may have a therapeutic potential via blocking viral entry in SARS-CoV-2 and other viruses that possess the furin cleavage domain.	('viral entry', 'CPA', (66, 77))	('furin', 'Gene', '5045', (14, 19))	('furin', 'Gene', (14, 19))	('furin', 'Gene', '5045', (127, 132))	('furin', 'Gene', (127, 132))	('blocking', 'NegReg', (57, 65))	('Inhibition', 'Var', (0, 10))	('SARS-CoV-2', 'Species', '2697049', (81, 91))
20731	33888147	In an attempt to reveal the mechanisms of action of three antiviral miRNAs, miR-124, miR-24, and miR-744, p38 was identified as a ubiquitous antiviral target in multiple viral infections, including influenza and respiratory syncytial virus (RSV) infection.	('infection', 'Disease', (246, 255))	('RSV', 'Species', '12814', (241, 244))	('viral infections', 'Disease', (170, 186))	('miR-24', 'Var', (85, 91))	('miR-744', 'Gene', (97, 104))	('infection', 'Disease', 'MESH:D007239', (246, 255))	('viral infections', 'Disease', 'MESH:D001102', (170, 186))	('infection', 'Disease', (176, 185))	('influenza', 'Disease', (198, 207))	('respiratory syncytial virus', 'Species', '12814', (212, 239))	('miR-744', 'Gene', '100126313', (97, 104))	('N', 'Gene', '43740575', (71, 72))	('infection', 'Disease', 'MESH:D007239', (176, 185))	('respiratory syncytial virus', 'Disease', (212, 239))	('multiple viral infections', 'Phenotype', 'HP:0004429', (161, 186))	('miR-124', 'Var', (76, 83))	('influenza', 'Species', '11320', (198, 207))
20741	33888147	As a significant regulator of numerous inflammatory cytokines and chemokines, targeting NF-kB transcription factors inhibits multiple pro-inflammatory cascades simultaneously, serving as a superior therapeutic candidate.	('N', 'Gene', '43740575', (88, 89))	('targeting', 'Var', (78, 87))	('inhibits', 'NegReg', (116, 124))	('transcription', 'biological_process', 'GO:0006351', ('94', '107'))
20748	33888147	miR-23b cluster and miR-125a-5p are confirmed to silence multiple components of KRAS and NF-kB pathways hence suppressing lung tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('miR-23b', 'Gene', '407011', (0, 7))	('KRAS', 'Gene', (80, 84))	('miR-23b', 'Gene', (0, 7))	('silence', 'NegReg', (49, 56))	('KRAS', 'Gene', '3845', (80, 84))	('suppressing', 'NegReg', (110, 121))	('miR-125a-5p', 'Var', (20, 31))	('N', 'Gene', '43740575', (89, 90))	('lung tumorigenesis', 'Disease', (122, 140))
20772	33888147	Mainly, exosomes can be loaded with small RNAs either by direct insertion of the nucleic acids into them or by their collection from genetically-modified MSCs (Fig.	('M', 'Gene', '43740571', (154, 155))	('M', 'Gene', '43740571', (0, 1))	('N', 'Gene', '43740575', (43, 44))	('MSC', 'Gene', '9242', (154, 157))	('insertion', 'Var', (64, 73))	('MSCs', 'molecular_function', 'GO:0043854', ('154', '158'))	('MSC', 'Gene', (154, 157))
20790	33274548	Downregulation of LPIN1 enhanced simultaneous inhibition of HDAC and PI3K by FK-A11 and enhanced the cytotoxicity of FK-A11.	('LPIN1', 'Gene', (18, 23))	('FK-A11', 'Chemical', '-', (117, 123))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('inhibition', 'NegReg', (46, 56))	('cytotoxicity', 'Disease', 'MESH:D064420', (101, 113))	('Downregulation', 'Var', (0, 14))	('HDAC', 'Gene', (60, 64))	('FK-A11', 'Gene', (77, 83))	('HDAC', 'Gene', '9734', (60, 64))	('FK-A11', 'Chemical', '-', (77, 83))	('cytotoxicity', 'Disease', (101, 113))	('enhanced', 'PosReg', (88, 96))	('PI3K', 'CPA', (69, 73))
20795	33274548	Activation of the genetic mutation of phosphatidylinositol-3 kinase (PI3K) is often observed in several types of cancer.	('genetic mutation', 'Var', (18, 34))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('phosphatidylinositol-3 kinase', 'Gene', (38, 67))	('cancer', 'Disease', (113, 119))	('Activation', 'PosReg', (0, 10))	('phosphatidylinositol-3 kinase', 'Gene', '5293', (38, 67))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
20799	33274548	7  Zhao et al reported that the HSP90 and PI3K dual inhibitor exhibited strong in vitro suppression of cell growth in the A375 melanoma cell line.	('A375', 'CellLine', 'CVCL:0132', (122, 126))	('suppression', 'NegReg', (88, 99))	('PI3K', 'Var', (42, 46))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('HSP90', 'Gene', (32, 37))	('HSP90', 'Gene', '3320', (32, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))
20803	33274548	10  It has also been reported that simultaneous inhibition of HDAC, PI3K, and mitogen-activated protein kinase (MEK) greatly reduced in vitro self-renewal of the KRAS mutant pancreatic cancer cell line.	('pancreatic cancer', 'Disease', (174, 191))	('HDAC', 'Gene', (62, 66))	('KRAS', 'Gene', (162, 166))	('MEK', 'Gene', (112, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (174, 191))	('MEK', 'Gene', '5609', (112, 115))	('HDAC', 'Gene', '9734', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('KRAS', 'Gene', '3845', (162, 166))	('reduced', 'NegReg', (125, 132))	('mitogen-activated protein kinase', 'Gene', (78, 110))	('mutant', 'Var', (167, 173))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (174, 191))	('mitogen-activated protein kinase', 'Gene', '5609', (78, 110))	('PI3K', 'Var', (68, 72))	('inhibition', 'NegReg', (48, 58))
20806	33274548	Previously, we revealed ID1 as a lethal synthetic gene with the most common TP53 mutation R175H in glioblastoma cell line SF126 using high-throughput RNA interfering screening.	('glioblastoma', 'Disease', (99, 111))	('ID1', 'Gene', (24, 27))	('RNA', 'cellular_component', 'GO:0005562', ('150', '153'))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('R175H', 'Mutation', 'rs28934578', (90, 95))	('R175H', 'Var', (90, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('TP53', 'Gene', (76, 80))	('SF126', 'CellLine', 'CVCL:1688', (122, 127))	('synthetic gene', 'Species', '2005392', (40, 54))
20816	33274548	Knockdown of ATG4A, EIF4B, HBXIP, LPIN1, and ML-IAP, which were identified from primary screening, were carried out using siRNA for ATG4A (sc-91197), EIF4B (sc-77253), HBXIP (sc-77371), LPIN1 (sc-60941), and ML-IAP (sc-37510) obtained from Santa Cruz Biotechnology, respectively.	('EIF4B', 'Gene', '1975', (150, 155))	('sc-77253', 'Var', (157, 165))	('HBXIP', 'Gene', (168, 173))	('HBXIP', 'Gene', '10542', (27, 32))	('sc-77371', 'Var', (175, 183))	('ML-IAP', 'Gene', (208, 214))	('sc-37510', 'Var', (216, 224))	('HBXIP', 'Gene', '10542', (168, 173))	('EIF4B', 'Gene', '1975', (20, 25))	('EIF4', 'cellular_component', 'GO:0008304', ('150', '154'))	('EIF4', 'cellular_component', 'GO:0008304', ('20', '24'))	('ML-IAP', 'Gene', '79444', (45, 51))	('EIF4B', 'Gene', (150, 155))	('ATG4A', 'Gene', (13, 18))	('ATG4A', 'Gene', '115201', (13, 18))	('ATG4A', 'Gene', (132, 137))	('EIF4B', 'Gene', (20, 25))	('ML-IAP', 'Gene', '79444', (208, 214))	('HBXIP', 'Gene', (27, 32))	('ATG4A', 'Gene', '115201', (132, 137))	('sc-60941', 'Var', (193, 201))	('ML-IAP', 'Gene', (45, 51))
20818	33274548	Knocked-out of LPIN1 in HT1080 was performed by using CRISPR/Cas9 plasmid (Lipin-1 CRISPR/Cas9 KO plasmid sc-418483, Santa Cruz Biotechnology).	('Cas', 'cellular_component', 'GO:0005650', ('61', '64'))	('LPIN1', 'Gene', (15, 20))	('Knocked-out', 'Var', (0, 11))	('Lipin-1', 'Gene', '23175', (75, 82))	('Lipin-1', 'Gene', (75, 82))	('Cas', 'cellular_component', 'GO:0005650', ('90', '93'))
20826	33274548	13   Western blot analysis was carried out as previously described 13  using monoclonal antibodies of phospho-AKT (Ser473 and Thr308), AKT, phospho-S6, S6, acetyl-histone H3 (H3K9), and beta-actin.	('Ser', 'cellular_component', 'GO:0005790', ('115', '118'))	('Thr308', 'Chemical', '-', (126, 132))	('beta-actin', 'Gene', (186, 196))	('Ser473', 'Var', (115, 121))	('Ser473', 'Chemical', '-', (115, 121))	('AKT', 'Gene', '207', (135, 138))	('AKT', 'Gene', (110, 113))	('H3K9', 'Protein', (175, 179))	('beta-actin', 'Gene', '728378', (186, 196))	('AKT', 'Gene', (135, 138))	('Thr308', 'Var', (126, 132))	('AKT', 'Gene', '207', (110, 113))	('acetyl-histone', 'Chemical', '-', (156, 170))
20836	33274548	We identified the candidate shRNA, whose amount in the FK-A11-treated group was reduced to less than 0.8 when compared to that of the DMSO-treated group.	('amount', 'MPA', (41, 47))	('FK-A11', 'Chemical', '-', (55, 61))	('reduced', 'NegReg', (80, 87))	('DMSO', 'Chemical', 'MESH:D004121', (134, 138))	('FK-A11-treated', 'Var', (55, 69))
20843	33274548	As shown in Figure 2, transfection of LPIN1 siRNA significantly enhanced cell reduction by FK-A11 treatment when compared to that by the scramble siRNA.	('transfection', 'Var', (22, 34))	('FK-A11', 'Gene', (91, 97))	('FK-A11', 'Chemical', '-', (91, 97))	('LPIN1', 'Gene', (38, 43))	('cell reduction', 'CPA', (73, 87))	('enhanced', 'PosReg', (64, 72))
20846	33274548	We have previously reported that even though the inhibition of either PI3K or HDAC did not enhance cell death, simultaneous inhibition of HDAC and PI3K strongly induced cell death through apoptosis.	('inhibition', 'NegReg', (124, 134))	('PI3K', 'Var', (147, 151))	('HDAC', 'Gene', (138, 142))	('cell death', 'biological_process', 'GO:0008219', ('169', '179'))	('HDAC', 'Gene', '9734', (138, 142))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('apoptosis', 'CPA', (188, 197))	('HDAC', 'Gene', (78, 82))	('induced', 'Reg', (161, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('HDAC', 'Gene', '9734', (78, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('cell death', 'CPA', (169, 179))	('cell death', 'biological_process', 'GO:0008219', ('99', '109'))
20847	33274548	13  As shown in Figure 3C, LIPIN1 knockdown enhanced HDAC inhibition and PI3K dual inhibition by FK-A11 which resulted in the enhancement of downregulation of phosphorylated AKT and induction of acetylated histone.	('enhancement', 'PosReg', (126, 137))	('LIPIN1', 'Gene', (27, 33))	('FK-A11', 'Gene', (97, 103))	('LIPIN1', 'Gene', '23175', (27, 33))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('PI3K dual', 'CPA', (73, 82))	('FK-A11', 'Chemical', '-', (97, 103))	('phosphorylated', 'MPA', (159, 173))	('AKT', 'Gene', '207', (174, 177))	('acetylated', 'MPA', (195, 205))	('HDAC', 'Gene', (53, 57))	('downregulation', 'NegReg', (141, 155))	('HDAC', 'Gene', '9734', (53, 57))	('knockdown', 'Var', (34, 43))	('AKT', 'Gene', (174, 177))	('enhanced', 'PosReg', (44, 52))
20852	33274548	The downregulation of phosphorylated AKT was not enhanced by the knockdown of LPIN1.	('AKT', 'Gene', '207', (37, 40))	('LPIN1', 'Gene', (78, 83))	('downregulation', 'NegReg', (4, 18))	('AKT', 'Gene', (37, 40))	('knockdown', 'Var', (65, 74))
20853	33274548	As shown in Figure S2A, the strongest enhancement of cytotoxicity of FK-A11 by the downregulation of LPIN1 was observed in the treatment of 10 nmol/L of FK-A11.	('LPIN1', 'Gene', (101, 106))	('cytotoxicity', 'Disease', (53, 65))	('FK-A11', 'Chemical', '-', (69, 75))	('FK-A11', 'Chemical', '-', (153, 159))	('downregulation', 'NegReg', (83, 97))	('cytotoxicity', 'Disease', 'MESH:D064420', (53, 65))	('enhancement', 'PosReg', (38, 49))	('FK-A11', 'Var', (153, 159))
20855	33274548	We performed LPIN1 knocked-out using the CRISPR-Cas9 technique in HT1080 cells and named the developed cell line "HT1080-LPIN1-KO."	('Cas', 'cellular_component', 'GO:0005650', ('48', '51'))	('LPIN1', 'Gene', (13, 18))	('HT1080-LPIN1', 'CellLine', 'CVCL:0317', (114, 126))	('knocked-out', 'Var', (19, 30))
20856	33274548	As shown in Figure 4A, LPIN1 knocked-out in HT1080-LPIN1-KO cells was validated by western blot analysis.	('HT1080-LPIN1', 'CellLine', 'CVCL:0317', (44, 56))	('knocked-out', 'Var', (29, 40))	('LPIN1', 'Gene', (23, 28))
20857	33274548	As shown in Figure 4B, enhanced cytotoxicity of FK-A11 was shown in HT1080-LPIN1-KO cells when compared to that of the control cells.	('enhanced', 'PosReg', (23, 31))	('FK-A11', 'Chemical', '-', (48, 54))	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('FK-A11', 'Var', (48, 54))	('HT1080-LPIN1', 'CellLine', 'CVCL:0317', (68, 80))	('cytotoxicity', 'Disease', (32, 44))
20859	33274548	As shown in Figure 4D, the enhancement of induction of apoptotic cells through the treatment of FK-A11 by the LPIN1 knocked-out was also confirmed by flow cytometry analysis using annexin V and PI double staining.	('knocked-out', 'Var', (116, 127))	('FK-A11', 'Chemical', '-', (96, 102))	('LPIN1', 'Gene', (110, 115))	('annexin V', 'Gene', '308', (180, 189))	('annexin V', 'Gene', (180, 189))	('apoptotic cells', 'CPA', (55, 70))	('enhancement', 'PosReg', (27, 38))
20865	33274548	The induction of cleaved PARP by treatment of FK-A11 in HT1080-LPIN1-KO cells was also suppressed by LPIN1 overexpression.	('HT1080-LPIN1', 'CellLine', 'CVCL:0317', (56, 68))	('PARP', 'Gene', (25, 29))	('induction', 'MPA', (4, 13))	('cleaved', 'MPA', (17, 24))	('FK-A11', 'Chemical', '-', (46, 52))	('suppressed', 'NegReg', (87, 97))	('PARP', 'Gene', '142', (25, 29))	('FK-A11', 'Var', (46, 52))
20884	33274548	Anti-tumor efficacy induced by combination treatment with FK-A11 and propranolol was evaluated using HT1080 xenograft mouse models.	('FK-A11', 'Chemical', '-', (58, 64))	('propranolol', 'Chemical', 'MESH:D011433', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('FK-A11', 'Var', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mouse', 'Species', '10090', (118, 123))	('tumor', 'Disease', (5, 10))
20886	33274548	As shown in Figure 6A, the tumor growth in the FK-A11 alone group was significantly inhibited when compared to that in the control group or the propranolol group, respectively.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('FK-A11', 'Var', (47, 53))	('tumor', 'Disease', (27, 32))	('FK-A11', 'Chemical', '-', (47, 53))	('propranolol', 'Chemical', 'MESH:D011433', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('inhibited', 'NegReg', (84, 93))
20887	33274548	Moreover, the tumor growth in the FK-A11 and propranolol combination group was significantly inhibited when compared to that in the FK-A11 alone group.	('tumor', 'Disease', (14, 19))	('FK-A11', 'Var', (34, 40))	('FK-A11', 'Chemical', '-', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('inhibited', 'NegReg', (93, 102))	('FK-A11', 'Chemical', '-', (34, 40))	('propranolol', 'Chemical', 'MESH:D011433', (45, 56))
20888	33274548	As shown in Figure 6B, tumor weight in the FK-A11 alone group was significantly smaller than that in the control group or the propranolol group.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('FK-A11', 'Chemical', '-', (43, 49))	('FK-A11 alone', 'Var', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('smaller', 'NegReg', (80, 87))	('tumor', 'Disease', (23, 28))	('propranolol', 'Chemical', 'MESH:D011433', (126, 137))
20889	33274548	Tumor weight in the FK-A11 and propranolol combination group was significantly smaller than that in the FK-A11 alone group.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FK-A11', 'Chemical', '-', (104, 110))	('FK-A11', 'Var', (20, 26))	('smaller', 'NegReg', (79, 86))	('Tumor weight', 'CPA', (0, 12))	('FK-A11', 'Chemical', '-', (20, 26))	('propranolol', 'Chemical', 'MESH:D011433', (31, 42))
20891	33274548	As shown in Figure 6C, the body weights of the FK-A11 group or combination group were slightly lower than those of control or propranolol groups.	('lower', 'NegReg', (95, 100))	('FK-A11', 'Var', (47, 53))	('body weights', 'CPA', (27, 39))	('FK-A11', 'Chemical', '-', (47, 53))	('propranolol', 'Chemical', 'MESH:D011433', (126, 137))
20892	33274548	However, body weight reduction was not enhanced by the FK-A11 and propranolol combination treatment when compared to that of FK-A11 alone.	('body weight', 'CPA', (9, 20))	('FK-A11', 'Chemical', '-', (55, 61))	('FK-A11', 'Chemical', '-', (125, 131))	('body weight reduction', 'Phenotype', 'HP:0004325', (9, 30))	('reduction', 'NegReg', (21, 30))	('FK-A11', 'Var', (55, 61))	('propranolol', 'Chemical', 'MESH:D011433', (66, 77))
20896	33274548	Induction of cleaved PARP was also enhanced by propranolol and FK-A11 combination treatment when compared to that of FK-A11 alone.	('FK-A11', 'Chemical', '-', (117, 123))	('FK-A11', 'Chemical', '-', (63, 69))	('combination', 'Var', (70, 81))	('PARP', 'Gene', (21, 25))	('enhanced', 'PosReg', (35, 43))	('propranolol', 'Chemical', 'MESH:D011433', (47, 58))	('PARP', 'Gene', '142', (21, 25))	('FK-A11', 'Gene', (63, 69))
20897	33274548	We previously reported that even though the simultaneous inhibition of both PI3K and HDAC strongly induced apoptosis in the colorectal cancer cell line, the inhibition of either PI3K or HDAC weakly induced apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('HDAC', 'Gene', '9734', (85, 89))	('induced', 'Reg', (99, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('HDAC', 'Gene', (186, 190))	('inhibition', 'NegReg', (57, 67))	('colorectal cancer', 'Disease', (124, 141))	('HDAC', 'Gene', '9734', (186, 190))	('PI3K', 'Var', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('178', '182'))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('HDAC', 'Gene', (85, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('apoptosis', 'CPA', (107, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))
20900	33274548	In this investigation, only downregulation of LPIN1 did not enhance either the inhibition of PI3K or of HDAC in the HT1080 cell line (Figures 3C and 4C).	('HDAC', 'Gene', (104, 108))	('HDAC', 'Gene', '9734', (104, 108))	('downregulation', 'Var', (28, 42))	('LPIN1', 'Gene', (46, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('PI3K', 'Pathway', (93, 97))
20904	33274548	20 ,  21 ,  22  It has been reported that LPIN1 deficiency resulted in rhabdomyolysis or exercise-induced myalgia in muscle-specific LPIN1 knocked-out mice.	('rhabdomyolysis', 'Disease', (71, 85))	('exercise-induced myalgia', 'Phenotype', 'HP:0003738', (89, 113))	('myalgia', 'Disease', 'MESH:D063806', (106, 113))	('mice', 'Species', '10090', (151, 155))	('myalgia', 'Disease', (106, 113))	('myalgia', 'Phenotype', 'HP:0003326', (106, 113))	('rhabdomyolysis', 'Phenotype', 'HP:0003201', (71, 85))	('exercise-induced', 'CPA', (89, 105))	('deficiency', 'Var', (48, 58))	('resulted in', 'Reg', (59, 70))	('rhabdomyolysis', 'Disease', 'MESH:D012206', (71, 85))	('LPIN1', 'Gene', (42, 47))
20909	33274548	The mechanisms for downregulation of LPIN1 mediated by the enhancement of inhibition of both HDAC and PI3K by FK-A11 has not yet been resolved.	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('HDAC', 'Gene', (93, 97))	('FK-A11', 'Chemical', '-', (110, 116))	('LPIN1', 'Gene', (37, 42))	('HDAC', 'Gene', '9734', (93, 97))	('FK-A11', 'Var', (110, 116))	('inhibition', 'MPA', (74, 84))	('downregulation', 'NegReg', (19, 33))	('enhancement', 'PosReg', (59, 70))
20931	33274548	29  It was reported that LPIIN1 and LPIN2 double silencing strongly inhibited in vitro prostate cancer cell proliferation.	('prostate cancer', 'Disease', (87, 102))	('LPIN2', 'Gene', '9663', (36, 41))	('LPIIN1', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('inhibited', 'NegReg', (68, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('LPIN2', 'Gene', (36, 41))	('double silencing', 'Var', (42, 58))
20932	33274548	14  In this study, cell count was strongly lowered by the FK-A11 and propranolol or FK-A11 and bromoenol lactone combination treatment (Figure 5A,D) when compared to treatment with FK-A11 under LPIN1 downregulation (Figures 3B and 4B).	('FK-A11', 'Chemical', '-', (58, 64))	('FK-A11', 'Chemical', '-', (181, 187))	('propranolol', 'Chemical', 'MESH:D011433', (69, 80))	('lowered', 'NegReg', (43, 50))	('FK-A11', 'Var', (58, 64))	('FK-A11', 'Chemical', '-', (84, 90))	('cell count', 'CPA', (19, 29))	('bromoenol lactone', 'Chemical', 'MESH:C068314', (95, 112))	('FK-A11', 'Var', (84, 90))
20935	33274548	The strong cell count reduction by combining FK-A11 with propranolol or bromoenol lactone was considered to be attributable to inhibition of both LPIN1 and LPIN2.	('LPIN2', 'Gene', '9663', (156, 161))	('FK-A11', 'Chemical', '-', (45, 51))	('bromoenol lactone', 'Chemical', 'MESH:C068314', (72, 89))	('LPIN1', 'Gene', (146, 151))	('reduction', 'NegReg', (22, 31))	('propranolol', 'Chemical', 'MESH:D011433', (57, 68))	('FK-A11', 'Var', (45, 51))	('inhibition', 'NegReg', (127, 137))	('cell count', 'CPA', (11, 21))	('LPIN2', 'Gene', (156, 161))
20938	33274548	Detailed examination of changes of gene expression with the treatment of FK-A11 might lead to the elucidation of the mechanisms of the enhancement of cytotoxicity of FK-A11 by the downregulation of LPIN1.	('FK-A11', 'Chemical', '-', (73, 79))	('cytotoxicity', 'Disease', (150, 162))	('enhancement', 'PosReg', (135, 146))	('LPIN1', 'Gene', (198, 203))	('FK-A11', 'Chemical', '-', (166, 172))	('FK-A11', 'Var', (73, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (150, 162))	('gene expression', 'biological_process', 'GO:0010467', ('35', '50'))	('downregulation', 'NegReg', (180, 194))	('FK-A11', 'Var', (166, 172))
20970	33121210	Once engaged, these nucleic acid-sensors activate multiple signalling pathways that converge on the production of type I IFNs and pro-inflammatory cytokines, facilitating T-cell cross-priming and infiltration.	('nucleic acid', 'cellular_component', 'GO:0005561', ('20', '32'))	('signalling', 'biological_process', 'GO:0023052', ('59', '69'))	('T-cell cross-priming', 'CPA', (171, 191))	('nucleic', 'Var', (20, 27))	('signalling pathways', 'Pathway', (59, 78))	('IFN', 'Gene', '3439', (121, 124))	('cross-priming', 'biological_process', 'GO:0042590', ('178', '191'))	('IFN', 'Gene', (121, 124))
20973	33121210	Unfortunately, clinical results obtained with STING agonists such as ADU-S100/MIW815 (NCT02675439), MK-1454 (NCT03010176), and E7766(NCT04144140 are modest and limited to patients with accessible solid tumours amenable to intratumoural delivery.	('solid tumours', 'Disease', (196, 209))	('NCT03010176', 'Var', (109, 120))	('MK-1454', 'Chemical', '-', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', (227, 233))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('tumour', 'Disease', (202, 208))	('patients', 'Species', '9606', (171, 179))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('solid tumours', 'Disease', 'MESH:D009369', (196, 209))	('NCT02675439', 'Var', (86, 97))
21009	33121210	In this way, either a type I IFN-driven immune response associated with an immunogenic form of cancer cell death mainly mediated by DCs, CD8+ T, and natural killer (NK) cells, or a direct cancer cell apoptosis can be induced (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('immune response', 'biological_process', 'GO:0006955', ('40', '55'))	('cell death', 'biological_process', 'GO:0008219', ('102', '112'))	('NK', 'Chemical', '-', (165, 167))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('IFN', 'Gene', (29, 32))	('CD8', 'Gene', (137, 140))	('DCs', 'Var', (132, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('cancer', 'Disease', (95, 101))	('CD8', 'Gene', '925', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('IFN', 'Gene', '3439', (29, 32))
21014	33121210	Likewise, gene silencing of transforming growth factor (TGF)-beta1 was achieved through a 5'-3P-siRNA that simultaneously triggers RIG-I in a murine model of pancreatic cancer.	('murine', 'Species', '10090', (142, 148))	('pancreatic cancer', 'Disease', (158, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('gene', 'Var', (10, 14))	('RIG-I', 'Gene', (131, 136))	('3P', 'Chemical', '-', (93, 95))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('triggers', 'Reg', (122, 130))	('gene silencing', 'biological_process', 'GO:0016458', ('10', '24'))	('transforming growth factor (TGF)-beta1', 'Gene', '21803', (28, 66))
21023	33121210	also demonstrated functional RIG-I expression in naive human NK cells and their direct activation upon RIG-I ligand (3pRNA) transfection.	('activation', 'PosReg', (87, 97))	('ligand', 'molecular_function', 'GO:0005488', ('109', '115'))	('RIG-I', 'Gene', (29, 34))	('human', 'Species', '9606', (55, 60))	('transfection', 'Var', (124, 136))	('NK', 'Chemical', '-', (61, 63))
21030	33121210	RIG-I activation has indeed been demonstrated to induce an anti-tumour effect in mouse models that is in part dependent or independent on NK cells.	('activation', 'Var', (6, 16))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('NK', 'Chemical', '-', (138, 140))	('RIG-I', 'Gene', (0, 5))	('mouse', 'Species', '10090', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
21043	33121210	Once introduced into mice, SLR10 and SLR14 (duplex length of 10 and 14 bp, respectively) induced high-levels of type I IFNs and activation of distinct genes essential for antiviral response and innate immunity.	('activation', 'PosReg', (128, 138))	('SLR14', 'Var', (37, 42))	('IFN', 'Gene', '3439', (119, 122))	('high-levels', 'MPA', (97, 108))	('SLR10', 'Var', (27, 32))	('mice', 'Species', '10090', (21, 25))	('IFN', 'Gene', (119, 122))	('innate immunity', 'biological_process', 'GO:0045087', ('194', '209'))	('antiviral response', 'biological_process', 'GO:0051607', ('171', '189'))
21050	33121210	Remarkably, antitumour immune response was partially mediated by T-cells in poorly immunogenic melanoma tumour, where SLR14 administration also induced direct activation of RIG-I pathway resulting in tumour cell death.	('SLR14', 'Var', (118, 123))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('tumour cell death', 'Disease', (200, 217))	('immune response', 'biological_process', 'GO:0006955', ('23', '38'))	('tumour', 'Disease', (200, 206))	('activation', 'PosReg', (159, 169))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('cell death', 'biological_process', 'GO:0008219', ('207', '217'))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('immunogenic melanoma tumour', 'Disease', (83, 110))	('RIG-I pathway', 'Pathway', (173, 186))	('tumour', 'Disease', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('immunogenic melanoma tumour', 'Disease', 'MESH:D008545', (83, 110))	('tumour', 'Disease', (16, 22))	('tumour cell death', 'Disease', 'MESH:D003643', (200, 217))
21052	33121210	This is in line with a previous report showing enhanced induction of antiviral and inflammatory genes in M8-treated primary human DCs, compared to treatment by other RNA agonists.	('M8-treated', 'Var', (105, 115))	('antiviral', 'Gene', (69, 78))	('enhanced', 'PosReg', (47, 55))	('human', 'Species', '9606', (124, 129))	('RNA', 'cellular_component', 'GO:0005562', ('166', '169'))	('induction', 'MPA', (56, 65))
21059	33121210	In line with this notion, combination treatment with SLR20 and the ICI alphaPD-L1 resulted in better control of tumour growth than single treatment.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('combination', 'Interaction', (26, 37))	('tumour', 'Disease', (112, 118))	('PD-L1', 'Gene', '29126', (76, 81))	('SLR20', 'Var', (53, 58))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('PD-L1', 'Gene', (76, 81))
21066	33121210	In a prophylactic vaccination schedule, CTLA-4 blockade significantly boosted expansion of Ag-specific CD8+ T-cells, which translated into strengthened antitumour immunity with systemic reduction of metastatic tumour burden.	('boosted', 'PosReg', (70, 77))	('reduction', 'NegReg', (186, 195))	('tumour', 'Disease', (156, 162))	('blockade', 'Var', (47, 55))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('expansion', 'CPA', (78, 87))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('CTLA-4', 'Gene', (40, 46))	('strengthened', 'PosReg', (139, 151))	('CD8', 'Gene', (103, 106))	('CD8', 'Gene', '925', (103, 106))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('tumour', 'Disease', (210, 216))
21070	33121210	Administration of 3P-RNA resulted in a specific CD8+T-cell-mediated response against disseminated AML and long-term survival in tumour-bearing mice.	('tumour', 'Disease', (128, 134))	('long-term survival', 'CPA', (106, 124))	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('3P', 'Chemical', '-', (18, 20))	('AML', 'Disease', 'MESH:D015470', (98, 101))	('CD8', 'Gene', (48, 51))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('3P-RNA', 'Var', (18, 24))	('AML', 'Disease', (98, 101))	('CD8', 'Gene', '925', (48, 51))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('mice', 'Species', '10090', (143, 147))
21087	33121210	Further, RIG-I activation resulted in increased TILs recruitment in the TME, thereby augmenting the sensitivity to anti-PD-L1-based therapy.	('TILs recruitment', 'MPA', (48, 64))	('RIG-I', 'Gene', (9, 14))	('sensitivity', 'MPA', (100, 111))	('TME', 'Chemical', '-', (72, 75))	('activation', 'Var', (15, 25))	('PD-L1', 'Gene', (120, 125))	('PD-L1', 'Gene', '29126', (120, 125))	('increased', 'PosReg', (38, 47))
21099	33121210	The HEPAVAC-101 (NCT03203005) clinical trial is being carried out by a combination of multi-peptide-based HCC vaccine (IMA970A), and the CV8102 in patients with very early, early, and intermediate stages of HCC.	('CV8102', 'Chemical', '-', (137, 143))	('patients', 'Species', '9606', (147, 155))	('HCC', 'Disease', (207, 210))	('CV8102', 'Var', (137, 143))
21129	33121210	This result led to phase 1/2 clinical trials that combines HVJ-E with pembrolizumab to demonstrate the ability of HVJ-E in augmenting the antitumour immunity of ICB.	('tumour', 'Disease', (142, 148))	('pembrolizumab', 'Chemical', 'MESH:C582435', (70, 83))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('augmenting', 'PosReg', (123, 133))	('HVJ-E', 'Var', (114, 119))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
21133	33121210	Two separate preclinical studies conducted in ovarian cancer and colorectal cancer cells demonstrated that epigenetic drugs will "trick" cancer cells into behaving as virus-infected cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('epigenetic drugs', 'Var', (107, 123))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('virus-infected', 'Disease', 'MESH:D001102', (167, 181))	('ovarian cancer', 'Disease', (46, 60))	('colorectal cancer', 'Disease', (65, 82))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))	('virus-infected', 'Disease', (167, 181))
21160	32937815	Association between EGFR Gene Mutation and Antioxidant Gene Polymorphism of Non-Small-Cell Lung Cancer EGFR mutation status is considered as an important predictor of therapeutic responsiveness in non-small-cell lung carcinoma patients.	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (20, 24))	('Small-Cell Lung Cancer', 'Phenotype', 'HP:0030357', (80, 102))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (197, 226))	('Association', 'Interaction', (0, 11))	('Non-Small-Cell Lung Cancer', 'Disease', 'MESH:D002289', (76, 102))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGFR', 'Gene', '1956', (20, 24))	('patients', 'Species', '9606', (227, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('EGFR', 'Gene', (103, 107))	('Lung Cancer', 'Phenotype', 'HP:0100526', (91, 102))	('non-small-cell lung carcinoma', 'Disease', (197, 226))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (197, 226))	('Non-Small-Cell Lung Cancer', 'Phenotype', 'HP:0030358', (76, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('mutation', 'Var', (108, 116))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (201, 226))	('Non-Small-Cell Lung Cancer', 'Disease', (76, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
21161	32937815	Recent evidence suggests that antioxidant gene polymorphisms are potential predictors of lung cancer risk.	('antioxidant', 'Gene', (30, 41))	('polymorphisms', 'Var', (47, 60))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))
21163	32937815	The present study was designed to evaluate the distribution frequency of antioxidant gene polymorphisms in lung adenocarcinoma, as well as its association with hotspot EGFR mutations.	('association', 'Interaction', (143, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('EGFR', 'Gene', '1956', (168, 172))	('lung adenocarcinoma', 'Disease', (107, 126))	('EGFR', 'Gene', (168, 172))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 126))	('mutations', 'Var', (173, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))
21164	32937815	The study findings revealed that a statistically significant association exists between EGFR L858R mutation and AG + GG genotypes of SOD rs4880 polymorphism.	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('SOD', 'Gene', '6647', (133, 136))	('SOD', 'molecular_function', 'GO:0004784', ('133', '136'))	('L858R', 'Var', (93, 98))	('L858R', 'Mutation', 'rs121434568', (93, 98))	('EGFR', 'Gene', '1956', (88, 92))	('SOD', 'Gene', (133, 136))	('rs4880', 'Mutation', 'rs4880', (137, 143))	('EGFR', 'Gene', (88, 92))	('significant association', 'Reg', (49, 72))
21165	32937815	Furthermore, the subgroup analysis data revealed that compared to AA genotype of SOD rs4880, AG + GG genotypes were significantly associated with advanced cancer stage and distant metastasis.	('SOD', 'Gene', '6647', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('SOD', 'Gene', (81, 84))	('rs4880', 'Mutation', 'rs4880', (85, 91))	('SOD', 'molecular_function', 'GO:0004784', ('81', '84'))	('distant metastasis', 'CPA', (172, 190))	('AG + GG', 'Var', (93, 100))	('cancer', 'Disease', (155, 161))	('associated with', 'Reg', (130, 145))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
21172	32937815	Activating mutations in EGFR gene are observed frequently in non-small-cell lung carcinoma patients, and EGFR gene polymorphisms are associated with the risk of lung cancer.	('EGFR', 'Gene', '1956', (24, 28))	('Activating', 'PosReg', (0, 10))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (61, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('EGFR', 'Gene', (105, 109))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (65, 90))	('non-small-cell lung carcinoma', 'Disease', (61, 90))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('patients', 'Species', '9606', (91, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (61, 90))	('EGFR', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('associated with', 'Reg', (133, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('lung cancer', 'Disease', (161, 172))	('polymorphisms', 'Var', (115, 128))
21173	32937815	It is well-documented that the most common EGFR mutations including exon 19 deletions and L858R mutations strongly predict the sensitivity of lung cancer patients to tyrosine kinase inhibitor treatments.	('L858R mutations', 'Var', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('sensitivity', 'MPA', (127, 138))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('predict', 'Reg', (115, 122))	('exon 19 deletions', 'Var', (68, 85))	('patients', 'Species', '9606', (154, 162))	('EGFR', 'Gene', '1956', (43, 47))	('lung cancer', 'Disease', (142, 153))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('175', '191'))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('L858R', 'Mutation', 'rs121434568', (90, 95))	('deletions', 'Var', (76, 85))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
21174	32937815	Moreover, studies conducted on erlotinib-treated lung cancer patients with EGFR mutations have shown that a specific polymorphism (181946C > T) in EGFR gene is associated with long-term progression-free and overall survival.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('EGFR', 'Gene', (147, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('mutations', 'Var', (80, 89))	('181946C > T', 'Var', (131, 142))	('patients', 'Species', '9606', (61, 69))	('overall survival', 'CPA', (207, 223))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('lung cancer', 'Disease', (49, 60))	('181946C > T', 'Mutation', 'g.181946C>T', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('EGFR', 'Gene', '1956', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('EGFR', 'Gene', '1956', (147, 151))	('progression-free', 'CPA', (186, 202))	('associated with', 'Reg', (160, 175))	('EGFR', 'Gene', (75, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (31, 40))
21180	32937815	Moreover, the study has pointed out that inhibition of both glutathione and TRX signaling pathways can induce cancer cell apoptosis.	('cancer', 'Disease', (110, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('glutathione', 'Chemical', 'MESH:D005978', (60, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('induce', 'PosReg', (103, 109))	('inhibition', 'Var', (41, 51))	('TRX', 'Gene', '7295', (76, 79))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('TRX', 'Gene', (76, 79))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('glutathione', 'Protein', (60, 71))
21183	32937815	Genetic polymorphisms of cellular antioxidants are known to play a significant role in the pathogenesis of various oxidative stress- and inflammation-related diseases, such as cancer.	('role', 'Reg', (79, 83))	('inflammation', 'biological_process', 'GO:0006954', ('137', '149'))	('play', 'Reg', (60, 64))	('inflammation-related diseases', 'Disease', 'MESH:D007249', (137, 166))	('inflammation-related diseases', 'Disease', (137, 166))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Genetic polymorphisms', 'Var', (0, 21))	('oxidative stress', 'Phenotype', 'HP:0025464', (115, 131))	('pathogenesis', 'biological_process', 'GO:0009405', ('91', '103'))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
21184	32937815	Recently, a meta-analysis study has stated that catalase C262 T polymorphism is associated with an increased risk of prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('catalase', 'Gene', (48, 56))	('C262 T', 'Mutation', 'c.262C>T', (57, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('catalase', 'Gene', '847', (48, 56))	('prostate cancer', 'Disease', (117, 132))	('C262 T polymorphism', 'Var', (57, 76))
21185	32937815	Similarly, polymorphisms in SOD gene is associated with the onset of different cancer types, including lung and colorectal cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancers', 'Disease', (112, 130))	('SOD', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung', 'Disease', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('polymorphisms', 'Var', (11, 24))	('SOD', 'molecular_function', 'GO:0004784', ('28', '31'))	('cancer', 'Disease', (123, 129))	('SOD', 'Gene', '6647', (28, 31))	('cancer', 'Disease', (79, 85))	('associated with', 'Reg', (40, 55))	('colorectal cancers', 'Disease', 'MESH:D015179', (112, 130))
21186	32937815	In case of lung cancer, one study has shown that glutathione S-transferase T1 gene polymorphism is associated with the lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Disease', (119, 130))	('polymorphism', 'Var', (83, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('glutathione S-transferase T1', 'Gene', (49, 77))	('glutathione S-transferase T1', 'Gene', '2952', (49, 77))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('associated', 'Reg', (99, 109))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
21187	32937815	Similarly, manganese SOD (MnSOD) gene polymorphisms (Ala16Val) together with the smoking status are known to be associated with an increased risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('manganese SOD', 'Gene', (11, 24))	('Ala16Val', 'Var', (53, 61))	('manganese SOD', 'Gene', '6648', (11, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('MnSOD', 'Gene', '6648', (26, 31))	('lung cancer', 'Disease', (149, 160))	('Ala16Val', 'SUBSTITUTION', 'None', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('SOD', 'molecular_function', 'GO:0004784', ('21', '24'))	('associated', 'Reg', (112, 122))	('MnSOD', 'Gene', (26, 31))
21192	32937815	Based on these study, in this present study we aimed to explore the correlation between SNPs and EGFR mutation in NSCLC patients.	('SNPs', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (97, 101))	('mutation', 'Var', (102, 110))	('NSCLC', 'Disease', (114, 119))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (120, 128))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
21198	32937815	The cobas EGFR Mutation Test v2 can identify 42 mutations in exons 18, 19, 20 and 21 of the EGFR gene, including G719X, ex19del, S768I, T790M, exon 20 insertions, L858R and L861Q.	('G719X', 'Mutation', 'p.G719X', (113, 118))	('G719X', 'Var', (113, 118))	('L858R', 'Mutation', 'rs121434568', (163, 168))	('L861Q', 'Mutation', 'rs121913444', (173, 178))	('EGFR', 'Gene', (10, 14))	('L861Q', 'Var', (173, 178))	('exon 20', 'Var', (143, 150))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))	('S768I', 'Var', (129, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('ex19del', 'Var', (120, 127))	('T790M', 'Mutation', 'rs121434569', (136, 141))	('L858R', 'Var', (163, 168))	('EGFR', 'Gene', '1956', (10, 14))	('S768I', 'Mutation', 'rs121913465', (129, 134))	('T790M', 'Var', (136, 141))	('insertions', 'Reg', (151, 161))	('EGFR', 'Gene', (92, 96))
21202	32937815	After controlling for other covariables, the odds ratio and 95% CIs of the association between the genotype frequencies and EGFR mutation risk and the clinicopathological features were calculated using multiple logistic regression models.	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('mutation', 'Var', (129, 137))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (124, 128))
21210	32937815	Table 2 shows the distribution frequency of antioxidant gene polymorphisms (SOD rs5746136 and SOD rs4880; CAT rs769218; OGG1 rs1052133; and TXN2 rs4821494) of lung adenocarcinoma patients.	('SOD', 'molecular_function', 'GO:0004784', ('76', '79'))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('SOD', 'Gene', (76, 79))	('rs5746136', 'Mutation', 'rs5746136', (80, 89))	('SOD', 'Gene', '6647', (76, 79))	('TXN2', 'Gene', (140, 144))	('CAT', 'molecular_function', 'GO:0004096', ('106', '109'))	('rs1052133', 'Var', (125, 134))	('CAT', 'Gene', (106, 109))	('patients', 'Species', '9606', (179, 187))	('rs4821494', 'Mutation', 'rs4821494', (145, 154))	('lung adenocarcinoma', 'Disease', (159, 178))	('SOD', 'Gene', (94, 97))	('OGG1', 'Gene', (120, 124))	('SOD', 'molecular_function', 'GO:0004784', ('94', '97'))	('OGG1', 'Gene', '4968', (120, 124))	('SOD', 'Gene', '6647', (94, 97))	('rs769218', 'Mutation', 'rs769218', (110, 118))	('rs1052133', 'Mutation', 'rs1052133', (125, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (159, 178))	('rs769218', 'Var', (110, 118))	('CAT', 'Gene', '847', (106, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))	('rs4880', 'Var', (98, 104))	('rs4880', 'Mutation', 'rs4880', (98, 104))	('TXN2', 'Gene', '25828', (140, 144))
21211	32937815	The alleles with the highest distribution frequency for SOD rs5746136 and SOD rs4880 in study participants were homozygous C/C and homozygous A/A for both the WT and EGFR-mutated groups, respectively.	('SOD', 'Gene', '6647', (74, 77))	('SOD', 'molecular_function', 'GO:0004784', ('74', '77'))	('SOD', 'Gene', (56, 59))	('rs5746136', 'Var', (60, 69))	('rs5746136', 'Mutation', 'rs5746136', (60, 69))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('rs4880', 'Mutation', 'rs4880', (78, 84))	('SOD', 'Gene', (74, 77))	('SOD', 'molecular_function', 'GO:0004784', ('56', '59'))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('SOD', 'Gene', '6647', (56, 59))	('participants', 'Species', '9606', (94, 106))
21212	32937815	For CAT rs769218; OGG1 rs1052133; and TXN2 rs4821494, the alleles with the highest distribution frequency among participants were homozygous G/G, homozygous C/C and homozygous G/G, respectively, for both the WT and EGFR-mutated groups.	('rs769218', 'Mutation', 'rs769218', (8, 16))	('TXN2', 'Gene', '25828', (38, 42))	('rs4821494', 'Mutation', 'rs4821494', (43, 52))	('TXN2', 'Gene', (38, 42))	('participants', 'Species', '9606', (112, 124))	('rs4821494', 'Var', (43, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('215', '219'))	('OGG1', 'Gene', '4968', (18, 22))	('EGFR', 'Gene', '1956', (215, 219))	('EGFR', 'Gene', (215, 219))	('rs769218', 'Var', (8, 16))	('CAT', 'Gene', (4, 7))	('rs1052133', 'Var', (23, 32))	('rs1052133', 'Mutation', 'rs1052133', (23, 32))	('CAT', 'Gene', '847', (4, 7))	('OGG1', 'Gene', (18, 22))	('CAT', 'molecular_function', 'GO:0004096', ('4', '7'))
21213	32937815	For all antioxidant gene polymorphisms, there was no statistically significant association between different genotypes and EGFR mutation status in lung adenocarcinoma patients.	('EGFR', 'Gene', (123, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('patients', 'Species', '9606', (167, 175))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('EGFR', 'Gene', '1956', (123, 127))	('mutation', 'Var', (128, 136))	('lung adenocarcinoma', 'Disease', (147, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))
21214	32937815	Table 3 represents the association between antioxidant gene polymorphisms (SOD rs5746136 and SOD rs4880; CAT rs769218; OGG1 rs1052133; and TXN2 rs4821494) and EGFR hotspot mutations in study participants.	('SOD', 'Gene', '6647', (75, 78))	('rs4880', 'Var', (97, 103))	('EGFR', 'Gene', '1956', (159, 163))	('rs4880', 'Mutation', 'rs4880', (97, 103))	('rs1052133', 'Mutation', 'rs1052133', (124, 133))	('EGFR', 'molecular_function', 'GO:0005006', ('159', '163'))	('TXN2', 'Gene', '25828', (139, 143))	('rs5746136', 'Mutation', 'rs5746136', (79, 88))	('rs4821494', 'Var', (144, 153))	('CAT', 'Gene', (105, 108))	('TXN2', 'Gene', (139, 143))	('participants', 'Species', '9606', (191, 203))	('OGG1', 'Gene', (119, 123))	('rs1052133', 'Var', (124, 133))	('rs4821494', 'Mutation', 'rs4821494', (144, 153))	('SOD', 'molecular_function', 'GO:0004784', ('93', '96'))	('CAT', 'molecular_function', 'GO:0004096', ('105', '108'))	('OGG1', 'Gene', '4968', (119, 123))	('EGFR', 'Gene', (159, 163))	('CAT', 'Gene', '847', (105, 108))	('rs769218', 'Mutation', 'rs769218', (109, 117))	('SOD', 'Gene', (93, 96))	('SOD', 'Gene', (75, 78))	('SOD', 'Gene', '6647', (93, 96))	('SOD', 'molecular_function', 'GO:0004784', ('75', '78'))	('rs769218', 'Var', (109, 117))
21215	32937815	In the present study, two hotspot EGFR mutations including L858R and exon 19 in-frame deletions were evaluated.	('EGFR', 'Gene', (34, 38))	('L858R', 'Var', (59, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('L858R', 'Mutation', 'rs121434568', (59, 64))	('EGFR', 'Gene', '1956', (34, 38))
21216	32937815	A significant association between L858R mutation and AG + GG genotypes of SOD rs4880 polymorphism was observed (AOR = 1.90; 95% CI = 1.01-3.58; p = 0.047).	('SOD', 'Gene', '6647', (74, 77))	('L858R', 'Var', (34, 39))	('AOR', 'molecular_function', 'GO:0033726', ('112', '115'))	('SOD', 'molecular_function', 'GO:0004784', ('74', '77'))	('rs4880', 'Mutation', 'rs4880', (78, 84))	('L858R', 'Mutation', 'rs121434568', (34, 39))	('SOD', 'Gene', (74, 77))
21217	32937815	However, there was no statistically significant association between SOD rs4880 genotypes and exon 19 in-frame deletions.	('rs4880', 'Var', (72, 78))	('rs4880', 'Mutation', 'rs4880', (72, 78))	('SOD', 'Gene', '6647', (68, 71))	('SOD', 'molecular_function', 'GO:0004784', ('68', '71'))	('SOD', 'Gene', (68, 71))
21218	32937815	For SOD rs5746136, CAT rs769218, OGG1 rs1052133 and TXN2 rs4821494 polymorphisms, no statistically significant association was observed between different genotypes and EGFR hotspot mutations.	('SOD', 'Gene', (4, 7))	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('EGFR', 'Gene', '1956', (168, 172))	('TXN2', 'Gene', '25828', (52, 56))	('rs4821494', 'Var', (57, 66))	('SOD', 'Gene', '6647', (4, 7))	('CAT', 'molecular_function', 'GO:0004096', ('19', '22'))	('rs1052133', 'Var', (38, 47))	('rs5746136', 'Var', (8, 17))	('rs5746136', 'Mutation', 'rs5746136', (8, 17))	('SOD', 'molecular_function', 'GO:0004784', ('4', '7'))	('CAT', 'Gene', (19, 22))	('TXN2', 'Gene', (52, 56))	('OGG1', 'Gene', (33, 37))	('rs4821494', 'Mutation', 'rs4821494', (57, 66))	('EGFR', 'Gene', (168, 172))	('OGG1', 'Gene', '4968', (33, 37))	('rs1052133', 'Mutation', 'rs1052133', (38, 47))	('CAT', 'Gene', '847', (19, 22))	('rs769218', 'Mutation', 'rs769218', (23, 31))	('rs769218', 'Var', (23, 31))
21219	32937815	To evaluate the correlation between clinicopathological features of EGFR hotspot mutations and SOD rs4880, a subgroup analysis of all lung adenocarcinoma cases as well as EGFR L858R and Exon 19 deletion mutations were performed (Table 4).	('EGFR', 'Gene', (171, 175))	('SOD', 'Gene', '6647', (95, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('171', '175'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (134, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('L858R', 'Var', (176, 181))	('SOD', 'Gene', (95, 98))	('lung adenocarcinoma', 'Disease', (134, 153))	('EGFR', 'Gene', '1956', (68, 72))	('rs4880', 'Mutation', 'rs4880', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('mutations', 'Var', (81, 90))	('L858R', 'Mutation', 'rs121434568', (176, 181))	('EGFR', 'Gene', '1956', (171, 175))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))	('SOD', 'molecular_function', 'GO:0004784', ('95', '98'))
21221	32937815	Moreover, a statistically significant correlation was observed between AG + GG genotypes and higher cancer staging irrespective of the EGFR mutation status.	('AG + GG', 'Var', (71, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('135', '139'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('EGFR', 'Gene', '1956', (135, 139))	('higher', 'Disease', (93, 99))	('EGFR', 'Gene', (135, 139))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('significant correlation', 'Reg', (26, 49))
21223	32937815	Finally, we evaluated the correlation between clinicopathological features in non-smoking NSCLC patients with EGFR mutations and SOD rs4880 (Table 5).	('mutations', 'Var', (115, 124))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('EGFR', 'Gene', (110, 114))	('SOD', 'Gene', '6647', (129, 132))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('rs4880', 'Mutation', 'rs4880', (133, 139))	('patients', 'Species', '9606', (96, 104))	('SOD', 'Gene', (129, 132))	('SOD', 'molecular_function', 'GO:0004784', ('129', '132'))
21225	32937815	Moreover, a statistically significant correlation was observed between AG + GG genotypes and higher cancer staging with non-smoking status (AOR = 3.15; 95% CI = 1.28-7.72; p = 0.012).	('AOR', 'molecular_function', 'GO:0033726', ('140', '143'))	('AG + GG', 'Var', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('higher', 'Disease', (93, 99))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('significant correlation', 'Reg', (26, 49))
21226	32937815	The present study was designed to evaluate the association between antioxidant gene polymorphisms (SOD rs5746136 and SOD rs4880; CAT rs769218; OGG1 rs1052133; and TXN2 rs4821494) and EGFR-mutated lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (196, 215))	('rs769218', 'Var', (133, 141))	('SOD', 'Gene', '6647', (99, 102))	('SOD', 'molecular_function', 'GO:0004784', ('117', '120'))	('TXN2', 'Gene', '25828', (163, 167))	('rs5746136', 'Mutation', 'rs5746136', (103, 112))	('association', 'Interaction', (47, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (196, 215))	('SOD', 'molecular_function', 'GO:0004784', ('99', '102'))	('rs1052133', 'Var', (148, 157))	('EGFR', 'Gene', (183, 187))	('CAT', 'Gene', (129, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('TXN2', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('OGG1', 'Gene', (143, 147))	('OGG1', 'Gene', '4968', (143, 147))	('rs4821494', 'Mutation', 'rs4821494', (168, 177))	('rs4880', 'Var', (121, 127))	('rs4880', 'Mutation', 'rs4880', (121, 127))	('rs1052133', 'Mutation', 'rs1052133', (148, 157))	('EGFR', 'Gene', '1956', (183, 187))	('CAT', 'Gene', '847', (129, 132))	('CAT', 'molecular_function', 'GO:0004096', ('129', '132'))	('SOD', 'Gene', (117, 120))	('rs769218', 'Mutation', 'rs769218', (133, 141))	('SOD', 'Gene', (99, 102))	('SOD', 'Gene', '6647', (117, 120))
21230	32937815	The analysis performed to investigate the relationship between antioxidant gene polymorphisms with EGFR hotspot mutations (L858R and Exon 19 deletion mutations) revealed that a statistically significant association exists between L858R mutation and AG + GG genotypes of SOD rs4880 polymorphism (Table 3).	('SOD', 'Gene', '6647', (270, 273))	('EGFR', 'Gene', (99, 103))	('L858R', 'Var', (230, 235))	('significant association', 'Reg', (191, 214))	('L858R', 'Mutation', 'rs121434568', (230, 235))	('SOD', 'Gene', (270, 273))	('L858R', 'Mutation', 'rs121434568', (123, 128))	('rs4880', 'Mutation', 'rs4880', (274, 280))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', '1956', (99, 103))	('SOD', 'molecular_function', 'GO:0004784', ('270', '273'))
21232	32937815	In particular, AG + GG genotypes were found to be correlated significantly with higher tumor stage and tumors with distant metastasis (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('AG + GG', 'Var', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (87, 92))	('tumors', 'Disease', (103, 109))	('correlated', 'Reg', (50, 60))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
21233	32937815	Additionally, we analyzed for clinical correlation in non-smoking NSCLC patients with EGFR mutations and SOD rs4880 (Table 5).	('SOD', 'molecular_function', 'GO:0004784', ('105', '108'))	('NSCLC', 'Disease', (66, 71))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('EGFR', 'Gene', (86, 90))	('rs4880', 'Mutation', 'rs4880', (109, 115))	('mutations', 'Var', (91, 100))	('SOD', 'Gene', (105, 108))	('SOD', 'Gene', '6647', (105, 108))	('patients', 'Species', '9606', (72, 80))
21234	32937815	Increased risk was observed in females; non-smokers; and with EGFR mutation.	('EGFR', 'Gene', (62, 66))	('EGFR', 'Gene', '1956', (62, 66))	('mutation', 'Var', (67, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))
21236	32937815	There is a growing-pool of evidence suggesting that antioxidant gene polymorphisms are important predictors of cancer risks.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('polymorphisms', 'Var', (69, 82))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('antioxidant gene', 'Gene', (52, 68))
21238	32937815	Moreover, genetic polymorphism-driven changes in the activity of cellular antioxidants can alter the therapeutic responsiveness of cancer patients through increased oxidative stress; thus, genetic polymorphism as a biomarker can be effective in identifying patient-specific therapeutic interventions and augmenting the responsiveness of personalized medicines.	('cancer', 'Disease', (131, 137))	('alter', 'Reg', (91, 96))	('increased', 'PosReg', (155, 164))	('oxidative stress', 'Phenotype', 'HP:0025464', (165, 181))	('patient', 'Species', '9606', (257, 264))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (155, 181))	('activity', 'MPA', (53, 61))	('changes', 'Reg', (38, 45))	('patient', 'Species', '9606', (138, 145))	('therapeutic responsiveness', 'MPA', (101, 127))	('augmenting', 'NegReg', (304, 314))	('responsiveness', 'MPA', (319, 333))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('oxidative stress', 'MPA', (165, 181))	('patients', 'Species', '9606', (138, 146))	('genetic polymorphism', 'Var', (189, 209))
21239	32937815	The current findings showed that genetic variants in oxidative stress related genes may modify prognosis in EGFR TKIs-treated NSCLC patients.	('modify', 'Reg', (88, 94))	('prognosis', 'MPA', (95, 104))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('patients', 'Species', '9606', (132, 140))	('genetic variants', 'Var', (33, 49))	('NSCLC', 'Disease', (126, 131))
21240	32937815	Cellular redox state is associated with the efficacy of EGFR TKIs treatment in NSCLC patients with activating EGFR mutations.	('activating', 'PosReg', (99, 109))	('Cellular redox state', 'MPA', (0, 20))	('mutations', 'Var', (115, 124))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('EGFR', 'Gene', '1956', (56, 60))	('patients', 'Species', '9606', (85, 93))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('NSCLC', 'Disease', (79, 84))
21243	32937815	In our findings, AG + GG genotypes of SOD rs4880 were associated with more aggressive lung adenocarcinoma phenotypes compared to AA genotype of SOD rs4880 in advance NSCLC.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('SOD', 'Gene', (38, 41))	('SOD', 'Gene', (144, 147))	('aggressive lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 105))	('rs4880', 'Mutation', 'rs4880', (148, 154))	('SOD', 'molecular_function', 'GO:0004784', ('38', '41'))	('SOD', 'molecular_function', 'GO:0004784', ('144', '147'))	('aggressive lung adenocarcinoma', 'Disease', (75, 105))	('NSCLC', 'Disease', (166, 171))	('SOD', 'Gene', '6647', (38, 41))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('SOD', 'Gene', '6647', (144, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('rs4880', 'Var', (42, 48))	('rs4880', 'Mutation', 'rs4880', (42, 48))
21248	32937815	The present study findings revealed that SOD rs4880 polymorphism is significantly associated with a specific EGFR hotspot mutation, L858R.	('SOD', 'Gene', (41, 44))	('associated', 'Reg', (82, 92))	('SOD', 'Gene', '6647', (41, 44))	('SOD', 'molecular_function', 'GO:0004784', ('41', '44'))	('EGFR', 'Gene', '1956', (109, 113))	('L858R', 'Var', (132, 137))	('EGFR', 'Gene', (109, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('rs4880', 'Var', (45, 51))	('rs4880', 'Mutation', 'rs4880', (45, 51))	('L858R', 'Mutation', 'rs121434568', (132, 137))
21254	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))
21273	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))
21285	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))	('sulfation', 'biological_process', 'GO:0051923', ('245', '254'))	('glucosamine', 'Chemical', 'MESH:D005944', (91, 102))	('glucosamine', 'Chemical', 'MESH:D005944', (210, 221))	('iduronic acid', 'Chemical', 'MESH:D007067', (144, 157))	('uronic acid', 'Chemical', 'MESH:D014574', (129, 140))	('sulfate', 'Chemical', 'MESH:D013431', (276, 283))	('uronic acid', 'Chemical', 'MESH:D014574', (146, 157))	('sulfation', 'biological_process', 'GO:0051923', ('78', '87'))	('HS', 'Chemical', 'MESH:D006497', (10, 12))	('N-deacetylation', 'MPA', (56, 71))	('sulfation', 'biological_process', 'GO:0051923', ('163', '172'))	('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))	('sulfation', 'biological_process', 'GO:0051923', ('181', '190'))
21290	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))
21292	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))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('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))	('sulfation', 'biological_process', 'GO:0051923', ('17', '26'))	('chondrosarcoma', 'Disease', 'MESH:D002813', (153, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('chondrosarcoma', 'Disease', (153, 167))	('3-OST', 'Gene', (113, 118))
21295	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))	('Mutations', 'Var', (0, 9))	('EXT2', 'Gene', (21, 25))	('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))
21296	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))
21297	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))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('non-melanoma skin cancer', 'Disease', (120, 144))	('HS chain synthesis', 'MPA', (73, 91))	('synthesis', 'biological_process', 'GO:0009058', ('82', '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))
21306	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))
21312	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))
21318	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))
21325	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.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('binding', 'Interaction', (108, 115))	('HSPG', 'Gene', '960', (96, 100))	('HSPG', 'Gene', (96, 100))	('ligand', 'molecular_function', 'GO:0005488', ('101', '107'))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('malignancy of the tumor', 'Disease', 'MESH:D009369', (163, 186))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))	('HSPG', 'Gene', '960', (36, 40))	('HSPG', 'Gene', (36, 40))	('affects', 'Reg', (88, 95))	('determining', 'Reg', (147, 158))	('aberrant expression', 'Var', (4, 23))	('malignancy of the tumor', 'Disease', (163, 186))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('signaling', 'MPA', (131, 140))
21330	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))	('promotes', 'PosReg', (13, 21))	('growth', 'MPA', (26, 32))	('myeloma tumors', 'Disease', 'MESH:D009101', (36, 50))	('Soluble', 'cellular_component', 'GO:0005625', ('0', '7'))	('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))
21331	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))	('mitogenic activity', 'biological_process', 'GO:0045840', ('44', '62'))	('inflammation', 'biological_process', 'GO:0006954', ('208', '220'))	('invasive potential', 'CPA', (67, 85))	('shedding', 'Var', (122, 130))	('angiogenesis', 'biological_process', 'GO:0001525', ('190', '202'))	('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))	('wound healing', 'biological_process', 'GO:0042060', ('175', '188'))	('promotes', 'PosReg', (166, 174))	('wound healing', 'CPA', (175, 188))	('pancreatic cancer', 'Disease', (89, 106))
21332	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))
21346	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))	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('PKC', 'molecular_function', 'GO:0004697', ('393', '396'))	('extracellular signal-regulated kinase', 'Gene', (189, 226))	('PKC', 'Gene', (393, 396))	('FGF', 'Protein', (44, 47))	('ERK', 'molecular_function', 'GO:0004707', ('228', '231'))	('extracellular signal-regulated kinase', 'Gene', '5594', (189, 226))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('transcription', 'biological_process', 'GO:0006351', ('349', '362'))	('MAPK', 'molecular_function', 'GO:0004707', ('183', '187'))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('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))	('extracellular', 'cellular_component', 'GO:0005576', ('189', '202'))	('STAT', 'Gene', '6774', (364, 368))	('PI3K', 'molecular_function', 'GO:0016303', ('265', '269'))	('protein', 'cellular_component', 'GO:0003675', ('375', '382'))	('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))	('JAK', 'molecular_function', 'GO:0004713', ('309', '312'))	('FGF binding', 'molecular_function', 'GO:0017134', ('44', '55'))	('HSPG', 'Gene', (29, 33))	('ERK', 'Gene', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('dimerization', 'Var', (69, 81))
21358	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))	('myeloma', 'Disease', (16, 23))	('activation', 'PosReg', (104, 114))	('cell proliferation', 'CPA', (137, 155))	('HGF', 'Gene', '3082', (44, 47))	('SDC1', 'Gene', (30, 34))	('promotes', 'PosReg', (35, 43))	('shed', 'Var', (25, 29))	('SDC1', 'Gene', '6382', (30, 34))	('PI3K cascade', 'biological_process', 'GO:0014065', ('91', '103'))	('enhanced', 'PosReg', (128, 136))	('paracrine signaling', 'biological_process', 'GO:0038001', ('48', '67'))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('myeloma', 'Disease', 'MESH:D009101', (16, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('MAPK', 'MPA', (82, 86))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))
21360	32916872	Dysregulation of HSPG-regulated HGF/c-MET signaling in tumor microenvironment plays a key role in hepatocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('HSPG', 'Gene', '960', (17, 21))	('c-MET', 'Gene', '4233', (36, 41))	('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))
21361	32916872	Strong evidence demonstrates a role for loss of HB-EGF in the tumor microenvironment in neuroblastoma pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('pathogenesis', 'biological_process', 'GO:0009405', ('102', '114'))	('neuroblastoma', 'Disease', 'MESH:D009447', (88, 101))	('HB-EGF', 'Gene', (48, 54))	('tumor', 'Disease', (62, 67))	('neuroblastoma', 'Disease', (88, 101))	('neuroblastoma', 'Phenotype', 'HP:0003006', (88, 101))	('loss', 'Var', (40, 44))	('HB-EGF', 'Gene', '1839', (48, 54))	('EGF', 'molecular_function', 'GO:0005154', ('51', '54'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
21432	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))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('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))
21441	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))	('M402', 'Var', (42, 46))	('anti-angiogenic', 'CPA', (72, 87))	('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))
21447	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))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (76, 97))	('SULF1', 'Gene', (33, 38))	('SULF1', 'Gene', '23213', (33, 38))	('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))
21448	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))
21463	32433811	In conclusion, crizotinib was considered to cause pleural effusion as an adverse event in a case of ROS1-rearranged lung adenocarcinoma with a complete response.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('ROS1', 'Gene', (100, 104))	('crizotinib', 'Var', (15, 25))	('pleural effusion', 'Disease', 'MESH:D010996', (50, 66))	('ROS1', 'Gene', '6098', (100, 104))	('lung adenocarcinoma', 'Disease', (116, 135))	('pleural effusion', 'Phenotype', 'HP:0002202', (50, 66))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('pleural effusion', 'Disease', (50, 66))	('crizotinib', 'Chemical', 'MESH:D000077547', (15, 25))
21471	32433811	The cancer stage was determined to be cT4N3M1c, stage IVB, isolated right cervical lymph node metastasis.	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (74, 104))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cT4N3M1c', 'Var', (38, 46))	('cancer', 'Disease', (4, 10))
21472	32433811	Molecular testing of the biopsied specimen revealed ROS1 rearrangement.	('rearrangement', 'Var', (57, 70))	('ROS1', 'Gene', (52, 56))	('ROS1', 'Gene', '6098', (52, 56))	('revealed', 'Reg', (43, 51))
21485	32433811	However, we found no case reports describing noncardiogenic pleural effusion due to crizotinib.	('crizotinib', 'Chemical', 'MESH:D000077547', (84, 94))	('pleural effusion', 'Phenotype', 'HP:0002202', (60, 76))	('crizotinib', 'Var', (84, 94))	('pleural effusion', 'Disease', 'MESH:D010996', (60, 76))	('pleural effusion', 'Disease', (60, 76))
21486	32433811	Crizotinib has inhibitory activity against CYP3A4 and may increase the blood concentration of other drugs.	('increase', 'PosReg', (58, 66))	('CYP3A4', 'Gene', '1576', (43, 49))	('blood concentration of other drugs', 'MPA', (71, 105))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('Crizotinib', 'Var', (0, 10))	('CYP3A4', 'molecular_function', 'GO:0033780', ('43', '49'))	('inhibitory activity', 'MPA', (15, 34))	('CYP3A4', 'Gene', (43, 49))
21497	32433811	12   In conclusion, crizotinib was considered to cause pleural effusion as an adverse event in a patient with ROS1-rearranged lung adenocarcinoma.	('crizotinib', 'Var', (20, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 145))	('pleural effusion', 'Disease', 'MESH:D010996', (55, 71))	('pleural effusion', 'Disease', (55, 71))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (126, 145))	('crizotinib', 'Chemical', 'MESH:D000077547', (20, 30))	('ROS1', 'Gene', (110, 114))	('pleural effusion', 'Phenotype', 'HP:0002202', (55, 71))	('patient', 'Species', '9606', (97, 104))	('ROS1', 'Gene', '6098', (110, 114))	('lung adenocarcinoma', 'Disease', (126, 145))
21503	32425893	By creating the LcpC-knockout strains, we showed that the deficiency in LcpC decreased the antimicrobial resistance to beta-lactams and glycopeptides and impeded the binding to various epithelial cells.	('binding', 'molecular_function', 'GO:0005488', ('166', '173'))	('glycopeptides', 'Chemical', 'MESH:D006020', (136, 149))	('LcpC', 'Chemical', '-', (72, 76))	('LcpC', 'Gene', (72, 76))	('deficiency', 'Var', (58, 68))	('impeded', 'NegReg', (154, 161))	('binding', 'Interaction', (166, 173))	('LcpC', 'Chemical', '-', (16, 20))	('decreased', 'NegReg', (77, 86))	('beta-lactams', 'Chemical', 'MESH:D047090', (119, 131))
21504	32425893	More importantly, the knockout of LcpC significantly reduced the pathogenicity of methicillin-resistant S. aureus (MRSA) in mice.	('S. aureus', 'Species', '1280', (104, 113))	('methicillin', 'Chemical', 'MESH:D008712', (82, 93))	('pathogenicity', 'MPA', (65, 78))	('mice', 'Species', '10090', (124, 128))	('knockout', 'Var', (22, 30))	('methicillin-resistant S. aureus', 'Disease', (82, 113))	('reduced', 'NegReg', (53, 60))	('LcpC', 'Chemical', '-', (34, 38))	('LcpC', 'Gene', (34, 38))
21509	32425893	The emergence of multi-drug-resistant S. aureus and its internalization into host cells further complicate the treatment of its infection.	('S. aureus', 'Gene', (38, 47))	('multi-drug-resistant', 'Var', (17, 37))	('S. aureus', 'Species', '1280', (38, 47))	('infection', 'Disease', (128, 137))	('internalization', 'MPA', (56, 71))	('infection', 'Disease', 'MESH:D007239', (128, 137))
21510	32425893	Multi-drug-resistant S. aureus poses a significant threat to public healthcare and animal production.	('Multi-drug-resistant', 'Var', (0, 20))	('S. aureus', 'Disease', (21, 30))	('S. aureus', 'Species', '1280', (21, 30))
21517	32425893	In addition to antimicrobial resistance, S. aureus is capable of evading antimicrobial chemotherapy and host immune defense via internalization into host cells.	('host immune defense', 'CPA', (104, 123))	('S. aureus', 'Var', (41, 50))	('evading antimicrobial chemotherapy', 'CPA', (65, 99))	('internalization', 'CPA', (128, 143))	('S. aureus', 'Species', '1280', (41, 50))
21523	32425893	Complete loss of WTA occurred when all three lcp genes were deleted, significantly reducing the antimicrobial resistance and impairing the cell division process.	('cell division process', 'CPA', (139, 160))	('lcp genes', 'Gene', (45, 54))	('impairing', 'NegReg', (125, 134))	('loss of WTA', 'Disease', 'MESH:D014786', (9, 20))	('reducing', 'NegReg', (83, 91))	('cell division', 'biological_process', 'GO:0051301', ('139', '152'))	('loss of WTA', 'Disease', (9, 20))	('deleted', 'Var', (60, 67))	('antimicrobial resistance', 'MPA', (96, 120))
21526	32425893	Despite the biological importance of LcpC as a ligase, two important questions still remain: whether and how LcpC could influence the antimicrobial resistance of S. aureus and whether and how the changes of the deficiency in LcpC could impair the pathogenicity of S. aureus to the host.	('S. aureus', 'Species', '1280', (264, 273))	('S. aureus', 'Species', '1280', (162, 171))	('influence', 'Reg', (120, 129))	('LcpC', 'Chemical', '-', (225, 229))	('pathogenicity', 'CPA', (247, 260))	('LcpC', 'Chemical', '-', (109, 113))	('LcpC', 'Chemical', '-', (37, 41))	('LcpC', 'Gene', (225, 229))	('changes', 'Var', (196, 203))	('antimicrobial', 'MPA', (134, 147))	('impair', 'NegReg', (236, 242))	('deficiency', 'Var', (211, 221))
21527	32425893	Here, we deleted lcpC in S. aureus strains and compared the multiple antibiotic resistance, as well as the adherence of S. aureus to host cells among the wild types, mutants, and complements.	('S. aureus', 'Species', '1280', (25, 34))	('lcpC', 'Chemical', '-', (17, 21))	('lcpC', 'Gene', (17, 21))	('adherence', 'MPA', (107, 116))	('deleted', 'Var', (9, 16))	('S. aureus', 'Species', '1280', (120, 129))	('compared', 'Reg', (47, 55))	('multiple antibiotic resistance', 'MPA', (60, 90))
21534	32425893	The deletions of lcpC were performed as previously described.	('lcpC', 'Chemical', '-', (17, 21))	('lcpC', 'Gene', (17, 21))	('deletions', 'Var', (4, 13))
21543	32425893	The plates were incubated for 24-36 h at 35 C. In parallel, the growth curves of S. aureus and their derivative strains were also recorded in the TSB medium supplemented with antibiotics, in order to compare the susceptibilities of the lcpC mutants to the wild types and the complements.	('mutants', 'Var', (241, 248))	('lcpC', 'Gene', (236, 240))	('lcpC', 'Chemical', '-', (236, 240))	('TSB medium', 'Chemical', '-', (146, 156))	('S. aureus', 'Species', '1280', (81, 90))
21576	32425893	Briefly, approximately 105 cells were infected with 107-CFU Mu50, DeltalcpC mutant, and the complement, respectively.	('lcpC', 'Chemical', '-', (71, 75))	('infected', 'Disease', 'MESH:D007239', (38, 46))	('mutant', 'Var', (76, 82))	('infected', 'Disease', (38, 46))	('DeltalcpC', 'Gene', (66, 75))	('Mu50', 'Var', (60, 64))
21581	32425893	To investigate the role of lcpC in antimicrobial resistance of S. aureus, lcpC knockout mutants were created by allelic exchange in four S. aureus strains, including two MRSA strains, Mu50 (a hospital-associated MRSA) and BA01611 (a livestock-associated MRSA), and two MSSA strains, Newman (a hospital-associated MSSA) and RN4220 (a laboratory strain).	('lcpC', 'Gene', (74, 78))	('BA01611', 'Chemical', '-', (222, 229))	('RN4220', 'Species', '561307', (323, 329))	('lcpC', 'Chemical', '-', (27, 31))	('S. aureus', 'Species', '1280', (137, 146))	('mutants', 'Var', (88, 95))	('lcpC', 'Chemical', '-', (74, 78))	('S. aureus', 'Species', '1280', (63, 72))
21586	32425893	Intriguingly, the knockout of lcpC affected the resistance to teicoplanin in different manners in the two MRSA strains.	('lcpC', 'Chemical', '-', (30, 34))	('lcpC', 'Gene', (30, 34))	('affected', 'Reg', (35, 43))	('knockout', 'Var', (18, 26))	('resistance to teicoplanin', 'MPA', (48, 73))	('teicoplanin', 'Chemical', 'MESH:D017334', (62, 73))
21587	32425893	The resistance to teicoplanin was reduced by the lcpC knockout in BA01611 (Figures 1A, 2A), while the deficiency of LcpC increased the resistance to teicoplanin in Mu50 (Figures 1B, 2B).	('knockout', 'Var', (54, 62))	('resistance to teicoplanin', 'MPA', (135, 160))	('reduced', 'NegReg', (34, 41))	('teicoplanin', 'Chemical', 'MESH:D017334', (149, 160))	('teicoplanin', 'Chemical', 'MESH:D017334', (18, 29))	('increased', 'PosReg', (121, 130))	('BA01611', 'Chemical', '-', (66, 73))	('deficiency of LcpC', 'Disease', (102, 120))	('lcpC', 'Chemical', '-', (49, 53))	('lcpC', 'Gene', (49, 53))	('resistance to teicoplanin', 'MPA', (4, 29))	('deficiency of LcpC', 'Disease', 'MESH:D007153', (102, 120))
21588	32425893	On the other hand, the resistance to oxacillin and cefazolin was decreased in Newman by the knockout of lcpC (Supplementary Figure S2A).	('decreased', 'NegReg', (65, 74))	('knockout', 'Var', (92, 100))	('lcpC', 'Chemical', '-', (104, 108))	('lcpC', 'Gene', (104, 108))	('cefazolin', 'Chemical', 'MESH:D002437', (51, 60))	('oxacillin', 'Chemical', 'MESH:D010068', (37, 46))
21599	32425893	Moreover, the decreased adherence in Mu50 DeltalcpC was observed in three cell lines, including MCF-7, HCMEC, and HaCaT.	('HaCaT', 'CellLine', 'CVCL:0038', (114, 119))	('decreased', 'NegReg', (14, 23))	('Mu50 DeltalcpC', 'Var', (37, 51))	('adherence', 'MPA', (24, 33))	('MCF-7', 'CellLine', 'CVCL:0031', (96, 101))	('HCMEC', 'CellLine', 'CVCL:U985', (103, 108))	('lcpC', 'Chemical', '-', (47, 51))
21600	32425893	The changes in adherence for RN4220 and its derivative strains were consistent in two methods.	('RN4220', 'Var', (29, 35))	('RN4220', 'Species', '561307', (29, 35))	('changes', 'Reg', (4, 11))	('adherence', 'MPA', (15, 24))
21604	32425893	Whether deletion of lcpC alone can alter staphylococcal morphology remains unknown.	('lcpC', 'Gene', (20, 24))	('staphylococcal morphology', 'MPA', (41, 66))	('lcpC', 'Chemical', '-', (20, 24))	('alter', 'Reg', (35, 40))	('deletion', 'Var', (8, 16))
21606	32425893	As shown in Figure 5 (the stationary phase) and Supplementary Figure S4 (the logarithmic phase), the cell wall architecture in these lcpC mutants (BA01611, Mu50, and RN4220) was significantly altered to be rougher and fuzzier, but those in the wild types and the complement strains are intact and smooth.	('lcpC', 'Gene', (133, 137))	('lcpC', 'Chemical', '-', (133, 137))	('BA01611', 'Var', (147, 154))	('RN4220', 'Species', '561307', (166, 172))	('BA01611', 'Chemical', '-', (147, 154))	('RN4220', 'Var', (166, 172))	('cell wall architecture', 'CPA', (101, 123))	('stationary phase', 'biological_process', 'GO:0070314', ('26', '42'))	('cell wall', 'cellular_component', 'GO:0005618', ('101', '110'))	('Mu50', 'Var', (156, 160))	('stationary phase', 'biological_process', 'GO:0072690', ('26', '42'))	('altered', 'Reg', (192, 199))
21607	32425893	Moreover, SEMs showed that the absence of LcpC caused dents and hollows on surfaces.	('LcpC', 'Chemical', '-', (42, 46))	('LcpC', 'Gene', (42, 46))	('dents', 'CPA', (54, 59))	('caused', 'Reg', (47, 53))	('absence', 'Var', (31, 38))	('hollows on surfaces', 'CPA', (64, 83))
21608	32425893	The decline in the antimicrobial resistance and the adherence to host cells led to a hypothesis that the deficiency in LcpC may reduce the toxicity of S. aureus in vivo.	('decline', 'NegReg', (4, 11))	('S. aureus', 'Species', '1280', (151, 160))	('LcpC', 'Chemical', '-', (119, 123))	('antimicrobial resistance', 'CPA', (19, 43))	('adherence', 'CPA', (52, 61))	('toxicity', 'Disease', 'MESH:D064420', (139, 147))	('reduce', 'NegReg', (128, 134))	('LcpC', 'Gene', (119, 123))	('deficiency', 'Var', (105, 115))	('toxicity', 'Disease', (139, 147))
21613	32425893	The histopathology in lung tissue by hematoxylin and eosin staining revealed that the DeltalcpC caused lower inflammation than those of the wild-type and the complement strains (Figure 7B).	('hematoxylin', 'Chemical', 'MESH:D006416', (37, 48))	('lcpC', 'Chemical', '-', (91, 95))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('eosin', 'Chemical', 'MESH:D004801', (53, 58))	('lower', 'NegReg', (103, 108))	('DeltalcpC', 'Var', (86, 95))	('inflammation', 'Disease', (109, 121))	('inflammation', 'biological_process', 'GO:0006954', ('109', '121'))
21614	32425893	Moreover, less bacteria were invaded in the lung and spleen in the DeltalcpC than in the wild-type and the complement strains (Figure 7C).	('lcpC', 'Chemical', '-', (72, 76))	('DeltalcpC', 'Var', (67, 76))	('less', 'NegReg', (10, 14))
21625	32425893	This study demonstrated that the absence of LcpC decreased the resistance to beta-lactams in MRSA (BA01611 and Mu50) and to certain glycopeptide and beta-lactam antibiotics in MSSA (Newman and RN4220).	('beta-lactam', 'Chemical', 'MESH:D047090', (77, 88))	('BA01611', 'Chemical', '-', (99, 106))	('beta-lactams', 'Chemical', 'MESH:D047090', (77, 89))	('absence', 'Var', (33, 40))	('RN4220', 'Species', '561307', (193, 199))	('decreased', 'NegReg', (49, 58))	('beta-lactam', 'Chemical', 'MESH:D047090', (149, 160))	('LcpC', 'Chemical', '-', (44, 48))	('glycopeptide', 'Chemical', 'MESH:D006020', (132, 144))	('resistance', 'MPA', (63, 73))
21626	32425893	Both TEM and SEM results showed that lcpC mutants had abnormal cell shape, as well as the dented and hollowed cell envelope, which may allow the cell wall active antibiotics easier access to the peptidoglycan terminus, therefore reducing the antimicrobial resistance to beta-lactam and certain glycopeptide antibiotics.	('lcpC', 'Chemical', '-', (37, 41))	('mutants', 'Var', (42, 49))	('antimicrobial resistance to beta-lactam', 'MPA', (242, 281))	('abnormal cell shape', 'Phenotype', 'HP:0025461', (54, 73))	('lcpC', 'Gene', (37, 41))	('cell wall', 'cellular_component', 'GO:0005618', ('145', '154'))	('glycopeptide', 'Chemical', 'MESH:D006020', (294, 306))	('cell envelope', 'cellular_component', 'GO:0030313', ('110', '123'))	('TEM', 'cellular_component', 'GO:0097197', ('5', '8'))	('allow', 'Reg', (135, 140))	('peptidoglycan', 'cellular_component', 'GO:0009274', ('195', '208'))	('beta-lactam', 'Chemical', 'MESH:D047090', (270, 281))	('reducing', 'NegReg', (229, 237))
21628	32425893	It has been reported that the deficiency of WTA due to mutation of the tar gene cluster sensitized MRSA strains to beta-lactams.	('tar', 'Gene', (71, 74))	('sensitized', 'Reg', (88, 98))	('beta-lactams', 'Chemical', 'MESH:D047090', (115, 127))	('WTA', 'Chemical', '-', (44, 47))	('mutation', 'Var', (55, 63))
21632	32425893	Both Mu50 and Mu3 contain a mutation in another LCP member, lcpA, and both are VISA.	('Mu3', 'Gene', (14, 17))	('Mu50', 'Var', (5, 9))	('mutation', 'Var', (28, 36))	('lcpA', 'Chemical', '-', (60, 64))
21633	32425893	Introduction of mutated lcpA into vancomycin-susceptible S. aureus (VSSA) strain N315DeltaIP increased the level of VISA.	('VISA', 'MPA', (116, 120))	('increased', 'PosReg', (93, 102))	('mutated', 'Var', (16, 23))	('lcpA', 'Gene', (24, 28))	('S. aureus', 'Species', '1280', (57, 66))	('vancomycin', 'Chemical', 'MESH:D014640', (34, 44))	('lcpA', 'Chemical', '-', (24, 28))
21639	32425893	The most important finding from this study was the demonstration that the DeltalcpC caused the attenuation in pathogenicity in a mouse septic shock model with oxacillin treatments.	('shock', 'Phenotype', 'HP:0031273', (142, 147))	('septic shock', 'Disease', (135, 147))	('attenuation', 'NegReg', (95, 106))	('septic shock', 'Phenotype', 'HP:0100806', (135, 147))	('mouse', 'Species', '10090', (129, 134))	('lcpC', 'Chemical', '-', (79, 83))	('oxacillin', 'Chemical', 'MESH:D010068', (159, 168))	('septic shock', 'Disease', 'MESH:D012772', (135, 147))	('DeltalcpC', 'Var', (74, 83))	('pathogenicity', 'MPA', (110, 123))
21642	32425893	It suggests that the presence of LcpC not only facilitates murine S. aureus carriage but also worsened distinct features of the disease as shown on both macroscopic and microscopic levels.	('facilitates', 'PosReg', (47, 58))	('worsened', 'NegReg', (94, 102))	('LcpC', 'Chemical', '-', (33, 37))	('LcpC', 'Var', (33, 37))	('presence', 'Var', (21, 29))	('murine', 'Species', '10090', (59, 65))	('S. aureus', 'Species', '1280', (66, 75))
21644	32425893	CPs enhance staphylococcal virulence by impeding phagocytosis, resulting in bacterial persistence in the bloodstream of infected hosts.	('CPs', 'Var', (0, 3))	('infected', 'Disease', 'MESH:D007239', (120, 128))	('virulence', 'biological_process', 'GO:0009406', ('27', '36'))	('phagocytosis', 'CPA', (49, 61))	('virulence', 'biological_process', 'GO:0009405', ('27', '36'))	('virulence', 'biological_process', 'GO:0016032', ('27', '36'))	('resulting in', 'Reg', (63, 75))	('enhance', 'PosReg', (4, 11))	('infected', 'Disease', (120, 128))	('staphylococcal virulence', 'MPA', (12, 36))	('CPs', 'Chemical', '-', (0, 3))	('bacterial persistence', 'Phenotype', 'HP:0002718', (76, 97))	('impeding', 'NegReg', (40, 48))	('bacterial persistence', 'MPA', (76, 97))	('phagocytosis', 'biological_process', 'GO:0006909', ('49', '61'))
21646	32425893	Moreover, WTA enhances the staphylococcal virulence and the skin abscess induction in an animal model.	('WTA', 'Chemical', '-', (10, 13))	('virulence', 'biological_process', 'GO:0009405', ('42', '51'))	('skin abscess induction in an animal model', 'CPA', (60, 101))	('skin abscess', 'Phenotype', 'HP:0031292', (60, 72))	('enhances', 'PosReg', (14, 22))	('virulence', 'biological_process', 'GO:0016032', ('42', '51'))	('WTA', 'Var', (10, 13))	('virulence', 'biological_process', 'GO:0009406', ('42', '51'))	('staphylococcal virulence', 'MPA', (27, 51))	('abscess', 'Phenotype', 'HP:0025615', (65, 72))
21648	32425893	Our results provide additional evidence for a new mechanism by which CPs and WTAs in S. aureus enhance the pathogenesis through enhanced antibiotic resistance and adhesion capability to host cells.	('CPs', 'Var', (69, 72))	('antibiotic resistance', 'MPA', (137, 158))	('enhanced', 'PosReg', (128, 136))	('CPs', 'Chemical', '-', (69, 72))	('adhesion capability', 'CPA', (163, 182))	('WTAs', 'Chemical', '-', (77, 81))	('S. aureus', 'Species', '1280', (85, 94))	('enhance', 'PosReg', (95, 102))	('pathogenesis', 'biological_process', 'GO:0009405', ('107', '119'))
21678	32268297	The dysregulated expression of MAZ was recently associated with malignant tumors, such as breast cancer, thyroid cancer, hepatocellular carcinoma and urothelial carcinoma.	('associated', 'Reg', (48, 58))	('urothelial carcinoma', 'Disease', (150, 170))	('hepatocellular carcinoma', 'Disease', (121, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('dysregulated', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('expression', 'MPA', (17, 27))	('thyroid cancer', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('thyroid cancer', 'Disease', 'MESH:D013964', (105, 119))	('malignant tumors', 'Disease', (64, 80))	('expression', 'Species', '29278', (17, 27))	('MAZ', 'Gene', (31, 34))	('malignant tumors', 'Disease', 'MESH:D009369', (64, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('thyroid cancer', 'Phenotype', 'HP:0002890', (105, 119))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (150, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
21691	32268297	To further determine the role of FOXK1 in GC tissues, we assessed whether the silencing of FOXK1 inhibits the lung partialization of diffuse GC cells in vivo and established a mouse tumor model via tail vein injection.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('lung partialization of', 'CPA', (110, 132))	('tumor', 'Disease', (182, 187))	('inhibits', 'NegReg', (97, 105))	('mouse', 'Species', '10090', (176, 181))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('silencing', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('FOXK1', 'Gene', (91, 96))
21698	32268297	In addition, IHC measurements of these metastatic nodules excised from the two groups of mice showed that the silencing of FOXK1 increased the expression of LC3-II and E-cadherin and decreased the expression of P62 and MMP9 compared with the expression levels observed in the control nodules (Figure 2E).	('expression', 'Species', '29278', (143, 153))	('MMP9', 'Protein', (219, 223))	('expression', 'Species', '29278', (197, 207))	('MMP9', 'molecular_function', 'GO:0004229', ('219', '223'))	('FOXK1', 'Gene', (123, 128))	('silencing', 'Var', (110, 119))	('P62', 'Gene', (211, 214))	('increased', 'PosReg', (129, 138))	('decreased', 'NegReg', (183, 192))	('expression', 'Species', '29278', (242, 252))	('LC3-II', 'Protein', (157, 163))	('expression', 'MPA', (143, 153))	('E-cadherin', 'Gene', (168, 178))	('E-cadherin', 'Gene', '999', (168, 178))	('expression', 'MPA', (197, 207))	('LC3-II', 'Chemical', '-', (157, 163))	('mice', 'Species', '10090', (89, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('170', '178'))	('P62', 'Gene', '23636', (211, 214))
21699	32268297	Furthermore, we orthotopically transplanted MGC803 cells infected with LV-ctrl, LV-shFOXK1-1 and shFOXK1-2 into the gastric wall of nude mice.	('nude mice', 'Species', '10090', (132, 141))	('MGC803', 'CellLine', 'CVCL:5334', (44, 50))	('LV-ctrl', 'Var', (71, 78))	('infected', 'Disease', (57, 65))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('infected', 'Disease', 'MESH:D007239', (57, 65))
21700	32268297	Twenty-eight days after orthotopic transplantation, we found that the inhibition of FOXK1 reduced the number of metastases and tumor weight in the gastric wall (Figure 2F-2H).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reduced', 'NegReg', (90, 97))	('tumor', 'Disease', (127, 132))	('metastases', 'Disease', (112, 122))	('inhibition', 'Var', (70, 80))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('FOXK1', 'Gene', (84, 89))
21701	32268297	The inhibition of FOXK1 has also been shown to decrease the number of diffuse liver metastases (Figure 2I, 2J).	('liver metastases', 'Disease', 'MESH:D009362', (78, 94))	('FOXK1', 'Gene', (18, 23))	('decrease', 'NegReg', (47, 55))	('inhibition', 'Var', (4, 14))	('liver metastases', 'Disease', (78, 94))
21702	32268297	As shown in Supplementary Figure 3, compared with the control group, the inhibition of FOXK1 in a normal environment resulted in increased LC3-II expression and decreased P62 expression, which indicated that the inhibition of FOXK1 under normal conditions can induce autophagy.	('P62', 'Gene', '23636', (171, 174))	('decreased', 'NegReg', (161, 170))	('FOXK1', 'Gene', (226, 231))	('expression', 'MPA', (146, 156))	('expression', 'MPA', (175, 185))	('increased', 'PosReg', (129, 138))	('autophagy', 'CPA', (267, 276))	('P62', 'Gene', (171, 174))	('autophagy', 'biological_process', 'GO:0016236', ('267', '276'))	('inhibition', 'Var', (73, 83))	('LC3-II', 'Protein', (139, 145))	('FOXK1', 'Gene', (87, 92))	('expression', 'Species', '29278', (146, 156))	('induce', 'Reg', (260, 266))	('expression', 'Species', '29278', (175, 185))	('autophagy', 'biological_process', 'GO:0006914', ('267', '276'))	('inhibition', 'Var', (212, 222))	('LC3-II', 'Chemical', '-', (139, 145))	('increased LC3', 'Phenotype', 'HP:0003141', (129, 142))
21703	32268297	In addition, the inhibition of FOXK1 under normal circumstances can increase the expression level of E-cadherin and suppress the expression of N-cadherin and Vimentin compared with that found in the control group.	('expression', 'Species', '29278', (129, 139))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('E-cadherin', 'Gene', (101, 111))	('Vimentin', 'cellular_component', 'GO:0045098', ('158', '166'))	('Vimentin', 'Protein', (158, 166))	('expression', 'MPA', (129, 139))	('expression level', 'MPA', (81, 97))	('E-cadherin', 'Gene', '999', (101, 111))	('inhibition', 'Var', (17, 27))	('Vimentin', 'cellular_component', 'GO:0045099', ('158', '166'))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('increase', 'PosReg', (68, 76))	('FOXK1', 'Gene', (31, 36))	('suppress', 'NegReg', (116, 124))	('expression', 'Species', '29278', (81, 91))
21706	32268297	Further transwell experiments confirmed that FOXK1 inhibition effectively reduced the invasion of MGC803 and AGS cells under both Matrigel and Matrigel-free conditions (Figure 3B, 3C).	('MGC803', 'CellLine', 'CVCL:5334', (98, 104))	('MGC803', 'Gene', (98, 104))	('FOXK1', 'Gene', (45, 50))	('AGS cells', 'CPA', (109, 118))	('inhibition', 'Var', (51, 61))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('reduced', 'NegReg', (74, 81))	('invasion', 'CPA', (86, 94))
21709	32268297	As shown in Figure 4A, the MGC803 cells belonging to the control group and transfected with mRFP-GFP-LC3 exhibited the basal levels of autophagy, and the knockout of FOXK1 expression significantly increased the number of red-only LC3 puncta, which indicates an increase in autophagic flux (Figure 4A, 4B).	('LC3', 'Gene', '84557', (230, 233))	('LC3', 'Gene', (230, 233))	('GC', 'Phenotype', 'HP:0012126', (28, 30))	('expression', 'Species', '29278', (172, 182))	('autophagy', 'biological_process', 'GO:0016236', ('135', '144'))	('autophagic flux', 'CPA', (273, 288))	('LC3', 'Gene', '84557', (101, 104))	('knockout', 'Var', (154, 162))	('increased', 'PosReg', (197, 206))	('FOXK1', 'Gene', (166, 171))	('MGC803', 'CellLine', 'CVCL:5334', (27, 33))	('autophagy', 'biological_process', 'GO:0006914', ('135', '144'))	('LC3', 'Gene', (101, 104))	('increase', 'PosReg', (261, 269))
21710	32268297	By transmission electron microscopy, we found that autophagosomes infected with shFOXK1-1 and shFOXK1-2 were significantly more autophagic than those belonging to the control group (Figure 4C, 4D).	('autophagic', 'CPA', (128, 138))	('more', 'PosReg', (123, 127))	('shFOXK1-1', 'Var', (80, 89))	('autophagosomes', 'CPA', (51, 65))	('infected', 'Disease', 'MESH:D007239', (66, 74))	('shFOXK1-2', 'Var', (94, 103))	('infected', 'Disease', (66, 74))
21711	32268297	Western blotting further confirmed that the silencing of FOXK1 in MGC803 and AGS cells increased the levels of LC3-II and Beclin1 proteins and decreased the levels of P62 proteins (Figure 4E).	('increased', 'PosReg', (87, 96))	('levels of LC3-II', 'MPA', (101, 117))	('Beclin1', 'Gene', (122, 129))	('decreased', 'NegReg', (143, 152))	('P62', 'Gene', '23636', (167, 170))	('LC3-II', 'Chemical', '-', (111, 117))	('MGC803', 'CellLine', 'CVCL:5334', (66, 72))	('P62', 'Gene', (167, 170))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('Beclin1', 'Gene', '8678', (122, 129))	('silencing', 'Var', (44, 53))	('FOXK1', 'Gene', (57, 62))
21714	32268297	In addition, cell scratch and transwell experiments confirmed that the inhibition of autophagy by 3-MA antagonized the inhibitory effect of the knockout of FOXK1 on the migration and invasion of GC cells (Figure 4F-4H).	('FOXK1', 'Gene', (156, 161))	('autophagy', 'biological_process', 'GO:0016236', ('85', '94'))	('migration', 'CPA', (169, 178))	('autophagy', 'biological_process', 'GO:0006914', ('85', '94'))	('inhibition', 'NegReg', (71, 81))	('knockout', 'Var', (144, 152))	('3-MA', 'Chemical', 'MESH:C025946', (98, 102))	('invasion', 'CPA', (183, 191))	('GC', 'Phenotype', 'HP:0012126', (195, 197))	('autophagy', 'CPA', (85, 94))
21716	32268297	Together, these results indicate that the inhibition of FOXK1 expression induces autophagy to inhibit migration and invasion.	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('expression', 'Species', '29278', (62, 72))	('inhibition', 'Var', (42, 52))	('FOXK1', 'Gene', (56, 61))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('induces', 'Reg', (73, 80))	('autophagy', 'CPA', (81, 90))	('inhibit', 'NegReg', (94, 101))
21725	32268297	Western blotting assays showed that the knockdown of MAZ significantly increased the expression level of LC3-II and decreased the expression level of P62 (Figure 6B).	('P62', 'Gene', '23636', (150, 153))	('knockdown', 'Var', (40, 49))	('P62', 'Gene', (150, 153))	('increased', 'PosReg', (71, 80))	('expression', 'Species', '29278', (85, 95))	('LC3-II', 'Protein', (105, 111))	('expression level', 'MPA', (85, 101))	('MAZ', 'Gene', (53, 56))	('expression', 'Species', '29278', (130, 140))	('decreased', 'NegReg', (116, 125))	('LC3-II', 'Chemical', '-', (105, 111))
21729	32268297	Increasing the expression of MAZ eliminated the sudden increase in red-only LC3 puncta caused by FOXK1 knockdown (Supplementary Figure 4B), which demonstrates that the knockout of FOXK1 induces autophagy and suppresses EMT, at least in part by downregulating MAZ.	('EMT', 'biological_process', 'GO:0001837', ('219', '222'))	('suppresses', 'NegReg', (208, 218))	('EMT', 'CPA', (219, 222))	('downregulating', 'NegReg', (244, 258))	('autophagy', 'biological_process', 'GO:0016236', ('194', '203'))	('expression', 'Species', '29278', (15, 25))	('autophagy', 'biological_process', 'GO:0006914', ('194', '203'))	('LC3', 'Gene', '84557', (76, 79))	('autophagy', 'CPA', (194, 203))	('induces', 'PosReg', (186, 193))	('FOXK1', 'Gene', (180, 185))	('MAZ', 'MPA', (259, 262))	('LC3', 'Gene', (76, 79))	('FOXK1', 'Gene', (97, 102))	('knockout', 'Var', (168, 176))
21730	32268297	As expected, the stable knockdown of FOXK1 increased the E-cadherin protein levels and significantly reduced the expression of N-cadherin and Vimentin (Figure 6G).	('expression', 'MPA', (113, 123))	('Vimentin', 'cellular_component', 'GO:0045098', ('142', '150'))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('Vimentin', 'Protein', (142, 150))	('reduced', 'NegReg', (101, 108))	('N-cadherin', 'Protein', (127, 137))	('expression', 'Species', '29278', (113, 123))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('increased', 'PosReg', (43, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('Vimentin', 'cellular_component', 'GO:0045099', ('142', '150'))	('knockdown', 'Var', (24, 33))	('FOXK1', 'Gene', (37, 42))
21735	32268297	As shown in Figure 7A, treatment with rapamycin or the silencing of FOXK1 resulted in a significant increase in the number of red-only LC3 puncta compared with that of the control group, and their combination exerted a synergistic effect (Figure 7A, 7B).	('FOXK1', 'Gene', (68, 73))	('silencing', 'Var', (55, 64))	('LC3', 'Gene', '84557', (135, 138))	('rapamycin', 'Chemical', 'MESH:D020123', (38, 47))	('LC3', 'Gene', (135, 138))	('increase', 'PosReg', (100, 108))
21747	32268297	Our results indicate that the inhibition of FOXK1 increases E-cadherin expression, reduces N-cadherin and Vimentin expression in an acidic microenvironment and also decrease the expression levels of MMP9.	('cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))	('reduces', 'NegReg', (83, 90))	('decrease', 'NegReg', (165, 173))	('Vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('increases', 'PosReg', (50, 59))	('FOXK1', 'Gene', (44, 49))	('E-cadherin', 'Gene', (60, 70))	('E-cadherin', 'Gene', '999', (60, 70))	('expression', 'Species', '29278', (115, 125))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('expression', 'MPA', (71, 81))	('Vimentin', 'Protein', (106, 114))	('expression', 'Species', '29278', (178, 188))	('Vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('MMP9', 'molecular_function', 'GO:0004229', ('199', '203'))	('expression levels', 'MPA', (178, 195))	('N-cadherin', 'Protein', (91, 101))	('inhibition', 'Var', (30, 40))	('expression', 'MPA', (115, 125))	('expression', 'Species', '29278', (71, 81))
21748	32268297	Previous studies have also revealed that the coexpression of FOXK1 and Vimentin can upregulate Snail to promote EMT in GC and thereby promotes the metastasis of GC cells in vitro and in vivo.	('FOXK1', 'Gene', (61, 66))	('GC', 'Phenotype', 'HP:0012126', (119, 121))	('upregulate', 'PosReg', (84, 94))	('Vimentin', 'cellular_component', 'GO:0045098', ('71', '79'))	('EMT in GC', 'CPA', (112, 121))	('GC', 'Phenotype', 'HP:0012126', (161, 163))	('promotes', 'PosReg', (134, 142))	('Vimentin', 'cellular_component', 'GO:0045099', ('71', '79'))	('Snail', 'MPA', (95, 100))	('promote', 'PosReg', (104, 111))	('coexpression', 'Var', (45, 57))	('expression', 'Species', '29278', (47, 57))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('metastasis', 'CPA', (147, 157))
21750	32268297	The silencing of FOXK1 promoted the conversion of LC3-I to LC3-II and increased the expression of E-cadherin, which indicated that the inhibition of FOXK1 induces autophagy and inhibits EMT in acidic GC.	('increased', 'PosReg', (70, 79))	('EMT in acidic GC', 'CPA', (186, 202))	('LC3', 'Gene', '84557', (59, 62))	('autophagy', 'biological_process', 'GO:0016236', ('163', '172'))	('LC3-II', 'Chemical', '-', (59, 65))	('conversion', 'MPA', (36, 46))	('expression', 'Species', '29278', (84, 94))	('LC3', 'Gene', '84557', (50, 53))	('promoted', 'PosReg', (23, 31))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('autophagy', 'biological_process', 'GO:0006914', ('163', '172'))	('inhibition', 'Var', (135, 145))	('silencing', 'Var', (4, 13))	('induces', 'PosReg', (155, 162))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('LC3', 'Gene', (59, 62))	('FOXK1', 'Gene', (17, 22))	('autophagy', 'CPA', (163, 172))	('expression', 'MPA', (84, 94))	('LC3', 'Gene', (50, 53))	('EMT', 'biological_process', 'GO:0001837', ('186', '189'))	('GC', 'Phenotype', 'HP:0012126', (200, 202))	('inhibits', 'NegReg', (177, 185))	('FOXK1', 'Gene', (149, 154))
21751	32268297	Interestingly, the inhibition of 3-MA-mediated autophagy significantly antagonized the inhibitory effect of the silencing of FOXK1 on acidic GC cell migration and invasion and extensively inhibited silent FOXK1-mediated EMT.	('EMT', 'biological_process', 'GO:0001837', ('220', '223'))	('acidic GC cell migration', 'CPA', (134, 158))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('inhibited', 'NegReg', (188, 197))	('inhibition', 'NegReg', (19, 29))	('autophagy', 'biological_process', 'GO:0016236', ('47', '56'))	('antagonized', 'NegReg', (71, 82))	('3-MA-mediated', 'Protein', (33, 46))	('silencing', 'Var', (112, 121))	('FOXK1', 'Gene', (125, 130))	('3-MA', 'Chemical', 'MESH:C025946', (33, 37))	('autophagy', 'biological_process', 'GO:0006914', ('47', '56'))	('cell migration', 'biological_process', 'GO:0016477', ('144', '158'))	('invasion', 'CPA', (163, 171))
21754	32268297	Interestingly, the overexpression of MAZ partially eliminated the induction of autophagy by FOXK1 knockdown in acidic GC cells.	('FOXK1', 'Gene', (92, 97))	('autophagy', 'CPA', (79, 88))	('knockdown', 'Var', (98, 107))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('eliminated', 'NegReg', (51, 61))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('expression', 'Species', '29278', (23, 33))
21756	32268297	Our study found that the combination of mTOR inhibition with FOXK1 inhibition induces autophagy in an acidic environment and that this combination is more effective than the antimetastatic effects observed in cells treated with acidic GC alone.	('FOXK1', 'Gene', (61, 66))	('inhibition', 'NegReg', (67, 77))	('induces', 'Reg', (78, 85))	('autophagy', 'CPA', (86, 95))	('mTOR', 'Gene', (40, 44))	('autophagy', 'biological_process', 'GO:0016236', ('86', '95'))	('mTOR', 'Gene', '2475', (40, 44))	('inhibition', 'Var', (45, 55))	('GC', 'Phenotype', 'HP:0012126', (235, 237))	('autophagy', 'biological_process', 'GO:0006914', ('86', '95'))
21758	32268297	This result suggests that the targeting of mTOR and FOXK1 can prevent GC metastasis by reversing EMT.	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('GC metastasis', 'Disease', (70, 83))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('EMT', 'CPA', (97, 100))	('targeting', 'Var', (30, 39))	('reversing', 'NegReg', (87, 96))	('prevent', 'NegReg', (62, 69))	('FOXK1', 'Gene', (52, 57))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))
21770	32268297	Autophagy double-labeled adenovirus (mRFP-GFP-LC3) was purchased from Hanbio Biotechnology Co., Ltd., and antibodies against E-cadherin (#14472), N-cadherin (#13116), Vimentin (#5741), LC3-I/II (#3868), beta-actin (#4970) and Beclin1 (#3495S) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('E-cadherin', 'Gene', '999', (125, 135))	('Beclin1', 'Gene', (226, 233))	('Vimentin', 'cellular_component', 'GO:0045098', ('167', '175'))	('#4970', 'Var', (215, 220))	('LC3', 'Gene', (46, 49))	('Signaling', 'biological_process', 'GO:0023052', ('268', '277'))	('adenovirus', 'Species', '10508', (25, 35))	('LC3', 'Gene', '84557', (185, 188))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('#5741', 'Var', (177, 182))	('#3868', 'Var', (195, 200))	('#13116', 'Var', (158, 164))	('#14472', 'Var', (137, 143))	('LC3', 'Gene', '84557', (46, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('127', '135'))	('Vimentin', 'cellular_component', 'GO:0045099', ('167', '175'))	('Beclin1', 'Gene', '8678', (226, 233))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('LC3', 'Gene', (185, 188))	('#3495S', 'Var', (235, 241))	('E-cadherin', 'Gene', (125, 135))
21838	32184655	Margolin et al reported homozygous mutations of OTUD4 in patients with ataxia and hypogonadism.	('homozygous mutations', 'Var', (24, 44))	('patients', 'Species', '9606', (57, 65))	('hypogonadism', 'Phenotype', 'HP:0000135', (82, 94))	('ataxia and hypogonadism', 'Disease', 'MESH:C535674', (71, 94))	('ataxia', 'Phenotype', 'HP:0001251', (71, 77))	('OTUD4', 'Gene', (48, 53))
21839	32184655	Silencing OTUD4 in zebrafish embryos leads to defects in the eyes, optic tectum, and cerebellum.	('defects', 'NegReg', (46, 53))	('tectum', 'cellular_component', 'GO:0043676', ('73', '79'))	('zebrafish', 'Species', '7955', (19, 28))	('Silencing', 'Var', (0, 9))	('OTUD4', 'Gene', (10, 15))
21840	32184655	Therefore, we intend to study the relationship between deregulated OTUD4 and multiple human tumors.	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('OTUD4', 'Gene', (67, 72))	('tumors', 'Disease', (92, 98))	('deregulated', 'Var', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
21842	32184655	Importantly, our results indicated that the expression of OTUD4 was significantly correlated with the overall survival time of BRCA, ESCA, LIHC, LUAD and OV patients.	('ESCA', 'Disease', (133, 137))	('OV', 'Phenotype', 'HP:0012887', (154, 156))	('BRCA', 'Gene', '672', (127, 131))	('LIHC', 'Disease', (139, 143))	('ESCA', 'Disease', 'MESH:D004938', (133, 137))	('expression', 'Var', (44, 54))	('LIHC', 'Disease', 'MESH:D006528', (139, 143))	('patients', 'Species', '9606', (157, 165))	('LUAD', 'Disease', (145, 149))	('correlated', 'Reg', (82, 92))	('LUAD', 'Phenotype', 'HP:0030078', (145, 149))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('OTUD4', 'Gene', (58, 63))	('BRCA', 'Gene', (127, 131))	('ESCA', 'Phenotype', 'HP:0011459', (133, 137))	('LUAD', 'Disease', 'MESH:D000077192', (145, 149))
21864	32184655	Statistical analysis revealed that OTUD4 expression was significantly positively associated with increased overall survival time of BRCA (HR=0.81; P=0.00013), ESCA (HR=0.41; P=0.027), LIHC (HR=0.54; P=0.023), LUAD (HR=0.47; P=6.6e-10), and OV (HR=0.53; P=0.018, Figure 2) patients.	('ESCA', 'Disease', 'MESH:D004938', (159, 163))	('OTUD4', 'Gene', (35, 40))	('LUAD', 'Disease', (209, 213))	('LIHC', 'Disease', (184, 188))	('increased', 'PosReg', (97, 106))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('BRCA', 'Gene', '672', (132, 136))	('LIHC', 'Disease', 'MESH:D006528', (184, 188))	('BRCA', 'Gene', (132, 136))	('OV', 'Phenotype', 'HP:0012887', (240, 242))	('LUAD', 'Disease', 'MESH:D000077192', (209, 213))	('ESCA', 'Phenotype', 'HP:0011459', (159, 163))	('ESCA', 'Disease', (159, 163))	('patients', 'Species', '9606', (272, 280))	('expression', 'Var', (41, 51))	('LUAD', 'Phenotype', 'HP:0030078', (209, 213))
21879	32184655	V1_DN) in a publicly available GEO database of breast (GEO70884), liver (GSE36411) and lung cancer (GSE32865) (Figure 4C), indicating that OTUD4 may inhibiting the AKT signaling pathway.	('AKT', 'Gene', (164, 167))	('AKT signaling', 'biological_process', 'GO:0043491', ('164', '177'))	('signaling pathway', 'biological_process', 'GO:0007165', ('168', '185'))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('OTUD4', 'Var', (139, 144))	('GSE36411', 'Var', (73, 81))	('inhibiting', 'NegReg', (149, 159))	('AKT', 'Gene', '207', (164, 167))	('lung cancer', 'Disease', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('liver', 'Disease', (66, 71))
21883	32184655	According to another published study, deregulated OTUD4 indeed affects the levels of ubiquitinated XPC in human cells, supporting the hypothesis that the OTUD4 deubiquitinating enzyme participates in the XPC recycling by cleaving the ubiquitin moiety.	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('160', '183'))	('human', 'Species', '9606', (106, 111))	('participates', 'Reg', (184, 196))	('XPC', 'Gene', (204, 207))	('deregulated', 'Var', (38, 49))	('OTUD4', 'Gene', (50, 55))	('XPC', 'Gene', (99, 102))	('OTUD4', 'Gene', (154, 159))	('cleaving the ubiquitin moiety', 'MPA', (221, 250))	('XPC', 'Gene', '7508', (204, 207))	('ubiquitin', 'molecular_function', 'GO:0031386', ('234', '243'))	('affects', 'Reg', (63, 70))	('XPC', 'Gene', '7508', (99, 102))
21887	32184655	The overall survival time of patients with OTUD4 high expression was significantly longer than that of patients with OTUD4 low expression.	('patients', 'Species', '9606', (29, 37))	('high expression', 'Var', (49, 64))	('OTUD4', 'Gene', (43, 48))	('longer', 'PosReg', (83, 89))	('survival', 'CPA', (12, 20))	('patients', 'Species', '9606', (103, 111))
21911	32184655	Overexpression of OTUD4 inhibits proliferation, migration, and invasion of breast, liver and lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('migration', 'CPA', (48, 57))	('inhibits', 'NegReg', (24, 32))	('liver and lung cancer', 'Disease', 'MESH:D006528', (83, 104))	('proliferation', 'CPA', (33, 46))	('invasion', 'CPA', (63, 71))	('Overexpression', 'Var', (0, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('OTUD4', 'Gene', (18, 23))	('breast', 'Disease', (75, 81))
21922	32046322	In myasthenia gravis, autoAbs against the acetylcholine receptor functionally block, alter, or destroy acetylcholine neurotransmission by targeting acetylcholine receptor organization on the postsynaptic neuronal plate.	('acetylcholine receptor', 'Gene', (42, 64))	('myasthenia gravis', 'Disease', (3, 20))	('autoAbs', 'Var', (22, 29))	('neurotransmission', 'biological_process', 'GO:0007268', ('117', '134'))	('acetylcholine', 'Chemical', 'MESH:D000109', (148, 161))	('acetylcholine', 'Chemical', 'MESH:D000109', (42, 55))	('alter', 'Reg', (85, 90))	('acetylcholine neurotransmission', 'MPA', (103, 134))	('myasthenia gravis', 'Disease', 'MESH:D009157', (3, 20))	('acetylcholine', 'Chemical', 'MESH:D000109', (103, 116))	('destroy', 'NegReg', (95, 102))	('myasthenia', 'Phenotype', 'HP:0003473', (3, 13))	('targeting', 'Reg', (138, 147))	('block', 'NegReg', (78, 83))	('acetylcholine receptor organization', 'MPA', (148, 183))
21925	32046322	Furthermore, some autoAbs induce inflammation by causing uncontrolled neutrophil activation, such as the anti-neutrophil cytoplasmic antibody (ANCA) in ANCA-associated vasculitis, or causing inflammation at the site of autoantibody binding, such as autoAbs targeting myosin in myocarditis or the anti-cyclic citrullinated peptide antibody in rheumatoid arthritis (RA).	('myocarditis', 'Disease', (277, 288))	('antibody', 'cellular_component', 'GO:0019815', ('330', '338'))	('inflammation', 'biological_process', 'GO:0006954', ('33', '45'))	('binding', 'molecular_function', 'GO:0005488', ('232', '239'))	('neutrophil activation', 'biological_process', 'GO:0042119', ('70', '91'))	('induce', 'Reg', (26, 32))	('antibody', 'cellular_component', 'GO:0019815', ('133', '141'))	('inflammation', 'biological_process', 'GO:0006954', ('191', '203'))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (342, 362))	('vasculitis', 'Disease', (168, 178))	('antibody', 'cellular_component', 'GO:0019814', ('330', '338'))	('myocarditis', 'Disease', 'MESH:D009205', (277, 288))	('vasculitis', 'Phenotype', 'HP:0002633', (168, 178))	('binding', 'Interaction', (232, 239))	('autoAbs', 'Var', (18, 25))	('myosin', 'Gene', '79784', (267, 273))	('inflammation', 'Disease', 'MESH:D007249', (191, 203))	('arthritis', 'Phenotype', 'HP:0001369', (353, 362))	('anti-neutrophil cytoplasmic antibody', 'Phenotype', 'HP:0032230', (105, 141))	('antibody', 'cellular_component', 'GO:0019814', ('133', '141'))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('antibody', 'molecular_function', 'GO:0003823', ('330', '338'))	('anti-cyclic citrullinated peptide antibody', 'Protein', (296, 338))	('uncontrolled neutrophil activation', 'MPA', (57, 91))	('RA', 'Disease', 'MESH:D001172', (364, 366))	('vasculitis', 'Disease', 'MESH:D014657', (168, 178))	('rheumatoid arthritis', 'Disease', (342, 362))	('antibody', 'cellular_component', 'GO:0042571', ('330', '338'))	('myocarditis', 'Phenotype', 'HP:0012819', (277, 288))	('causing', 'Reg', (49, 56))	('inflammation', 'Disease', (191, 203))	('antibody', 'molecular_function', 'GO:0003823', ('133', '141'))	('causing', 'Reg', (183, 190))	('inflammation', 'Disease', (33, 45))	('antibody', 'cellular_component', 'GO:0042571', ('133', '141'))	('myosin', 'Gene', (267, 273))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (342, 362))
21937	32046322	For example, chronic fibrosing IIPs with anti-aminoacyl-tRNA synthetase (ARS) autoAbs were reported to show good responses to steroid therapy and have a better prognosis compared with IPF.	('ARS', 'Gene', (73, 76))	('steroid', 'Chemical', 'MESH:D013256', (126, 133))	('autoAbs', 'Var', (78, 85))	('IPF', 'Disease', (184, 187))	('ARS', 'Gene', '57152', (73, 76))	('anti-aminoacyl-tRNA synthetase', 'Gene', (41, 71))	('IIPs', 'Disease', 'MESH:D054988', (31, 35))	('anti-aminoacyl-tRNA synthetase', 'Gene', '57152', (41, 71))	('IIPs', 'Disease', (31, 35))	('tRNA', 'molecular_function', 'GO:0030533', ('56', '60'))	('IPF', 'Disease', 'MESH:D054990', (184, 187))
21957	32046322	For example, we found that autoAbs against lysyl oxidase-like 2 (LOXL2), an enzyme that promotes crosslinking of extracellular matrix molecules such as collagen and elastin through oxidation, are frequent in INSIP patients.	('INSIP', 'Disease', (208, 213))	('elastin', 'cellular_component', 'GO:0001529', ('165', '172'))	('patients', 'Species', '9606', (214, 222))	('lysyl oxidase-like 2', 'Gene', '4017', (43, 63))	('lysyl oxidase-like 2', 'Gene', (43, 63))	('LOXL2', 'Gene', (65, 70))	('frequent', 'Reg', (196, 204))	('elastin', 'molecular_function', 'GO:0030023', ('165', '172'))	('elastin', 'molecular_function', 'GO:0001528', ('165', '172'))	('crosslinking', 'MPA', (97, 109))	('collagen', 'molecular_function', 'GO:0005202', ('152', '160'))	('autoAbs', 'Var', (27, 34))	('LOXL2', 'Gene', '4017', (65, 70))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('113', '133'))
21959	32046322	Recently, a genomic mismatch in the LIMS1 gene was identified as a cause of previously unpredictable rejection.	('LIMS1', 'Gene', '3987', (36, 41))	('cause', 'Reg', (67, 72))	('LIMS1', 'Gene', (36, 41))	('rejection', 'Disease', (101, 110))	('genomic mismatch', 'Var', (12, 28))
21967	32046322	Sometimes, diagnosis is difficult because sarcoidosis shares common features with several autoimmune diseases, although typical autoAbs, such as anti-nuclear antibody (ANA) and anti-extractable nuclear antigen antibody (ENA), are usually negative.	('autoimmune disease', 'Phenotype', 'HP:0002960', (90, 108))	('antibody', 'cellular_component', 'GO:0019814', ('158', '166'))	('antibody', 'molecular_function', 'GO:0003823', ('210', '218'))	('sarcoidosis', 'Disease', 'MESH:D012507', (42, 53))	('autoimmune diseases', 'Disease', 'MESH:D001327', (90, 109))	('antibody', 'molecular_function', 'GO:0003823', ('158', '166'))	('antibody', 'cellular_component', 'GO:0042571', ('210', '218'))	('anti-nuclear', 'Var', (145, 157))	('autoimmune diseases', 'Disease', (90, 109))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (90, 109))	('antibody', 'cellular_component', 'GO:0019815', ('210', '218'))	('antibody', 'cellular_component', 'GO:0042571', ('158', '166'))	('sarcoidosis', 'Disease', (42, 53))	('antibody', 'cellular_component', 'GO:0019814', ('210', '218'))	('antibody', 'cellular_component', 'GO:0019815', ('158', '166'))
21973	32046322	Furthermore, a non-synonymous single nucleotide polymorphism (SNP) was reported to be associated with sarcoidosis in 490 German patients in a genome-wide association study (GWAS).	('associated', 'Reg', (86, 96))	('sarcoidosis', 'Disease', (102, 113))	('non-synonymous single nucleotide polymorphism', 'Var', (15, 60))	('patients', 'Species', '9606', (128, 136))	('sarcoidosis', 'Disease', 'MESH:D012507', (102, 113))
22007	32046322	There have been no reports of cases developing aPAP caused by administration of these antibodies as a therapeutic agent for RA, but one report has shown the appearance of foamy macrophages after administering an anti-GM-CSF receptor alpha monoclonal antibody to cynomolgus monkeys.	('RA', 'Disease', 'MESH:D001172', (124, 126))	('antibody', 'molecular_function', 'GO:0003823', ('250', '258'))	('anti-GM-CSF', 'Var', (212, 223))	('antibody', 'cellular_component', 'GO:0042571', ('250', '258'))	('foamy macrophages', 'Phenotype', 'HP:0003651', (171, 188))	('antibody', 'cellular_component', 'GO:0019815', ('250', '258'))	('aPAP', 'Disease', 'MESH:C567049', (47, 51))	('cynomolgus monkeys', 'Species', '9541', (262, 280))	('antibody', 'cellular_component', 'GO:0019814', ('250', '258'))	('aPAP', 'Disease', (47, 51))
22011	32046322	More recently, mutations of the OAS1 gene in humans were revealed to cause genetic PAP.	('PAP', 'Disease', 'MESH:D011649', (83, 86))	('OAS1', 'Gene', (32, 36))	('OAS1', 'Gene', '4938', (32, 36))	('mutations', 'Var', (15, 24))	('PAP', 'Disease', (83, 86))	('PAP', 'molecular_function', 'GO:0043751', ('83', '86'))	('cause', 'Reg', (69, 74))	('humans', 'Species', '9606', (45, 51))
22012	32046322	Furthermore, autoAbs against hematopoietic lineage cell-specific protein (HCLS1), a downstream effector of GM-CSF signaling, were enriched in aPAP patient sera.	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('hematopoietic lineage cell-specific protein', 'Gene', (29, 72))	('sera', 'molecular_function', 'GO:0004617', ('155', '159'))	('aPAP', 'Disease', (142, 146))	('patient', 'Species', '9606', (147, 154))	('aPAP', 'Disease', 'MESH:C567049', (142, 146))	('autoAbs', 'Var', (13, 20))	('hematopoietic lineage cell-specific protein', 'Gene', '3059', (29, 72))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('HCLS1', 'Gene', '3059', (74, 79))	('HCLS1', 'Gene', (74, 79))
22017	32046322	The failure of IL-10 signaling related to mutation in IL-10 receptor was associated with several diseases.	('IL-10', 'molecular_function', 'GO:0005141', ('15', '20'))	('diseases', 'Disease', (97, 105))	('IL-10', 'Gene', (15, 20))	('IL-10', 'molecular_function', 'GO:0005141', ('54', '59'))	('IL-10', 'Gene', (54, 59))	('associated', 'Reg', (73, 83))	('mutation', 'Var', (42, 50))	('IL-10', 'Gene', '3586', (15, 20))	('failure', 'NegReg', (4, 11))	('IL-10', 'Gene', '3586', (54, 59))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))
22018	32046322	Modulation of IL-10 signaling by autoAbs to IL10RB may alter inflammatory responses in the lung of aPAP patients.	('aPAP', 'Disease', (99, 103))	('Modulation', 'Var', (0, 10))	('autoAbs', 'Var', (33, 40))	('IL10RB', 'Gene', (44, 50))	('IL-10', 'Gene', '3586', (14, 19))	('patients', 'Species', '9606', (104, 112))	('inflammatory responses', 'CPA', (61, 83))	('IL-10', 'Gene', (14, 19))	('IL10RB', 'Gene', '3588', (44, 50))	('IL10', 'molecular_function', 'GO:0005141', ('44', '48'))	('IL-10', 'molecular_function', 'GO:0005141', ('14', '19'))	('alter', 'Reg', (55, 60))	('aPAP', 'Disease', 'MESH:C567049', (99, 103))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
22025	32046322	AutoAbs against BMPR2 may modulate aPAP disease course by regulating TGF-beta responses.	('TGF-beta', 'Gene', (69, 77))	('AutoAbs against', 'Var', (0, 15))	('regulating', 'Reg', (58, 68))	('aPAP', 'Disease', (35, 39))	('modulate', 'Reg', (26, 34))	('aPAP', 'Disease', 'MESH:C567049', (35, 39))	('TGF-beta', 'Gene', '7039', (69, 77))	('BMPR2', 'Gene', (16, 21))	('BMPR2', 'Gene', '659', (16, 21))
22029	32046322	Therefore, anti-GM-CSF autoAbs might originate from natural autoantibodies produced under inflammatory conditions by inhalation exposure, and inflammatory conditions caused by anti-GM-CSF autoAb might trigger the secondary autoimmune diseases mediated by the natural autoantibody.	('autoimmune diseases', 'Disease', 'MESH:D001327', (223, 242))	('anti-GM-CSF autoAb', 'Var', (176, 194))	('autoimmune diseases', 'Disease', (223, 242))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (223, 242))	('autoimmune disease', 'Phenotype', 'HP:0002960', (223, 241))	('autoAb', 'Var', (188, 194))	('trigger', 'Reg', (201, 208))
22034	32042433	Primary resistance to osimertinib despite acquired T790M Current National Comprehensive Cancer Network (NCCN) guidelines suggest plasma-based testing (liquid biopsy) for T790M in epidermal growth factor receptor (EGFR)-mutated non-small cell lung carcinoma (NSCLC) with acquired resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs).	('T790M', 'SUBSTITUTION', 'None', (51, 56))	('SCLC', 'Phenotype', 'HP:0030357', (259, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (231, 256))	('EGFR', 'Gene', '1956', (213, 217))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('T790M', 'Mutation', 'rs121434569', (170, 175))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (227, 256))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('non-small cell lung carcinoma', 'Disease', (227, 256))	('SCLC', 'Gene', '7864', (259, 263))	('osimertinib', 'Chemical', 'None', (22, 33))	('SCLC', 'Gene', (259, 263))	('EGFR', 'Gene', (318, 322))	('Cancer', 'Disease', (88, 94))	('T790M', 'Mutation', 'rs121434569', (51, 56))	('NSCLC', 'Disease', (258, 263))	('epidermal growth factor receptor', 'Gene', (179, 211))	('T790M', 'Var', (170, 175))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('179', '202'))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('epidermal growth factor receptor', 'Gene', '1956', (179, 211))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (231, 256))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('Cancer', 'Disease', 'MESH:D009369', (88, 94))	('T790M', 'Var', (51, 56))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (227, 256))	('EGFR', 'Gene', (213, 217))	('EGFR', 'Gene', '1956', (318, 322))	('EGFR', 'molecular_function', 'GO:0005006', ('318', '322'))	('T790M', 'SUBSTITUTION', 'None', (170, 175))	('tyrosine', 'Chemical', 'None', (323, 331))
22035	32042433	We report a rare case of primary resistance to osimertinib, although liquid biopsy revealed EGFR T790M positivity.	('EGFR', 'Gene', (92, 96))	('T790M', 'SUBSTITUTION', 'None', (97, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('T790M', 'Var', (97, 102))
22038	32042433	Osimertinib was initiated when liquid biopsy showed EGFR T790M positivity.	('T790M', 'SUBSTITUTION', 'None', (57, 62))	('EGFR', 'Gene', (52, 56))	('Osimertinib', 'Chemical', 'None', (0, 11))	('T790M', 'Var', (57, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
22041	32042433	Liquid biopsy to diagnose T790M presence in non-small cell lung carcinoma (NSCLC) patients resistant to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) might miss other possible resistance mechanisms.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('104', '127'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('146', '162'))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('T790M', 'SUBSTITUTION', 'None', (26, 31))	('SCLC', 'Phenotype', 'HP:0030357', (76, 80))	('T790M', 'Var', (26, 31))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (48, 73))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (44, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('non-small cell lung carcinoma', 'Disease', (44, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))
22043	32042433	One of the most well-known resistant mechanisms is the acquired EGFR T790M mutation, which accounts for 40-50% of all cases of resistance to first-generation EGFR-TKIs.	('T790M', 'SUBSTITUTION', 'None', (69, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', (64, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))	('T790M', 'Var', (69, 74))
22045	32042433	A test of resistance mutation via liquid biopsy revealed EGFR exon 19 deletion and T790M (mutant allele frequency: 0.21%).	('deletion', 'Var', (70, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('T790M', 'SUBSTITUTION', 'None', (83, 88))	('EGFR', 'Gene', (57, 61))	('T790M', 'Var', (83, 88))
22051	32042433	This report demonstrated the ineffectiveness of osimertinib in a case of lung cancer with liquid biopsy confirmed EGFR ex19del and T790M mutation and later shown to exhibit small cell transformation on biopsy.	('T790M', 'Var', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('EGFR', 'Gene', (114, 118))	('T790M', 'SUBSTITUTION', 'None', (131, 136))
22052	32042433	The AURA trials revealed that only 10% of patients were switched to osimertinib after EGFR T790M detection in liquid biopsy resulted in disease progression 1.	('T790M', 'SUBSTITUTION', 'None', (91, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('T790M', 'Var', (91, 96))	('EGFR', 'Gene', (86, 90))	('disease', 'MPA', (136, 143))
22054	32042433	(allelic fraction >0.06% for T790M) 2, our patient tested positive for T790M (allelic fraction: 0.21%).	('T790M', 'SUBSTITUTION', 'None', (29, 34))	('T790M', 'SUBSTITUTION', 'None', (71, 76))	('T790M', 'Var', (29, 34))	('positive', 'Reg', (58, 66))	('T790M', 'Var', (71, 76))
22057	32042433	All the patients showed low T790M/activating mutation ratio in the blood before osimertinib treatment (lower than 0.03) 5.	('T790M', 'Var', (28, 33))	('low', 'NegReg', (24, 27))	('T790M', 'SUBSTITUTION', 'None', (28, 33))
22059	32042433	However, our patient presented a higher T790M/activating mutation ratio of 0.126.	('T790M', 'SUBSTITUTION', 'None', (40, 45))	('higher', 'PosReg', (33, 39))	('T790M', 'Var', (40, 45))
22061	32042433	Although liquid biopsy is a promising method for the diagnosis of T790M mutation in EGFR-mutated NSCLC after resistance to first-/second-generation EGFR-TKIs, it may miss other possible resistance mechanisms.	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('EGFR-mutated', 'Gene', (84, 96))	('T790M', 'SUBSTITUTION', 'None', (66, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('SCLC', 'Phenotype', 'HP:0030357', (98, 102))	('T790M', 'Var', (66, 71))
22062	32042433	A low T790M/activating mutation ratio may assist clinicians to make decisions regarding tissue re-biopsy; however, the cut-off point of the ratio may need to be assessed in further studies.	('assist', 'Reg', (42, 48))	('T790M', 'Var', (6, 11))	('T790M', 'SUBSTITUTION', 'None', (6, 11))
22091	31921862	For example, overexpression of Drp1 was detected in breast cancer metastatic cells compared to the non-metastatic, whereas silencing of Drp1 or overexpression of Mfn1 resulted in mitochondrial elongation and significantly suppressed the metastatic properties of breast cancer cells.	('suppressed', 'NegReg', (222, 232))	('Mfn1', 'Gene', (162, 166))	('Drp1', 'Gene', (136, 140))	('Drp1', 'Gene', '10059', (31, 35))	('Mfn1', 'Gene', '55669', (162, 166))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('resulted in', 'Reg', (167, 178))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('breast cancer', 'Disease', (52, 65))	('mitochondrial elongation', 'CPA', (179, 203))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('Drp1', 'Gene', (31, 35))	('Drp1', 'Gene', '10059', (136, 140))	('silencing', 'Var', (123, 132))
22101	31921862	Another study has shown that inhibition of mitochondrial fusion may abolish invasion of syntaphilin-depleted prostate adenocarcinoma cells.	('mitochondrial fusion', 'biological_process', 'GO:0008053', ('43', '63'))	('syntaphilin', 'Gene', (88, 99))	('syntaphilin', 'Gene', '9751', (88, 99))	('mitochondrial fusion', 'CPA', (43, 63))	('prostate adenocarcinoma', 'Disease', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('abolish', 'NegReg', (68, 75))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (109, 132))	('inhibition', 'Var', (29, 39))	('invasion', 'CPA', (76, 84))
22104	31921862	Thereby, the silencing of both Mfn1, 2 and syntaphilin abolished mitochondrial trafficking and abrogated the migratory response.	('mitochondrial trafficking', 'CPA', (65, 90))	('Mfn1', 'Gene', (31, 35))	('Mfn1', 'Gene', '55669', (31, 35))	('abolished', 'NegReg', (55, 64))	('rat', 'Species', '10116', (112, 115))	('migratory response', 'CPA', (109, 127))	('syntaphilin', 'Gene', (43, 54))	('abrogated', 'NegReg', (95, 104))	('syntaphilin', 'Gene', '9751', (43, 54))	('silencing', 'Var', (13, 22))
22112	31921862	ROS promote the inactivation of the tumor suppressor PTEN by oxidizing active-site cysteine residues, causing the formation of a disulfide bond, which prevents PTEN from inactivating the PI3K pathway.	('oxidizing', 'MPA', (61, 70))	('PTEN', 'Gene', (53, 57))	('tumor', 'Disease', (36, 41))	('PI3K pathway', 'Pathway', (187, 199))	('inactivation', 'MPA', (16, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PTEN', 'Gene', '5728', (53, 57))	('formation of', 'MPA', (114, 126))	('ROS', 'Var', (0, 3))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('PTEN', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('cysteine', 'Chemical', 'MESH:D003545', (83, 91))	('PTEN', 'Gene', '5728', (160, 164))	('PI3K', 'molecular_function', 'GO:0016303', ('187', '191'))	('disulfide', 'Chemical', 'MESH:D004220', (129, 138))	('disulfide bond', 'MPA', (129, 143))
22113	31921862	Since ROS can inactivate protein tyrosine phosphatases through oxidation of cysteine residues, ROS may have many yet-to-be discovered effects on diverse, mitogen-activated pathways that are normally inhibited by phosphatases.	('oxidation', 'MPA', (63, 72))	('ROS', 'Var', (6, 9))	('inactivate', 'NegReg', (14, 24))	('protein tyrosine phosphatases', 'Enzyme', (25, 54))	('tyrosine', 'Chemical', 'None', (33, 41))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('ROS', 'Var', (95, 98))	('mitogen-activated pathways', 'Pathway', (154, 180))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
22114	31921862	ROS can stimulate the phosphorylation of MAPK and extracellular signal-regulated kinase (ERK), cyclin D1 expression and JUN N-terminal kinase (JNK) activation, all of which are linked to tumor cell survival and growth.	('cyclin', 'molecular_function', 'GO:0016538', ('95', '101'))	('activation', 'PosReg', (148, 158))	('ERK', 'Gene', '5594', (89, 92))	('JUN N-terminal kinase', 'Gene', '5599', (120, 141))	('tumor', 'Disease', (187, 192))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('JNK', 'Gene', (143, 146))	('expression', 'MPA', (105, 115))	('JNK', 'Gene', '5599', (143, 146))	('stimulate', 'PosReg', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('cyclin D1', 'Gene', (95, 104))	('ERK', 'Gene', (89, 92))	('JUN N-terminal kinase', 'Gene', (120, 141))	('extracellular signal-regulated kinase', 'Gene', (50, 87))	('phosphorylation', 'MPA', (22, 37))	('ROS', 'Var', (0, 3))	('extracellular', 'cellular_component', 'GO:0005576', ('50', '63'))	('extracellular signal-regulated kinase', 'Gene', '5594', (50, 87))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cyclin D1', 'Gene', '595', (95, 104))	('MAPK', 'Protein', (41, 45))	('JNK', 'molecular_function', 'GO:0004705', ('143', '146'))
22124	31921862	Importantly, ROS accumulation leads to the stabilization of HIF-1 due to inhibition of the HIF-degrading enzyme prolyl hydroxylase.	('ROS', 'Var', (13, 16))	('stabilization', 'MPA', (43, 56))	('inhibition', 'NegReg', (73, 83))	('HIF-1', 'Gene', '3091', (60, 65))	('prolyl', 'Chemical', 'MESH:C065612', (112, 118))	('prolyl hydroxylase', 'Enzyme', (112, 130))	('HIF-1', 'Gene', (60, 65))
22127	31921862	ROS may affect the activation of TGF-beta downstream effector Smad, while treatment with the ROS scavenger N-acetyl cysteine (NAC) abolishes Smad phosphorylation.	('ROS', 'Var', (0, 3))	('NAC', 'cellular_component', 'GO:0005854', ('126', '129'))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (107, 124))	('affect', 'Reg', (8, 14))	('Smad', 'Protein', (62, 66))	('TGF-beta', 'Gene', '7040', (33, 41))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('NAC', 'Chemical', 'MESH:D000111', (126, 129))	('TGF-beta', 'Gene', (33, 41))	('phosphorylation', 'MPA', (146, 161))	('abolishes', 'NegReg', (131, 140))	('activation', 'MPA', (19, 29))
22134	31921862	In cervical carcinoma SiHa cells depletion of ROS leads to increase of E-cadherin and downregulation of Snail, the main negative regulator of E-cadherin.	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('depletion', 'Var', (33, 42))	('increase', 'PosReg', (59, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cervical carcinoma SiHa', 'Disease', (3, 26))	('Snail', 'Gene', (104, 109))	('downregulation', 'NegReg', (86, 100))	('cervical carcinoma SiHa', 'Disease', 'MESH:D002583', (3, 26))	('cadherin', 'molecular_function', 'GO:0008014', ('144', '152'))	('Snail', 'Gene', '6615', (104, 109))	('ROS', 'Gene', (46, 49))
22141	31921862	Recent data have demonstrated that Nrf2 activation can stimulate cancer cell migration and metastasis and Nrf2 deletion attenuates metastatic potential breast cancer cells suppressing RhoA GTPases activity.	('suppressing', 'NegReg', (172, 183))	('Nrf2', 'Gene', '4780', (35, 39))	('RhoA', 'Gene', '387', (184, 188))	('rat', 'Species', '10116', (24, 27))	('cancer', 'Disease', (65, 71))	('deletion', 'Var', (111, 119))	('cancer', 'Disease', (159, 165))	('rat', 'Species', '10116', (80, 83))	('Nrf2', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('activity', 'MPA', (197, 205))	('Nrf2', 'Gene', (35, 39))	('stimulate', 'PosReg', (55, 64))	('attenuates', 'NegReg', (120, 130))	('activation', 'PosReg', (40, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('RhoA', 'Gene', (184, 188))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('Nrf2', 'Gene', '4780', (106, 110))
22145	31921862	It is known that mtDNA mutations can contribute to tumor initiation and progression.	('mtDNA', 'Gene', (17, 22))	('contribute', 'Reg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor initiation', 'Disease', (51, 67))	('mutations', 'Var', (23, 32))	('mtDNA', 'cellular_component', 'GO:0000262', ('17', '22'))	('progression', 'CPA', (72, 83))	('tumor initiation', 'Disease', 'MESH:D009369', (51, 67))
22146	31921862	Variations in copy number of mtDNA are associated with tumorigenesis and depend on tumor type.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (55, 60))	('mtDNA', 'Gene', (29, 34))	('Variations', 'Var', (0, 10))	('associated', 'Reg', (39, 49))	('mtDNA', 'cellular_component', 'GO:0000262', ('29', '34'))	('copy number', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
22148	31921862	On the other hand, increased copy number of mtDNA was found in prostate, head and neck, and colorectal cancers.	('colorectal cancers', 'Disease', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('copy number', 'Var', (29, 40))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('mtDNA', 'Gene', (44, 49))	('increased', 'PosReg', (19, 28))	('mtDNA', 'cellular_component', 'GO:0000262', ('44', '49'))	('prostate', 'Disease', (63, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('colorectal cancers', 'Disease', 'MESH:D015179', (92, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
22149	31921862	Mutations and variations in mtDNA content might be associated with regulation of the metastatic properties of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('variations', 'Var', (14, 24))	('associated', 'Reg', (51, 61))	('Mutations', 'Var', (0, 9))	('mtDNA content', 'Gene', (28, 41))	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))	('mtDNA', 'cellular_component', 'GO:0000262', ('28', '33'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
22150	31921862	mtDNA mutations are also associated with EMT of cancer cells.	('mtDNA', 'cellular_component', 'GO:0000262', ('0', '5'))	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))	('mtDNA', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
22152	31921862	Conversely, knockdown of mitochondrial transcription factor A (TFAM) leads to a decrease in mtDNA copy number, upregulation of E-cadherin expression, and suppression of cell migration rate in esophageal squamous cell carcinoma.	('mitochondrial transcription factor A', 'Gene', '7019', (25, 61))	('rat', 'Species', '10116', (184, 187))	('TFAM', 'Gene', (63, 67))	('expression', 'MPA', (138, 148))	('mtDNA', 'cellular_component', 'GO:0000262', ('92', '97'))	('mitochondrial transcription factor A', 'Gene', (25, 61))	('upregulation', 'PosReg', (111, 123))	('transcription factor', 'molecular_function', 'GO:0000981', ('39', '59'))	('knockdown', 'Var', (12, 21))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('esophageal squamous cell carcinoma', 'Disease', (192, 226))	('mtDNA', 'Gene', (92, 97))	('cell migration', 'biological_process', 'GO:0016477', ('169', '183'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('mitochondrial transcription', 'biological_process', 'GO:0006390', ('25', '52'))	('TFAM', 'Gene', '7019', (63, 67))	('copy number', 'MPA', (98, 109))	('suppression', 'NegReg', (154, 165))	('rat', 'Species', '10116', (177, 180))	('cell migration rate', 'CPA', (169, 188))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (192, 226))	('E-cadherin', 'Gene', (127, 137))	('E-cadherin', 'Gene', '999', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('decrease', 'NegReg', (80, 88))
22154	31921862	Furthermore, mtDNA mutations contribute to the acquisition of an aggressive phenotype in oncocytic thyroid tumors leading to their bioenergetic crisis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oncocytic thyroid tumors', 'Disease', (89, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (19, 28))	('mtDNA', 'cellular_component', 'GO:0000262', ('13', '18'))	('mtDNA', 'Gene', (13, 18))	('bioenergetic crisis', 'MPA', (131, 150))	('oncocytic thyroid tumors', 'Disease', 'MESH:C535584', (89, 113))
22156	31921862	Thus, oxygen deprivation may provide positive selective pressure for cancer cells carrying damaging mtDNA mutations.	('mtDNA', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('oxygen', 'Chemical', 'MESH:D010100', (6, 12))	('mtDNA', 'cellular_component', 'GO:0000262', ('100', '105'))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
22158	31921862	These data are consistent with the observation that in human mammary epithelial cells (hMECs) a decrease in mtDNA copy number promotes calcineurin-mediated mitochondrial retrograde signaling, which initiates EMT.	('mtDNA', 'Gene', (108, 113))	('calcineurin', 'molecular_function', 'GO:0004723', ('135', '146'))	('promotes', 'PosReg', (126, 134))	('human', 'Species', '9606', (55, 60))	('calcineurin', 'molecular_function', 'GO:0004722', ('135', '146'))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('decrease', 'NegReg', (96, 104))	('EMT', 'biological_process', 'GO:0001837', ('208', '211'))	('mtDNA', 'cellular_component', 'GO:0000262', ('108', '113'))	('copy number', 'Var', (114, 125))
22160	31921862	A recent study has revealed that increased mtDNA copy number may sustain tumor progression and metastasis by upregulating OXPHOS function in cancer cells that rely on mitochondrial OXPHOS.	('upregulating', 'PosReg', (109, 121))	('sustain', 'PosReg', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('OXPHOS', 'biological_process', 'GO:0002082', ('122', '128'))	('OXPHOS', 'biological_process', 'GO:0002082', ('181', '187'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mtDNA', 'cellular_component', 'GO:0000262', ('43', '48'))	('mtDNA', 'Gene', (43, 48))	('increased', 'PosReg', (33, 42))	('metastasis', 'CPA', (95, 105))	('tumor', 'Disease', (73, 78))	('copy number', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('OXPHOS function', 'MPA', (122, 137))	('cancer', 'Disease', (141, 147))
22162	31921862	Summing up, mtDNA mutations and variations of mtDNA copy number are associated with EMT, increased invasiveness and metastasis in different types of cancer.	('cancer', 'Disease', (149, 155))	('associated', 'Reg', (68, 78))	('mtDNA', 'Gene', (46, 51))	('EMT', 'biological_process', 'GO:0001837', ('84', '87'))	('mtDNA', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mtDNA', 'cellular_component', 'GO:0000262', ('12', '17'))	('invasiveness', 'CPA', (99, 111))	('EMT', 'CPA', (84, 87))	('mtDNA', 'cellular_component', 'GO:0000262', ('46', '51'))	('metastasis', 'CPA', (116, 126))	('variations', 'Var', (32, 42))	('increased', 'PosReg', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutations', 'Var', (18, 27))
22190	31921862	Overexpression of Bcl-w is associated with the infiltrative morphotypes of gastric cancer and is overexpressed in patients with lung and breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (137, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('Bcl-w', 'Gene', '599', (18, 23))	('gastric cancer', 'Disease', (75, 89))	('overexpressed', 'PosReg', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (27, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('rat', 'Species', '10116', (53, 56))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('Overexpression', 'Var', (0, 14))	('lung and breast cancers', 'Disease', 'MESH:D001943', (128, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Bcl-w', 'Gene', (18, 23))
22199	31921862	Thus, in human triple-negative breast cancer (TNBC) the lack of Bnip3 results in tumor progression and metastasis via storage of dysfunctional mitochondria and subsequent ROS accumulation; the events that, as was discussed earlier, lead to expression of HIF-inducible genes including metastasis-related angiogenesis genes.	('Bnip3', 'Gene', (64, 69))	('metastasis via storage of dysfunctional mitochondria', 'Disease', 'MESH:D009362', (103, 155))	('storage', 'biological_process', 'GO:0051235', ('118', '125'))	('human', 'Species', '9606', (9, 14))	('angiogenesis', 'biological_process', 'GO:0001525', ('303', '315'))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('lack', 'Var', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('expression', 'MPA', (240, 250))	('breast cancer', 'Disease', (31, 44))	('tumor', 'Disease', (81, 86))	('lead to', 'Reg', (232, 239))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('accumulation', 'PosReg', (175, 187))	('mitochondria', 'cellular_component', 'GO:0005739', ('143', '155'))	('HIF-inducible', 'PosReg', (254, 267))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ROS', 'MPA', (171, 174))	('Bnip3', 'Gene', '664', (64, 69))	('results in', 'Reg', (70, 80))	('metastasis-related angiogenesis genes', 'Gene', (284, 321))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
22200	31921862	Conversely, in melanoma cells Bnip3 silencing reduces the formation of lamellipodia and filopodia as well as cell migration through the downregulation of integrin-associated glycoprotein CD47, Rac1 and Cdc42.	('Rac1', 'Gene', (193, 197))	('rat', 'Species', '10116', (117, 120))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('Cdc42', 'Gene', (202, 207))	('melanoma', 'Disease', (15, 23))	('downregulation', 'NegReg', (136, 150))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('CD47', 'Gene', '961', (187, 191))	('Bnip3', 'Gene', '664', (30, 35))	('Cdc42', 'Gene', '998', (202, 207))	('silencing', 'Var', (36, 45))	('CD47', 'Gene', (187, 191))	('Rac1', 'Gene', '5879', (193, 197))	('cell migration', 'biological_process', 'GO:0016477', ('109', '123'))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('Bnip3', 'Gene', (30, 35))	('reduces', 'NegReg', (46, 53))	('cell migration', 'CPA', (109, 123))
22211	31921862	Methylation of Bim and Bnip3 genes is associated with metastasis and the gene methylation rate is increased among colorectal and pancreatic cancer patients compared to healthy individuals.	('colorectal and pancreatic cancer', 'Disease', 'MESH:D015179', (114, 146))	('gene methylation rate', 'MPA', (73, 94))	('associated', 'Reg', (38, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('Methylation', 'Var', (0, 11))	('Bnip3', 'Gene', '664', (23, 28))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('patients', 'Species', '9606', (147, 155))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('increased', 'PosReg', (98, 107))	('metastasis', 'CPA', (54, 64))	('Bnip3', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Bim', 'Gene', (15, 18))	('Bim', 'Gene', '10018', (15, 18))	('rat', 'Species', '10116', (90, 93))
22235	31921862	Therefore, NCLX tightly regulates mitochondrial Ca2+ level and prevents excessive Ca2+ accumulation in mitochondria that can lead to the increase of the mtROS level and subsequent SOCE suppression via oxidation of redox-sensitive Cys195 of Orai1.	('mitochondria', 'cellular_component', 'GO:0005739', ('103', '115'))	('suppression', 'NegReg', (185, 196))	('mtROS level', 'MPA', (153, 164))	('Cys195', 'Var', (230, 236))	('Orai1', 'Gene', (240, 245))	('increase', 'PosReg', (137, 145))	('NCLX', 'Gene', '80024', (11, 15))	('oxidation', 'Var', (201, 210))	('Ca2+ accumulation', 'MPA', (82, 99))	('Orai1', 'Gene', '84876', (240, 245))	('SOCE', 'biological_process', 'GO:0002115', ('180', '184'))	('NCLX', 'Gene', (11, 15))
22237	31921862	The mutations in BH1 domain of Bcl-2 protein leads to STIM1, Orai1-3, TRPC1 overexpression and SOCE enhancement.	('SOCE', 'CPA', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('Bcl-2', 'Gene', (31, 36))	('Bcl-2', 'Gene', '596', (31, 36))	('Bcl-2', 'molecular_function', 'GO:0015283', ('31', '36'))	('Orai1-3', 'Gene', '84876;80228;93129', (61, 68))	('Orai1-3', 'Gene', (61, 68))	('STIM1', 'Gene', (54, 59))	('SOCE', 'biological_process', 'GO:0002115', ('95', '99'))	('TRPC1', 'Gene', '7220', (70, 75))	('TRPC1', 'Gene', (70, 75))	('mutations', 'Var', (4, 13))	('STIM1', 'Gene', '6786', (54, 59))	('enhancement', 'PosReg', (100, 111))	('overexpression', 'PosReg', (76, 90))
22238	31921862	It has been established, that hyperactive SOCE induced by STIM1 and Orai1 overexpression correlates with increased metastasis in different types of cancer.	('cancer', 'Disease', (148, 154))	('hyperactive', 'Disease', 'MESH:D006948', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('hyperactive', 'Disease', (30, 41))	('metastasis', 'CPA', (115, 125))	('STIM1', 'Gene', '6786', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('SOCE', 'MPA', (42, 46))	('Orai1', 'Gene', (68, 73))	('SOCE', 'biological_process', 'GO:0002115', ('42', '46'))	('Orai1', 'Gene', '84876', (68, 73))	('increased', 'PosReg', (105, 114))	('STIM1', 'Gene', (58, 63))	('overexpression', 'Var', (74, 88))
22245	31921862	Both Bcl-2 and Bcl-XL interact with VDAC1 through BH4 domain; however, Bcl-XL BH4 is more effective than Bcl-2-BH4 in targeting VDAC1 activity.	('VDAC1', 'Gene', (128, 133))	('BH4', 'Var', (78, 81))	('Bcl-XL', 'Gene', '598', (15, 21))	('VDAC1', 'Gene', (36, 41))	('Bcl-XL', 'Gene', (71, 77))	('Bcl-2', 'molecular_function', 'GO:0015283', ('5', '10'))	('VDAC1', 'Gene', '7416', (128, 133))	('Bcl-XL', 'Gene', (15, 21))	('Bcl-2', 'Gene', (105, 110))	('VDAC1', 'Gene', '7416', (36, 41))	('Bcl-2', 'Gene', (5, 10))	('Bcl-2', 'Gene', '596', (105, 110))	('Bcl-2', 'Gene', '596', (5, 10))	('Bcl-2', 'molecular_function', 'GO:0015283', ('105', '110'))	('activity', 'MPA', (134, 142))	('Bcl-XL', 'Gene', '598', (71, 77))
22251	31921862	It has been revealed, that inhibition of ryanodine receptor subtype IP3R3 and subsequent decrease in Ca2+ release results in suppression of the invasion and migration of glioblastoma cell lines and metastasis in glioblastoma mouse model.	('Ca2+ release', 'MPA', (101, 113))	('rat', 'Species', '10116', (160, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('glioblastoma', 'Disease', (212, 224))	('decrease', 'NegReg', (89, 97))	('suppression', 'NegReg', (125, 136))	('IP3R3', 'Gene', (68, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (212, 224))	('mouse', 'Species', '10090', (225, 230))	('ryanodine', 'Chemical', 'MESH:D012433', (41, 50))	('inhibition', 'Var', (27, 37))	('metastasis in', 'CPA', (198, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (212, 224))	('ryanodine receptor', 'molecular_function', 'GO:0005219', ('41', '59'))	('glioblastoma', 'Disease', (170, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (170, 182))
22252	31921862	Overexpression of IP3R3, but not of IP3R1 and IP3R2, leads to stimulation of the migration properties of breast cancer cells sustaining Ca2+ signaling.	('IP3R3', 'Var', (18, 23))	('IP3R1', 'Gene', (36, 41))	('IP3R2', 'Gene', '3709', (46, 51))	('stimulation', 'PosReg', (62, 73))	('rat', 'Species', '10116', (84, 87))	('IP3R2', 'Gene', (46, 51))	('IP3R1', 'Gene', '3708', (36, 41))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('migration properties', 'CPA', (81, 101))	('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))
22258	31921862	Silencing of this uniporter results in decreased mitochondrial Ca2+ level and ROS production, as well as migratory and invasiveness capacities.	('rat', 'Species', '10116', (108, 111))	('ROS production', 'MPA', (78, 92))	('decreased', 'NegReg', (39, 48))	('Silencing', 'Var', (0, 9))	('mitochondrial Ca2+ level', 'MPA', (49, 73))
22259	31921862	MCU gene deletion reduces tumor metastasis in TNBC MDA-MB-231 xenografts via HIF-1-dependent gene expression.	('MCU', 'Gene', (0, 3))	('deletion', 'Var', (9, 17))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('reduces', 'NegReg', (18, 25))	('HIF-1', 'Gene', '3091', (77, 82))	('MCU', 'Gene', '90550', (0, 3))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('HIF-1', 'Gene', (77, 82))	('tumor metastasis', 'Disease', 'MESH:D009362', (26, 42))	('tumor metastasis', 'Disease', (26, 42))
22287	31921862	For example, expression of hexokinase 2 (HK2), the embryonic isoform of hexokinase, the enzyme which defines the start of glycolysis, is associated with increased risk of recurrence, and adverse clinical outcome for breast cancer, pancreatic cancer, and neuroblastoma patients.	('recurrence', 'CPA', (171, 181))	('expression', 'Var', (13, 23))	('HK2', 'Gene', (41, 44))	('neuroblastoma', 'Disease', (254, 267))	('patients', 'Species', '9606', (268, 276))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))	('neuroblastoma', 'Phenotype', 'HP:0003006', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('associated with', 'Reg', (137, 152))	('neuroblastoma', 'Disease', 'MESH:D009447', (254, 267))	('HK2', 'molecular_function', 'GO:0008256', ('41', '44'))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('pancreatic cancer', 'Disease', 'MESH:D010190', (231, 248))	('glycolysis', 'biological_process', 'GO:0006096', ('122', '132'))	('clinical', 'Species', '191496', (195, 203))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('breast cancer', 'Disease', (216, 229))	('pancreatic cancer', 'Disease', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
22297	31921862	Inhibition of glycolysis attenuates cell motility even while mitochondrial ATP synthesis remains intact, and inhibition of mitochondrial respiration reduces cell motility only minimally compared to inhibition of glycolysis.	('attenuates', 'NegReg', (25, 35))	('cell motility', 'biological_process', 'GO:0048870', ('36', '49'))	('cell motility', 'CPA', (157, 170))	('inhibition', 'Var', (109, 119))	('rat', 'Species', '10116', (142, 145))	('respiration', 'biological_process', 'GO:0045333', ('137', '148'))	('Inhibition of glycolysis', 'biological_process', 'GO:0045820', ('0', '24'))	('cell motility', 'biological_process', 'GO:0048870', ('157', '170'))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('198', '222'))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))	('ATP synthesis', 'biological_process', 'GO:0006754', ('75', '88'))	('respiration', 'biological_process', 'GO:0007585', ('137', '148'))	('mitochondrial respiration', 'MPA', (123, 148))	('cell motility', 'CPA', (36, 49))
22300	31921862	In turn, inhibition of glycolysis suppresses the migration properties of prostate cancer cells.	('prostate cancer', 'Disease', (73, 88))	('rat', 'Species', '10116', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('suppresses', 'NegReg', (34, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('9', '33'))	('glycolysis', 'MPA', (23, 33))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('inhibition', 'Var', (9, 19))
22302	31921862	In breast cancer, loss of fructose-1,6-bisphosphatase together with the loss of E-cadherin promotes cancer stem cell (CSC)-like features and cancer cell dissemination by enhancing beta-catenin signaling and the EMT program.	('cadherin', 'molecular_function', 'GO:0008014', ('82', '90'))	('loss', 'Var', (72, 76))	('signaling', 'biological_process', 'GO:0023052', ('193', '202'))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (10, 16))	('promotes', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (141, 147))	('fructose', 'Chemical', 'MESH:D005632', (26, 34))	('EMT program', 'CPA', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('beta-catenin', 'Gene', (180, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('beta-catenin', 'Gene', '1499', (180, 192))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (100, 106))	('enhancing', 'PosReg', (170, 179))	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('loss', 'Var', (18, 22))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('EMT', 'biological_process', 'GO:0001837', ('211', '214'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
22332	31921862	Importantly, a more recent study demonstrated that the use of modified lonidamine is significantly more efficacious in inhibiting mitochondrial bioenergetics in lung cancer cells, leading to suppression of lung cancer progression and metastasis.	('lonidamine', 'Chemical', 'MESH:C016371', (71, 81))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('mitochondrial bioenergetics', 'MPA', (130, 157))	('inhibiting', 'NegReg', (119, 129))	('progression', 'CPA', (218, 229))	('lung cancer', 'Disease', (161, 172))	('suppression of lung cancer', 'Disease', (191, 217))	('rat', 'Species', '10116', (40, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('lonidamine', 'Gene', (71, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('modified', 'Var', (62, 70))	('suppression of lung cancer', 'Disease', 'MESH:D008175', (191, 217))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('metastasis', 'CPA', (234, 244))
22333	31921862	Mitochondrial-lonidamine activates the generation of ROS in lung cancer cells, which leads to the inactivation of the Akt/mTOR/p70S6K signaling pathways and autophagic cell death.	('activates', 'PosReg', (25, 34))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('Akt', 'Gene', (118, 121))	('rat', 'Species', '10116', (43, 46))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('p70S6K', 'Gene', (127, 133))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('p70S6K', 'Gene', '6198', (127, 133))	('autophagic cell death', 'biological_process', 'GO:0048102', ('157', '178'))	('Mitochondrial-lonidamine', 'Var', (0, 24))	('lonidamine', 'Chemical', 'MESH:C016371', (14, 24))	('Akt', 'Gene', '207', (118, 121))	('ROS', 'Protein', (53, 56))	('autophagic cell death', 'CPA', (157, 178))	('inactivation', 'NegReg', (98, 110))
22342	31921862	Furthermore, the treatment with NAC was shown to enhance the metastatic dissemination of human melanoma cells, providing evidence that oxidative stress may, in certain circumstances, stimulate metastasis.	('human', 'Species', '9606', (89, 94))	('NAC', 'Chemical', 'MESH:D000111', (32, 35))	('oxidative stress', 'MPA', (135, 151))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('enhance', 'PosReg', (49, 56))	('melanoma', 'Disease', (95, 103))	('metastasis', 'CPA', (193, 203))	('NAC', 'cellular_component', 'GO:0005854', ('32', '35'))	('NAC', 'Var', (32, 35))	('stimulate', 'PosReg', (183, 192))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
22357	31921862	Furthermore, Ch282-5 provided suppression of colon cancer cell migration, invasion and liver metastasis.	('colon cancer', 'Disease', (45, 57))	('invasion', 'CPA', (74, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('Ch282-5', 'Var', (13, 20))	('suppression', 'NegReg', (30, 41))	('rat', 'Species', '10116', (66, 69))	('liver metastasis', 'CPA', (87, 103))
22359	31921862	Conversely, inhibition of Drp1 in combination with BH3-mimetic treatment significantly enhanced apoptotic response in melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('Drp1', 'Gene', (26, 30))	('inhibition', 'Var', (12, 22))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('apoptotic response', 'CPA', (96, 114))	('enhanced', 'PosReg', (87, 95))	('Drp1', 'Gene', '10059', (26, 30))
22360	31921862	Additionally, inhibition of Drp1 by Mdivi-1 increased the cytotoxic effect of combination treatment with A-1210477 and ABT-263 in different melanoma cell lines.	('Mdivi-1', 'Gene', (36, 43))	('Drp1', 'Gene', '10059', (28, 32))	('combination', 'Interaction', (78, 89))	('cytotoxic effect', 'CPA', (58, 74))	('ABT-263', 'Chemical', 'MESH:C528561', (119, 126))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('Drp1', 'Gene', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('increased', 'PosReg', (44, 53))	('A-1210477', 'Var', (105, 114))	('inhibition', 'NegReg', (14, 24))
22380	31142513	We defined non-synonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8+ and CD4+ T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens.	('CD8', 'Gene', (209, 212))	('upregulation', 'PosReg', (242, 254))	('malignant lesions', 'Disease', (270, 287))	('adaptive immune response', 'biological_process', 'GO:0002250', ('319', '343'))	('CD8', 'Gene', '925', (209, 212))	('malignant lesions', 'Disease', 'MESH:D009369', (270, 287))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD-L1', 'Gene', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', (95, 100))
22385	31142513	Targeted sequencing of AAH lesions identified mutations in several cancer-related genes and clonality between AAH and associated ADC.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('AAH lesions', 'Disease', (23, 34))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', (67, 73))	('AAH', 'Chemical', '-', (23, 26))	('AAH lesions', 'Disease', 'MESH:D001768', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('AAH', 'Chemical', '-', (110, 113))	('ADC', 'Disease', (129, 132))
22386	31142513	As suggested by the clinical efficacy of checkpoint blockade immunotherapies for lung cancer, non-synonymous mutations can yield neoepitopes resulting in immune recognition.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('neoepitopes', 'MPA', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('non-synonymous mutations', 'Var', (94, 118))	('yield', 'Reg', (123, 128))	('resulting in', 'Reg', (141, 153))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('immune recognition', 'MPA', (154, 172))
22390	31142513	We identified progression-associated somatic mutations and oncogenic pathways as well as the association between putative neoantigens and adaptive immune responses in AAH.	('oncogenic', 'CPA', (59, 68))	('mutations', 'Var', (45, 54))	('AAH', 'Chemical', '-', (167, 170))	('adaptive immune responses', 'CPA', (138, 163))	('association', 'Interaction', (93, 104))
22423	31142513	Finally, a pathway was defined to be deregulated by a certain mutated gene group if the corresponding ES was greater or equal to 2 (FDR = 0.03).	('ES', 'Chemical', '-', (102, 104))	('mutated', 'Var', (62, 69))	('deregulated', 'Reg', (37, 48))
22435	31142513	Antibodies used for detection of a single marker per slide included: CD8 (Dako #M7103), CD4 (Cell Marque #104R-16), Granzyme B (Dako #M7236), PD1 (Cell Marque #315M), PD-L1 (Spring Bio M4420), and FOXP3 (Bio SB #BSB676).	('Granzyme B', 'Gene', '100233184', (116, 126))	('Granzyme B', 'Gene', (116, 126))	('CD8', 'Gene', (69, 72))	('CD8', 'Gene', '925', (69, 72))	('Dako #M7236', 'Var', (128, 139))
22443	31142513	Analysis of the mutations in oncogenes and tumor suppressor genes (from the UniProt database) demonstrated that somatic mutations in these genes are found more frequently in ADC than in AAH lesions (Figure 1A).	('found', 'Reg', (149, 154))	('AAH lesions', 'Disease', 'MESH:D001768', (186, 197))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('mutations', 'Var', (120, 129))	('AAH lesions', 'Disease', (186, 197))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('ADC', 'Disease', (174, 177))
22466	31142513	Here, these driver mutations were predominantly found in ADC but rarely in AAH (Supplementary Table S3).	('mutations', 'Var', (19, 28))	('AAH', 'Chemical', '-', (75, 78))	('found', 'Reg', (48, 53))	('ADC', 'Disease', (57, 60))
22467	31142513	Of note, oncogenic KRAS mutations were also found in ADC from 4 patients that were not included in Supplementary Table S3 because these mutations were present in low numbers of reads and our mutation calling algorithm could not classify them as true positives; nonetheless, these mutations produced a positive signal on allele-specific PCR.	('patients', 'Species', '9606', (64, 72))	('mutations', 'Var', (280, 289))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('mutations', 'Var', (24, 33))
22468	31142513	Oncogenic BRAF and KRAS mutations were found only in ADC, but not in AAH lesions from the same patients.	('AAH lesions', 'Disease', 'MESH:D001768', (69, 80))	('patients', 'Species', '9606', (95, 103))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('AAH lesions', 'Disease', (69, 80))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('mutations', 'Var', (24, 33))	('ADC', 'Disease', (53, 56))
22474	31142513	The O-glycan biosynthesis pathway was the only pathway more frequently deregulated by PAMs then by MSMs.	('O-glycan biosynthesis pathway', 'Pathway', (4, 33))	('O-glycan', 'Chemical', '-', (4, 12))	('glycan biosynthesis', 'biological_process', 'GO:0000271', ('6', '25'))	('PAMs', 'Var', (86, 90))
22476	31142513	In Group H, mutations in KRAS, BRAF and EGFR genes were MSMs, whereas PI3KCA and PI3K/AKT pathway components were PAMs.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('AKT', 'Gene', (86, 89))	('KRAS', 'Gene', '3845', (25, 29))	('mutations', 'Var', (12, 21))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('BRAF', 'Gene', '673', (31, 35))	('AKT', 'Gene', '207', (86, 89))	('KRAS', 'Gene', (25, 29))	('BRAF', 'Gene', (31, 35))
22486	31142513	Multiple algorithms were applied to predict binding affinity (IC50) between mutant proteins and patient HLAs based on the Immune Epitope Database recommendations.	('proteins', 'Protein', (83, 91))	('mutant', 'Var', (76, 82))	('patient', 'Species', '9606', (96, 103))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))	('binding', 'Interaction', (44, 51))
22488	31142513	The total number of aggregated putative neoantigens per lesion was highly correlated with the corresponding mutational load (Kendall's tau = 0.9) (Supplementary Table S1).	('mutational load', 'Var', (108, 123))	('tau', 'Gene', '4137', (135, 138))	('tau', 'Gene', (135, 138))
22499	31142513	These groups were not significantly associated with tumor stage (X2 test p = 0.14 for stage I vs. stage II and higher), however, the overall survival was marginally higher in Gr1 compared to Gr2 (log-rank test (LRT) p = 0.063).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('higher', 'PosReg', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Gr1', 'Var', (175, 178))
22501	31142513	Together, these results suggest that modulation of the immune-related pathways, especially at the earliest stages of lung ADC, may have a significant impact on outcomes of lung cancer patients.	('patients', 'Species', '9606', (184, 192))	('immune-related pathways', 'Pathway', (55, 78))	('lung cancer', 'Disease', (172, 183))	('impact', 'Reg', (150, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('modulation', 'Var', (37, 47))	('lung ADC', 'Disease', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
22508	31142513	Analysis of 29 driver genes, frequently mutated in ADC, demonstrated that driver mutations were predominantly found in ADC but rarely in AAH (Supplementary Table S3), suggesting that malignant progression was induced by the driver mutations occurring in some, but not all, premalignant lesions.	('ADC', 'Disease', (119, 122))	('malignant lesions', 'Disease', 'MESH:D009369', (276, 293))	('malignant progression', 'CPA', (183, 204))	('mutations', 'Var', (231, 240))	('induced', 'Reg', (209, 216))	('AAH', 'Chemical', '-', (137, 140))	('malignant lesions', 'Disease', (276, 293))
22511	31142513	Previous studies suggest that passenger mutations can promote malignant progression by modulating the activity of oncogenic or tumor suppressor pathways.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('promote', 'PosReg', (54, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('127', '143'))	('passenger mutations', 'Var', (30, 49))	('tumor', 'Disease', (127, 132))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('127', '143'))	('modulating', 'Reg', (87, 97))	('activity', 'MPA', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('malignant progression', 'CPA', (62, 83))	('oncogenic', 'Pathway', (114, 123))
22513	31142513	Deregulated expression of mucins promotes tumor cell invasion and migration, and increases drug resistance in a variety of malignancies.	('promotes', 'PosReg', (33, 41))	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Disease', (42, 47))	('Deregulated', 'Var', (0, 11))	('migration', 'CPA', (66, 75))	('mucin', 'Gene', (26, 31))	('malignancies', 'Disease', (123, 135))	('drug resistance', 'biological_process', 'GO:0009315', ('91', '106'))	('drug resistance', 'CPA', (91, 106))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('drug resistance', 'Phenotype', 'HP:0020174', (91, 106))	('expression', 'MPA', (12, 22))	('mucin', 'Gene', '100508689', (26, 31))	('drug resistance', 'biological_process', 'GO:0042493', ('91', '106'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('increases', 'PosReg', (81, 90))
22514	31142513	Genetic variation of MUC4 has been associated with increased lung cancer risk, and here we find that PAMs of MUC4 were present in over 90% of patients.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('Genetic variation', 'Var', (0, 17))	('MUC4', 'Gene', (21, 25))	('MUC4', 'Gene', '4585', (109, 113))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('patients', 'Species', '9606', (142, 150))	('MUC4', 'Gene', '4585', (21, 25))	('MUC4', 'Gene', (109, 113))
22515	31142513	These mutations produced a total of 132 PANs in 31 of 41 patients.	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (6, 15))	('PANs', 'Chemical', '-', (40, 44))	('produced', 'Reg', (16, 24))
22516	31142513	Two of the recurring PAN-producing mutations in MUC4 were found in 4 patients, 6 of these were in 3 patients and 18 in 2 patients.	('MUC4', 'Gene', (48, 52))	('PAN', 'cellular_component', 'GO:0022623', ('21', '24'))	('patients', 'Species', '9606', (100, 108))	('mutations', 'Var', (35, 44))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (121, 129))	('MUC4', 'Gene', '4585', (48, 52))	('PAN-producing', 'Reg', (21, 34))
22526	31142513	Consistent with findings in melanoma and colorectal cancer, our analysis of mutations in lung adenocarcinoma indicates that while there are many common driver mutations among tumors from different patients, mutations producing PANs are most often unique to individual patients.	('tumors', 'Disease', (175, 181))	('patients', 'Species', '9606', (197, 205))	('colorectal cancer', 'Disease', (41, 58))	('patients', 'Species', '9606', (268, 276))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('mutations', 'Var', (159, 168))	('mutations', 'Var', (207, 216))	('lung adenocarcinoma', 'Disease', (89, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('PANs', 'Chemical', '-', (227, 231))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (28, 36))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
22530	31142513	The notion that genes bearing somatic mutations often encode tumor specific neoantigens capable of eliciting immunity and tumor rejection was first described in murine models sixty years ago.	('encode', 'Reg', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('murine', 'Species', '10090', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (38, 47))	('immunity', 'CPA', (109, 117))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (61, 66))
22538	31142513	Thus, it has been suggested that unleashing the immune response against pulmonary premalignancy may facilitate a blockade of the progression of premalignancy to invasive cancer at the earliest stages of disease.	('pulmonary premalignancy', 'Disease', (72, 95))	('pulmonary premalignancy', 'Disease', 'MESH:D008171', (72, 95))	('premalignancy to invasive cancer', 'Disease', 'MESH:D009362', (144, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('premalignancy to invasive cancer', 'Disease', (144, 176))	('unleashing', 'Var', (33, 43))	('immune response', 'biological_process', 'GO:0006955', ('48', '63'))
22540	31142513	Findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy.	('association', 'Interaction', (84, 95))	('adaptive immune responses', 'CPA', (133, 158))	('mutations', 'Var', (49, 58))	('adenomatous premalignancy', 'Disease', 'MESH:D011125', (162, 187))	('adenomatous premalignancy', 'Disease', (162, 187))	('oncogenic', 'CPA', (60, 69))
22547	31572680	Lastly, we demonstrated that knockdown of KLK5 and L1CAM increases anlotinib-induced cytotoxicity in anlotinib-resistant NCI-H1975 cells.	('L1CAM', 'Gene', (51, 56))	('knockdown', 'Var', (29, 38))	('anlotinib-induced', 'MPA', (67, 84))	('L1CAM', 'Gene', '3897', (51, 56))	('anlotinib', 'Chemical', 'None', (101, 110))	('KLK5', 'Gene', '25818', (42, 46))	('cytotoxicity', 'Disease', (85, 97))	('increases', 'PosReg', (57, 66))	('anlotinib', 'Chemical', 'None', (67, 76))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('KLK5', 'Gene', (42, 46))
22550	31572680	Genomic features, such as gene amplification, point mutations, gene over-expression, and chromosomal translocation, have been identified as biomarkers in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('gene', 'Var', (63, 67))	('NSCLC', 'Disease', (154, 159))	('chromosomal', 'Disease', (89, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('gene amplification', 'Var', (26, 44))	('over-expression', 'PosReg', (68, 83))	('point mutations', 'Var', (46, 61))
22552	31572680	Precision therapies have dramatically improved progression free survival (PFS) and overall survival (OS) of NSCLC patients whose tumors harbor positive driver gene mutations, such as EGFR (19 Del and L858R), rearranged ROS1, or translocated ALK.	('rearranged', 'Var', (208, 218))	('tumors', 'Disease', (129, 135))	('L858R', 'Mutation', 'p.L858R', (200, 205))	('overall', 'MPA', (83, 90))	('progression', 'MPA', (47, 58))	('ROS1', 'Gene', '6098', (219, 223))	('ALK', 'Gene', '238', (241, 244))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('EGFR', 'Gene', (183, 187))	('ALK', 'Gene', (241, 244))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('patients', 'Species', '9606', (114, 122))	('translocated', 'Var', (228, 240))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('improved', 'PosReg', (38, 46))	('ROS1', 'Gene', (219, 223))	('NSCLC', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('EGFR', 'Gene', '1956', (183, 187))	('L858R', 'Var', (200, 205))
22558	31572680	Moreover, mechanistic studies indicated that anlotinib is actively involved in anti-angiogenesis and may selectively inhibit VEGFR (2/3), PDGFR (alpha/beta), and FGFR (1-4), and other targets.	('anlotinib', 'Chemical', 'None', (45, 54))	('anlotinib', 'Var', (45, 54))	('PDGFR (alpha/beta', 'Gene', '5156;5159', (138, 155))	('VEGFR', 'Gene', '3791', (125, 130))	('FGFR (1-4', 'Gene', '2260;2263;2261;2264', (162, 171))	('anti-angiogenesis', 'CPA', (79, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('angiogenesis', 'biological_process', 'GO:0001525', ('84', '96'))	('inhibit', 'NegReg', (117, 124))	('VEGFR', 'Gene', (125, 130))
22613	31572680	Further analysis suggested that modulation of angiogenesis-related genes (including ANGPTL4, FN1, HSPG2, SRPX2, KLK5, L1CAM, Prr22, FOXJ1, IL24, and TRIM54) potentially contributes to anlotinib resistance (Figures 2D,E, Tables S3, S4), as anlotinib is a multi-targeted anti-angiogenesis drug for cancer therapy.	('KLK5', 'Gene', '25818', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('SRPX2', 'Gene', '27286', (105, 110))	('contributes', 'Reg', (169, 180))	('ANGPTL4', 'Gene', '51129', (84, 91))	('TRIM54', 'Gene', '57159', (149, 155))	('FOXJ1', 'Gene', (132, 137))	('IL24', 'Gene', '11009', (139, 143))	('L1CAM', 'Gene', '3897', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('FN1', 'Gene', '2335', (93, 96))	('angiogenesis', 'biological_process', 'GO:0001525', ('46', '58'))	('IL24', 'Gene', (139, 143))	('SRPX2', 'Gene', (105, 110))	('IL24', 'molecular_function', 'GO:0045520', ('139', '143'))	('FOXJ1', 'Gene', '2302', (132, 137))	('Prr22', 'Gene', '163154', (125, 130))	('HSPG2', 'Gene', (98, 103))	('TRIM54', 'Gene', (149, 155))	('HSPG2', 'Gene', '3339', (98, 103))	('KLK5', 'Gene', (112, 116))	('modulation', 'Var', (32, 42))	('Prr', 'molecular_function', 'GO:0038187', ('125', '128'))	('Prr22', 'Gene', (125, 130))	('FN1', 'Gene', (93, 96))	('anlotinib resistance', 'MPA', (184, 204))	('L1CAM', 'Gene', (118, 123))	('angiogenesis', 'biological_process', 'GO:0001525', ('274', '286'))	('S4', 'Chemical', 'MESH:D013455', (231, 233))	('anlotinib', 'Chemical', 'None', (184, 193))	('anlotinib', 'Chemical', 'None', (239, 248))	('ANGPTL4', 'Gene', (84, 91))	('cancer', 'Disease', (296, 302))
22624	31572680	The NSCLC patients with low levels of serum KLK5 had greater OS benefit from anlotinib treatment [Low (n = 11), Median OS = 315 days vs. High (n = 17), Median PFS = 240 days, P = 0.031] (Figure 4C).	('KLK5', 'Gene', '25818', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('KLK5', 'Gene', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('anlotinib', 'Gene', (77, 86))	('patients', 'Species', '9606', (10, 18))	('low', 'Var', (24, 27))	('anlotinib', 'Chemical', 'None', (77, 86))	('NSCLC', 'Disease', (4, 9))
22628	31572680	When anlotinib was administered, knockdown of KLK5 or L1CAM significantly decreased the cell viabilities of anlotinib-resistant NCI-H1975 cells (Figure 5A).	('KLK5', 'Gene', (46, 50))	('knockdown', 'Var', (33, 42))	('L1CAM', 'Gene', (54, 59))	('anlotinib', 'Chemical', 'None', (108, 117))	('cell viabilities', 'CPA', (88, 104))	('decreased', 'NegReg', (74, 83))	('anlotinib', 'Chemical', 'None', (5, 14))	('L1CAM', 'Gene', '3897', (54, 59))	('KLK5', 'Gene', '25818', (46, 50))
22629	31572680	Meanwhile, anlotinib-induced apoptosis increased significantly, with combined knockdown of KLK5 or L1CAM (Figures 5B,C).	('apoptosis', 'CPA', (29, 38))	('L1CAM', 'Gene', '3897', (99, 104))	('combined', 'Interaction', (69, 77))	('KLK5', 'Gene', '25818', (91, 95))	('knockdown', 'Var', (78, 87))	('anlotinib', 'Chemical', 'None', (11, 20))	('L1CAM', 'Gene', (99, 104))	('KLK5', 'Gene', (91, 95))	('anlotinib-induced', 'Gene', (11, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))
22630	31572680	Consistent with these results, the invasive ability of anlotinib-resistant NCI-H1975 cells decreased remarkably, after anlotinib administration and knockdown of KLK5 or L1CAM were performed simultaneously (Figures 5D,E).	('L1CAM', 'Gene', (169, 174))	('anlotinib', 'Chemical', 'None', (119, 128))	('KLK5', 'Gene', '25818', (161, 165))	('invasive ability', 'CPA', (35, 51))	('anlotinib', 'Chemical', 'None', (55, 64))	('L1CAM', 'Gene', '3897', (169, 174))	('KLK5', 'Gene', (161, 165))	('decreased', 'NegReg', (91, 100))	('knockdown', 'Var', (148, 157))
22631	31572680	These data indicated that anlotinib-induced cytotoxicity was partially recovered in anlotinib-resistant NCI-H1975 cells after KLK5 or L1CAM knockdown.	('cytotoxicity', 'Disease', (44, 56))	('KLK5', 'Gene', '25818', (126, 130))	('L1CAM', 'Gene', (134, 139))	('KLK5', 'Gene', (126, 130))	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('anlotinib-resistant', 'Disease', (84, 103))	('anlotinib', 'Chemical', 'None', (84, 93))	('knockdown', 'Var', (140, 149))	('anlotinib', 'Chemical', 'None', (26, 35))	('L1CAM', 'Gene', '3897', (134, 139))
22632	31572680	Previous studies have demonstrated that anlotinib prolongs PFS and OS in refractory advanced NSCLC patients in clinical trials and indicated that anlotinib may play an important role in anti-angiogenesis and proliferation inhibition.	('NSCLC', 'Disease', (93, 98))	('prolongs', 'PosReg', (50, 58))	('PFS', 'MPA', (59, 62))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('anlotinib', 'Chemical', 'None', (146, 155))	('patients', 'Species', '9606', (99, 107))	('proliferation', 'CPA', (208, 221))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('angiogenesis', 'biological_process', 'GO:0001525', ('191', '203'))	('anlotinib', 'Chemical', 'None', (40, 49))	('anlotinib', 'Var', (40, 49))
22636	31572680	Cancer cells can acquire resistance to the anti-tumor drugs by various mechanisms, including over-expression or mutation of the drug target, activation of pro-survival pathways, and eliminative induction of cell death.	('cell death', 'CPA', (207, 217))	('tumor', 'Disease', (48, 53))	('mutation', 'Var', (112, 120))	('pro-survival pathways', 'Pathway', (155, 176))	('cell death', 'biological_process', 'GO:0008219', ('207', '217'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('pro-survival', 'biological_process', 'GO:0043066', ('155', '167'))	('over-expression', 'PosReg', (93, 108))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('resistance', 'MPA', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('activation', 'PosReg', (141, 151))
22637	31572680	For example, studies have demonstrated the mechanisms of acquired resistance to 1st generation TKIs in NSCLC patients with a positive EGFR mutation, including EGFRT790M mutation, MET amplification, HER-2 mutation, HGF over-expression, etc..	('mutation', 'Var', (204, 212))	('HGF', 'Gene', (214, 217))	('EGFR', 'Gene', '1956', (134, 138))	('EGFR', 'Gene', (134, 138))	('HER-2', 'Gene', '2064', (198, 203))	('MET amplification', 'Var', (179, 196))	('NSCLC', 'Disease', (103, 108))	('EGFR', 'Gene', '1956', (159, 163))	('patients', 'Species', '9606', (109, 117))	('HGF', 'Gene', '3082', (214, 217))	('HER-2', 'Gene', (198, 203))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('EGFRT790M', 'Mutation', 'rs121434569', (159, 168))	('EGFR', 'Gene', (159, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('over-expression', 'PosReg', (218, 233))
22638	31572680	In other words, NSCLC patients are not suitable for 1st generation TKI therapy when primary tumors harbor resistant mutations or over-expression.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (116, 125))	('NSCLC', 'Disease', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('tumors', 'Disease', (92, 98))	('over-expression', 'PosReg', (129, 144))
22654	31572680	Our data indicated that knockdown of KLK5 or L1CAM contributes to increased anlotinib-induced cytotoxicity upon anlotinib-resistant NCI-H1975 cells.	('increased', 'PosReg', (66, 75))	('KLK5', 'Gene', '25818', (37, 41))	('L1CAM', 'Gene', '3897', (45, 50))	('cytotoxicity', 'Disease', 'MESH:D064420', (94, 106))	('KLK5', 'Gene', (37, 41))	('anlotinib', 'Chemical', 'None', (76, 85))	('anlotinib', 'Chemical', 'None', (112, 121))	('knockdown', 'Var', (24, 33))	('anlotinib-induced', 'MPA', (76, 93))	('cytotoxicity', 'Disease', (94, 106))	('L1CAM', 'Gene', (45, 50))
22678	31358938	Furthermore, evidence indicates that targeting CD4+ T cells can significantly increase cancer immunotherapy efficacy, and may induce more durable tumour control than targeting CD8+ T cells.	('CD8', 'Gene', '925', (176, 179))	('cancer', 'Disease', (87, 93))	('tumour', 'Disease', (146, 152))	('induce', 'PosReg', (126, 132))	('CD4+ T', 'Var', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('increase', 'PosReg', (78, 86))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('CD8', 'Gene', (176, 179))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
22679	31358938	The comprehensive monitoring of tumour-reactive CD4+ T cells is hampered by several hurdles, such as tumour antigen selection, HLA class II polymorphism, low frequencies of antigen-specific CD4+ T cells and the plasticity of CD4+ helper T cells.	('tumour', 'Disease', (101, 107))	('tumour', 'Disease', (32, 38))	('low frequencies of antigen-specific CD4+ T', 'Phenotype', 'HP:0005407', (154, 196))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('polymorphism', 'Var', (140, 152))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
22707	31358938	PBMC (2 x 106) were cultured in 24-well plates with TERT-derived class II peptides as above and with the following blocking antibodies: anti-PD-1 (Nivolumab, BMS, Pharmacy unit, University Hospital Besancon), anti-TIM-3 (clone F38-2E2, eBioscience) and anti-PD-L1 (clone MIH1, eBioscience).	('MIH1', 'Gene', (271, 275))	('PD-L1', 'Gene', (258, 263))	('PD-L1', 'Gene', '29126', (258, 263))	('MIH1', 'Gene', '837', (271, 275))	('anti-TIM-3', 'Var', (209, 219))	('anti-PD-1', 'Var', (136, 145))
22733	31358938	3a, patients with an anti-TERT Th1 response had significantly lower rates of circulating PD-1+/TIM-3+ CD4+ T cells than non-responders NSCLC patients.	('rates', 'MPA', (68, 73))	('PD-1+/TIM-3', 'Gene', (89, 100))	('NSCLC', 'Disease', (135, 140))	('lower', 'NegReg', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('PD-1+/TIM-3', 'Gene', '100037293', (89, 100))	('patients', 'Species', '9606', (4, 12))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))	('patients', 'Species', '9606', (141, 149))	('anti-TERT', 'Var', (21, 30))
22734	31358938	Particularly, the association with the presence of anti-TERT Th1 response was more pronounced with TIM-3 expressing CD4 and CD8 T cells (Fig.	('anti-TERT Th1 response', 'MPA', (51, 73))	('CD8', 'Gene', (124, 127))	('CD8', 'Gene', '925', (124, 127))	('TIM-3', 'Gene', (99, 104))	('CD4', 'Var', (116, 119))
22739	31358938	As expected, we showed low expression of the proliferation marker Ki-67 on PD-1+/TIM3+ CD4+ T cells and in PD-1+/TIM3+ CD8+ T cells (Fig.	('low', 'NegReg', (23, 26))	('CD8', 'Gene', (119, 122))	('CD8', 'Gene', '925', (119, 122))	('Ki-67', 'Gene', (66, 71))	('expression', 'MPA', (27, 37))	('PD-1+/TIM3+', 'Var', (75, 86))
22752	31358938	We found that NSCLC patients who exhibited high rates of anti-TERT Th1 cells (anti-TERT Th1high) had better median OS compared with patients with anti-TERT Th1low (not reached versus 12 months, P = 0.009).	('NSCLC', 'Disease', (14, 19))	('anti-TERT Th1 cells', 'Var', (57, 76))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('patients', 'Species', '9606', (20, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('median OS', 'CPA', (108, 117))	('patients', 'Species', '9606', (132, 140))	('better', 'PosReg', (101, 107))
22759	31358938	Although, the rate of T cells expressing the single receptor PD-1 did not affected patients clinical outcome, some trend of a negative association was found with high level of TIM-3+ CD4+ T cells (Supplementary Fig.	('patients', 'Species', '9606', (83, 91))	('negative', 'NegReg', (126, 134))	('TIM-3+ CD4+ T cells', 'Var', (176, 195))
22761	31358938	The best group represents patients with anti-TERT Th1high/exhausted CD4+PD-1+TIM-3+low profile (median OS not reached), the group of patients with anti-TERT Th1low/exhausted CD4+PD-1+TIM-3+high profile had a poor prognosis (median OS = 4 months) and the third group with intermediate survival had a similar evolution of the two immune parameters (high/high or low/low) (Fig.	('CD4+PD-1+TIM-3+high', 'Var', (174, 193))	('CD4+PD-1+TIM-3+low', 'Var', (68, 86))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (26, 34))	('anti-TERT Th1high/exhausted CD4+PD-1+TIM-3+low', 'Var', (40, 86))	('anti-TERT Th1low/exhausted CD4+PD-1+TIM-3+high', 'Var', (147, 193))
22774	31358938	These data support that a pre-existing antitumor CD4+ Th1 signature in peripheral blood may confer tumour protection.	('CD4+ Th1', 'Var', (49, 57))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('pre', 'molecular_function', 'GO:0003904', ('26', '29'))	('tumour', 'Disease', (99, 105))	('antitumor', 'CPA', (39, 48))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
22777	31358938	Indeed, many evidences support that CD4+ Th1 subset orchestrates cell-mediated immunity against cancer cells mainly by enhance tumour-specific CD8+ T-cell functions, survival and migration in the TME.	('enhance', 'PosReg', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('CD8', 'Gene', (143, 146))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('CD8', 'Gene', '925', (143, 146))	('CD4+ Th1', 'Var', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cell-mediated immunity', 'biological_process', 'GO:0002456', ('65', '87'))	('cell-mediated immunity', 'biological_process', 'GO:0002449', ('65', '87'))	('tumour', 'Disease', (127, 133))	('survival', 'CPA', (166, 174))	('migration', 'CPA', (179, 188))	('cancer', 'Disease', (96, 102))	('TME', 'Chemical', '-', (196, 199))
22779	31358938	Furthermore, a clinical benefit associated with Th1-polarised signature in the TME has been reported in many human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('TME', 'Chemical', '-', (79, 82))	('benefit', 'PosReg', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Th1-polarised signature', 'Var', (48, 71))
22786	31358938	To search for factors influencing the presence of a TERT-reactive CD4+ Th1 response in peripheral blood, we found an inverse correlation between the presence of anti-TERT Th1 response and the level of exhausted PD-1+/TIM-3+ T cells, particularly T cells expressing TIM-3.	('anti-TERT Th1 response', 'MPA', (161, 183))	('PD-1+/TIM-3', 'Gene', (211, 222))	('PD-1+/TIM-3', 'Gene', '100037293', (211, 222))	('TIM-3', 'Var', (265, 270))
22788	31358938	Previous reports in lung cancer, showed co-expression of PD-1 and TIM-3 on TIL are associated with poor prognosis.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('co-expression', 'Var', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('TIM-3', 'Gene', (66, 71))	('lung cancer', 'Disease', (20, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('PD-1', 'Gene', (57, 61))
22792	31358938	In a recent investigation using deep single-cell RNA sequencing to analyse the T-cell landscape in lung adenocarcinoma, the authors found that a high ratio of pre-exhausted to exhausted PD-1+TIM-3+ T cells was associated with better prognosis.	('pre', 'molecular_function', 'GO:0003904', ('159', '162'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('PD-1+TIM-3+ T', 'Var', (186, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung adenocarcinoma', 'Disease', (99, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 118))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))
22798	31358938	For example, reactivation of a systemic anti-TERT Th1 response after everolimus treatment improved patient survival in renal cell carcinoma by counterbalancing immune-suppressive Tregs.	('systemic anti-TERT Th1 response', 'MPA', (31, 62))	('patient', 'Species', '9606', (99, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (69, 79))	('improved', 'PosReg', (90, 98))	('renal cell carcinoma', 'Disease', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('reactivation', 'Var', (13, 25))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('patient survival', 'CPA', (99, 115))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (119, 139))
22865	31208279	Kaplan-Meier survival estimate showed that the patients with high miR-25 expression had shorter survival compared with the patients with low miR-25 expression.	('shorter', 'NegReg', (88, 95))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (123, 131))	('miR-25', 'Gene', '407014', (141, 147))	('miR-25', 'Gene', '407014', (66, 72))	('miR-25', 'Gene', (141, 147))	('miR-25', 'Gene', (66, 72))	('survival', 'MPA', (96, 104))
22868	31208279	Furthermore, multivariate Cox proportional hazard regression analysis was performed using all three variables and showed that high miR-25 expression was an unfavorable prognostic factor (p = 0.012; risk ratio 1.84; 95% confidence interval, 0.98-4.14) along with TNM stage (p = 0.043; risk ratio 3.14; 95% confidence interval, 1.42-4.94) (Table 2).	('TNM', 'Gene', '10178', (262, 265))	('high', 'Var', (126, 130))	('expression', 'MPA', (138, 148))	('miR-25', 'Gene', '407014', (131, 137))	('TNM', 'Gene', (262, 265))	('miR-25', 'Gene', (131, 137))
22870	31208279	miR-25 expression was detected by qRT-PCR in H2087, HCC44, Calu-1, H358, H1993 cells, showing that H358 cells have the lowest miR-25 expression, and Calu-1 has the highest miR-25 expression (Figure 2a).	('expression', 'MPA', (133, 143))	('miR-25', 'Gene', '407014', (126, 132))	('Calu-1', 'CellLine', 'CVCL:0608', (59, 65))	('HCC44', 'CellLine', 'CVCL:2060', (52, 57))	('lowest', 'NegReg', (119, 125))	('H2087', 'CellLine', 'CVCL:1524', (45, 50))	('miR-25', 'Gene', '407014', (172, 178))	('miR-25', 'Gene', '407014', (0, 6))	('miR-25', 'Gene', (126, 132))	('H1993', 'CellLine', 'CVCL:1512', (73, 78))	('H358', 'Var', (99, 103))	('miR-25', 'Gene', (172, 178))	('miR-25', 'Gene', (0, 6))	('Calu-1', 'CellLine', 'CVCL:0608', (149, 155))
22876	31208279	And knock-down of miR-25 in Calu-1 cells inhibited invasion compared with the control (Figure 2g).	('Calu-1', 'CellLine', 'CVCL:0608', (28, 34))	('knock-down', 'Var', (4, 14))	('inhibited', 'NegReg', (41, 50))	('invasion', 'CPA', (51, 59))	('miR-25', 'Gene', '407014', (18, 24))	('miR-25', 'Gene', (18, 24))
22877	31208279	However, overexpression of miR-25 in H358 cells and knock-down of miR-25 in Calu-1 cells had no significant effect on cell apoptosis and proliferation (Figure 2h,i).	('cell apoptosis', 'CPA', (118, 132))	('Calu-1', 'CellLine', 'CVCL:0608', (76, 82))	('miR-25', 'Gene', '407014', (27, 33))	('knock-down', 'Var', (52, 62))	('miR-25', 'Gene', '407014', (66, 72))	('miR-25', 'Gene', (27, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('miR-25', 'Gene', (66, 72))	('proliferation', 'CPA', (137, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))
22881	31208279	CDH1 was detected in H2087, HCC44, Calu-1, H358, H1993 cells, showing that H358 cells have the highest miR-25 expression, and Calu-1 has the lowest miR-25 expression (Figure 3a), and there was a strong inverse relationship between miR-25 expression and CDH1 protein level in five NSCLC cell lines (Figure 2a).	('NSCLC', 'Phenotype', 'HP:0030358', (280, 285))	('lowest', 'NegReg', (141, 147))	('CDH1', 'Gene', (253, 257))	('miR-25', 'Gene', '407014', (148, 154))	('miR-25', 'Gene', (103, 109))	('Calu-1', 'CellLine', 'CVCL:0608', (126, 132))	('miR-25', 'Gene', (231, 237))	('H358', 'Var', (75, 79))	('inverse', 'NegReg', (202, 209))	('expression', 'MPA', (238, 248))	('H2087', 'CellLine', 'CVCL:1524', (21, 26))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('protein level', 'MPA', (258, 271))	('miR-25', 'Gene', '407014', (103, 109))	('expression', 'MPA', (110, 120))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))	('miR-25', 'Gene', (148, 154))	('miR-25', 'Gene', '407014', (231, 237))	('HCC44', 'CellLine', 'CVCL:2060', (28, 33))	('CDH1', 'Gene', '999', (0, 4))	('Calu-1', 'CellLine', 'CVCL:0608', (35, 41))	('H1993', 'CellLine', 'CVCL:1512', (49, 54))	('expression', 'MPA', (155, 165))	('NSCLC', 'Disease', (280, 285))	('CDH1', 'Gene', '999', (253, 257))	('CDH1', 'Gene', (0, 4))
22889	31208279	We confirmed above that targeting miR-25 markedly increased migration and invasion of Calu-1 cells, followed by increased CDH1 expression.	('CDH1', 'Gene', '999', (122, 126))	('invasion', 'CPA', (74, 82))	('expression', 'MPA', (127, 137))	('miR-25', 'Gene', '407014', (34, 40))	('increased', 'PosReg', (50, 59))	('targeting', 'Var', (24, 33))	('Calu-1', 'CellLine', 'CVCL:0608', (86, 92))	('miR-25', 'Gene', (34, 40))	('increased', 'PosReg', (112, 121))	('migration', 'CPA', (60, 69))	('CDH1', 'Gene', (122, 126))
22898	31208279	Furthermore, targeting CDH1 abrogated the effect of targeting miR-25 on cell invasion and migration (Figure 4b).	('miR-25', 'Gene', '407014', (62, 68))	('cell invasion', 'CPA', (72, 85))	('CDH1', 'Gene', (23, 27))	('targeting', 'Var', (13, 22))	('miR-25', 'Gene', (62, 68))	('abrogated', 'NegReg', (28, 37))	('CDH1', 'Gene', '999', (23, 27))
22913	31208279	In our study, overexpression of miR-25 in H358 cells and targeting miR-25 in Calu-1 cells had no significant effect on cell apoptosis and proliferation, suggesting that targeting miR-25 inhibited NSCLC cell migration and invasion not via promoting cell apoptosis.	('miR-25', 'Gene', (67, 73))	('targeting', 'Var', (169, 178))	('miR-25', 'Gene', (32, 38))	('NSCLC', 'Disease', (196, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('253', '262'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('miR-25', 'Gene', '407014', (179, 185))	('miR-25', 'Gene', (179, 185))	('Calu-1', 'CellLine', 'CVCL:0608', (77, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('cell migration', 'biological_process', 'GO:0016477', ('202', '216'))	('apoptosis', 'biological_process', 'GO:0097194', ('253', '262'))	('miR-25', 'Gene', '407014', (67, 73))	('inhibited', 'NegReg', (186, 195))	('invasion', 'CPA', (221, 229))	('miR-25', 'Gene', '407014', (32, 38))
22915	31208279	Although targeting miR-25 inhibited A549 and Calu1 invasion in vitro in Ding's study, they did not study whether miR-25 could affect cell apoptosis and proliferation, which is associated with cell invasion.	('miR-25', 'Gene', '407014', (19, 25))	('miR-25', 'Gene', (19, 25))	('inhibited', 'NegReg', (26, 35))	('miR-25', 'Gene', '407014', (113, 119))	('miR-25', 'Gene', (113, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('affect', 'Reg', (126, 132))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('targeting', 'Var', (9, 18))
22920	31208279	It has been proven that loss of expression and/or abnormal function of CDH1 lead to loss of cell polarity and derangement of normal tissue architecture.	('loss of', 'NegReg', (24, 31))	('derangement', 'Reg', (110, 121))	('loss', 'NegReg', (84, 88))	('cell polarity', 'biological_process', 'GO:0007163', ('92', '105'))	('CDH1', 'Gene', (71, 75))	('abnormal', 'Var', (50, 58))	('cell polarity', 'CPA', (92, 105))	('expression', 'MPA', (32, 42))	('CDH1', 'Gene', '999', (71, 75))
22922	31208279	Loss or reduction of CDH1 expression can be caused by a variety of mechanisms, such as somatic mutations, chromosomal deletions, proteolytic cleavage, and silencing of the CDH1 promoter.	('expression', 'MPA', (26, 36))	('CDH1', 'Gene', (172, 176))	('silencing', 'Var', (155, 164))	('reduction', 'NegReg', (8, 17))	('CDH1', 'Gene', '999', (21, 25))	('CDH1', 'Gene', '999', (172, 176))	('Loss', 'NegReg', (0, 4))	('CDH1', 'Gene', (21, 25))
22931	31208279	Overexpression of miR-25 is correlated with lymph node metastasis and poor prognosis.	('miR-25', 'Gene', '407014', (18, 24))	('lymph node metastasis', 'CPA', (44, 65))	('Overexpression', 'Var', (0, 14))	('miR-25', 'Gene', (18, 24))
22979	30453490	Moreover, pristine G increases cell proliferation and causes cells to rearrange the architecture of their cytoskeleton.	('increases', 'PosReg', (21, 30))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('106', '118'))	('rearrange the architecture of their cytoskeleton', 'CPA', (70, 118))	('rat', 'Species', '10116', (43, 46))	('cell proliferation', 'CPA', (31, 49))	('pristine G', 'Var', (10, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))
22982	30453490	Another group reported that exfoliated pristine G caused a significant decrease in the viability of rat alveolar macrophage cells (NR8383), again measured by a WST-1 assay.	('decrease', 'NegReg', (71, 79))	('exfoliated pristine G', 'Var', (28, 49))	('rat', 'Species', '10116', (100, 103))
23032	30453490	Another study demonstrated that rGO-AgNP has great cytotoxic potential in different subpopulations of human ovarian cancer stem cells (OvSCs), especially in ALDH+CD133+ cells, which are characterized by high tumorigenicity.	('ovarian cancer', 'Disease', (108, 122))	('ALDH', 'molecular_function', 'GO:0004030', ('157', '161'))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cytotoxic potential', 'CPA', (51, 70))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('rat', 'Species', '10116', (21, 24))	('rGO-AgNP', 'Var', (32, 40))	('tumor', 'Disease', (208, 213))	('GO', 'Chemical', 'MESH:C000628730', (33, 35))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('human', 'Species', '9606', (102, 107))
23052	30453490	For example, the incorporation of GO into polyvinyl acetate (PVA)-based hydrogels significantly enhanced the tensile strength (132%) and the compressive strength (36%) of composite hydrogel soft solids without affecting the cytotoxicity toward osteoblast cells.	('polyvinyl acetate', 'Chemical', 'MESH:C013215', (42, 59))	('cytotoxicity', 'Disease', 'MESH:D064420', (224, 236))	('incorporation', 'Var', (17, 30))	('GO', 'Chemical', 'MESH:C000628730', (34, 36))	('enhanced', 'PosReg', (96, 104))	('PVA', 'Chemical', 'MESH:C013215', (61, 64))	('compressive strength', 'CPA', (141, 161))	('cytotoxicity', 'Disease', (224, 236))	('tensile strength', 'CPA', (109, 125))	('rat', 'Species', '10116', (24, 27))
23095	30453490	The incorporation of GO into GelMa hydrogels enhanced their mechanical and electrical properties with no adverse effects on encapsulated fibroblast cells, which highlights the potential of the use of GO as a nanofiller in hydrogels for 3D cell culture growth applications and the engineering of functional tissue constructs.	('incorporation', 'Var', (4, 17))	('GO', 'Chemical', 'MESH:C000628730', (21, 23))	('enhanced', 'PosReg', (45, 53))	('GO', 'Chemical', 'MESH:C000628730', (200, 202))	('rat', 'Species', '10116', (11, 14))
23154	30073261	Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib Osimertinib is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor (TKI) resistance mediated by the EGFR T790M mutation.	('T790M', 'Mutation', 'rs121434569', (84, 89))	('EGFR', 'Gene', '1956', (79, 83))	('Osimertinib', 'Chemical', 'MESH:C000603933', (138, 149))	('EGFR', 'Gene', '1956', (188, 192))	('Patients', 'Species', '9606', (65, 73))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('EGFR', 'Gene', '1956', (299, 303))	('non-small cell lung cancer', 'Disease', (200, 226))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('249', '265'))	('T790M', 'Mutation', 'rs121434569', (304, 309))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('NSCLC', 'Disease', (228, 233))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('299', '303'))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('Osimertinib', 'Chemical', 'MESH:C000603933', (150, 161))	('EGFR', 'Gene', (79, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (228, 233))	('Lung Cancer', 'Phenotype', 'HP:0100526', (99, 110))	('T790M', 'Var', (304, 309))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (200, 226))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('EGFR', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('EGFR', 'Gene', (299, 303))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (204, 226))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (200, 226))
23157	30073261	Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR TKI were identified from a multi-institutional cohort and a confirmatory trial cohort (NCT01802632).	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('acquired resistance', 'MPA', (73, 92))	('T790M-positive', 'Var', (58, 72))	('osimertinib', 'Chemical', 'MESH:C000603933', (42, 53))	('NSCLC', 'Disease', (23, 28))	('Patients', 'Species', '9606', (0, 8))	('T790M', 'Mutation', 'rs121434569', (58, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
23161	30073261	Among 13 patients (32%) with maintained T790M at time of resistance, EGFR C797S was seen in 9 (22% of all patients).	('patients', 'Species', '9606', (9, 17))	('EGFR', 'Gene', '1956', (69, 73))	('C797S', 'Var', (74, 79))	('EGFR', 'Gene', (69, 73))	('T790M', 'Mutation', 'rs121434569', (40, 45))	('T790M', 'Var', (40, 45))	('patients', 'Species', '9606', (106, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('C797S', 'Mutation', 'rs1057519861', (74, 79))
23162	30073261	Among 28 (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms like acquired KRAS mutations and targetable gene fusions.	('loss', 'Var', (20, 24))	('KRAS', 'Gene', (133, 137))	('detected', 'Reg', (82, 90))	('T790M', 'Mutation', 'rs121434569', (28, 33))	('KRAS', 'Gene', '3845', (133, 137))	('T790M', 'Var', (28, 33))	('mutations', 'Var', (138, 147))
23163	30073261	TTD was shorter in patients with T790M loss, suggesting emergence of a pre-existing resistant clones; this was confirmed in a validation cohort of 110 patients with plasma cfDNA genotyping performed following osimertinib resistance.	('T790M', 'Mutation', 'rs121434569', (33, 38))	('patients', 'Species', '9606', (19, 27))	('osimertinib', 'Chemical', 'MESH:C000603933', (209, 220))	('TTD', 'MPA', (0, 3))	('patients', 'Species', '9606', (151, 159))	('shorter', 'NegReg', (8, 15))	('T790M loss', 'Var', (33, 43))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
23164	30073261	Studying serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a less dramatic decrease in levels of the EGFR driver mutation after 1-3 weeks of therapy (p=0.01).	('EGFR', 'Gene', (136, 140))	('T790M', 'Mutation', 'rs121434569', (54, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('T790M', 'Var', (54, 59))	('levels', 'MPA', (122, 128))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('decrease', 'NegReg', (110, 118))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('loss of T790M', 'Var', (46, 59))
23165	30073261	Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms.	('osimertinib', 'Chemical', 'MESH:C000603933', (23, 34))	('Acquired resistance', 'MPA', (0, 19))	('early resistance', 'MPA', (93, 109))	('T790M', 'Mutation', 'rs121434569', (59, 64))	('loss', 'NegReg', (47, 51))	('T790M', 'Var', (59, 64))
23167	30073261	Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) targeting mutant epidermal growth factor receptor (EGFR) now available worldwide for the management of non-small cell lung cancer (NSCLC) carrying the EGFR T790M resistance mutation after acquired resistance to prior EGFR TKI therapy.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('43', '59'))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('EGFR', 'molecular_function', 'GO:0005006', ('283', '287'))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('EGFR', 'Gene', (217, 221))	('non-small cell lung cancer', 'Disease', (169, 195))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('EGFR', 'Gene', '1956', (117, 121))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('83', '106'))	('EGFR', 'Gene', '1956', (283, 287))	('NSCLC', 'Disease', (197, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('epidermal growth factor receptor', 'Gene', (83, 115))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (169, 195))	('epidermal growth factor receptor', 'Gene', '1956', (83, 115))	('EGFR', 'Gene', '1956', (217, 221))	('T790M', 'Mutation', 'rs121434569', (222, 227))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (173, 195))	('EGFR', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('T790M resistance', 'Var', (222, 238))	('EGFR', 'Gene', (283, 287))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (169, 195))
23171	30073261	A range of mechanisms of resistance has been described, including EGFR C797S mutations, MET amplification, and small cell transformation.	('C797S', 'Mutation', 'rs1057519861', (71, 76))	('small cell transformation', 'CPA', (111, 136))	('MET', 'CPA', (88, 91))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('C797S', 'Var', (71, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
23174	30073261	We previously used genomic analysis of plasma cell-free DNA (cfDNA) to describe two new resistance mechanisms: acquired EGFR C797S mutations and loss of the T790M mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('C797S', 'Mutation', 'rs1057519861', (125, 130))	('T790M', 'Mutation', 'rs121434569', (157, 162))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('T790M', 'Var', (157, 162))	('EGFR', 'Gene', '1956', (120, 124))	('C797S mutations', 'Var', (125, 140))	('EGFR', 'Gene', (120, 124))
23176	30073261	Patients were included who received single-agent osimertinib for acquired resistance to prior EGFR TKI and were EGFR T790M-positive in either tumor or plasma.	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('EGFR', 'Gene', '1956', (94, 98))	('tumor', 'Disease', (142, 147))	('EGFR', 'Gene', (94, 98))	('T790M-positive', 'Var', (117, 131))	('Patients', 'Species', '9606', (0, 8))	('osimertinib', 'Chemical', 'MESH:C000603933', (49, 60))	('T790M', 'Mutation', 'rs121434569', (117, 122))	('EGFR', 'Gene', '1956', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
23183	30073261	Plasma cfDNA was studied for EGFR driver (L858R and exon 19 del) and resistance mutations (T790M and C797S) using droplet digital PCR (ddPCR) or BEAMing, as previously described.	('C797S', 'Var', (101, 106))	('del', 'Var', (60, 63))	('L858R', 'Var', (42, 47))	('T790M', 'Mutation', 'rs121434569', (91, 96))	('L858R', 'Mutation', 'rs121434568', (42, 47))	('T790M', 'Var', (91, 96))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('C797S', 'Mutation', 'rs1057519861', (101, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))
23184	30073261	Patients with no detectable EGFR driver mutation in resistance plasma were excluded due to no evidence of tumor DNA for analysis.	('mutation', 'Var', (40, 48))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('tumor', 'Disease', (106, 111))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
23190	30073261	Logistic regression modeling was used to estimate the association of time on therapy with the odds of T790M loss at the time of resistance.	('T790M', 'Mutation', 'rs121434569', (102, 107))	('T790M', 'Var', (102, 107))	('loss', 'NegReg', (108, 112))
23196	30073261	Maintained EGFR T790M was detected in 13 patients (32%) while loss of T790M was seen in 28 patients (68%).	('T790M', 'Var', (70, 75))	('patients', 'Species', '9606', (91, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('T790M', 'Mutation', 'rs121434569', (16, 21))	('EGFR', 'Gene', '1956', (11, 15))	('T790M', 'Var', (16, 21))	('EGFR', 'Gene', (11, 15))	('patients', 'Species', '9606', (41, 49))	('T790M', 'Mutation', 'rs121434569', (70, 75))
23197	30073261	EGFR C797S mutations were detected in 9 patients (22% overall; 69% of those with retained T790M), all in cis with a maintained T790M.	('T790M', 'Var', (90, 95))	('EGFR', 'Gene', (0, 4))	('C797S', 'Mutation', 'rs1057519861', (5, 10))	('patients', 'Species', '9606', (40, 48))	('C797S', 'Var', (5, 10))	('T790M', 'Mutation', 'rs121434569', (127, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('T790M', 'Var', (127, 132))	('EGFR', 'Gene', '1956', (0, 4))	('T790M', 'Mutation', 'rs121434569', (90, 95))
23198	30073261	Non-EGFR resistance mechanisms were identified in 19 patients, 17 of them occurring with T790M loss (Figure 1A).	('T790M loss', 'Var', (89, 99))	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', (4, 8))	('T790M', 'Mutation', 'rs121434569', (89, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (4, 8))
23199	30073261	Of the 28 patients with T790M loss, 13 developed resistance mechanisms which are well described after 1st-generation EGFR TKIs: 6 small cell lung cancer transformation, 4 MET amplification, 2 PIK3CA mutations, and 2 BRAF mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('cell lung cancer', 'Disease', (136, 152))	('PIK3CA', 'Gene', (192, 198))	('T790M loss', 'Var', (24, 34))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('resistance mechanisms', 'MPA', (49, 70))	('cell lung cancer', 'Disease', 'MESH:D008175', (136, 152))	('BRAF', 'Gene', '673', (216, 220))	('T790M', 'Mutation', 'rs121434569', (24, 29))	('PIK3CA', 'Gene', '5290', (192, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('BRAF', 'Gene', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (10, 18))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('developed', 'Reg', (39, 48))
23200	30073261	Other patients with T790M loss developed unexpected resistance mechanisms, including RET, FGFR3, and BRAF fusions (1 each).	('BRAF', 'Gene', (101, 105))	('RET', 'Gene', (85, 88))	('resistance mechanisms', 'MPA', (52, 73))	('FGFR3', 'Gene', '2261', (90, 95))	('T790M', 'Mutation', 'rs121434569', (20, 25))	('developed', 'Reg', (31, 40))	('patients', 'Species', '9606', (6, 14))	('RET', 'Gene', '5979', (85, 88))	('BRAF', 'Gene', '673', (101, 105))	('FGFR3', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('T790M loss', 'Var', (20, 30))
23204	30073261	In a patient with acquired EGFR C797S, an initial complete response in plasma was followed by emergence of the T790M plus two EGFR C797S variants (eFigure 1B, top left).	('C797S', 'Mutation', 'rs1057519861', (32, 37))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('patient', 'Species', '9606', (5, 12))	('C797S', 'Var', (32, 37))	('EGFR', 'Gene', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('EGFR', 'Gene', '1956', (126, 130))	('C797S', 'Mutation', 'rs1057519861', (131, 136))	('T790M', 'Mutation', 'rs121434569', (111, 116))	('C797S', 'Var', (131, 136))	('T790M', 'Var', (111, 116))
23205	30073261	Finally, in the patient with an acquired KRAS mutation, a new ddPCR assay was developed to confirm the presence of the KRAS Q61K mutation, which was absent pre-therapy but gradually emerged with resistance (Figure 1B); interestingly, the T790M mutation reemerged in plasma but was not detected on tumor NGS.	('KRAS', 'Gene', '3845', (41, 45))	('T790M', 'Mutation', 'rs121434569', (238, 243))	('pre', 'molecular_function', 'GO:0003904', ('156', '159'))	('T790M', 'Var', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('KRAS', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('KRAS', 'Gene', '3845', (119, 123))	('KRAS', 'Gene', (41, 45))	('tumor', 'Disease', (297, 302))	('patient', 'Species', '9606', (16, 23))	('Q61K', 'Mutation', 'rs121913238', (124, 128))
23206	30073261	In several cases plasma genotyping detected resistance mechanisms not detected on tumor NGS: one patient had a KRAS mutation (G12V) detected on plasma NGS at resistance that was not detected in tumor, one patient with MET amplification detected in tumor had T790M and an ALK rearrangement detected on plasma NGS, and one patient with SCLC on biopsy had T790M and EGFR G724S detected in plasma (eTable 1).	('T790M', 'Mutation', 'rs121434569', (258, 263))	('tumor', 'Disease', (194, 199))	('patient', 'Species', '9606', (97, 104))	('EGFR', 'Gene', '1956', (363, 367))	('tumor', 'Disease', (82, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('363', '367'))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('T790M', 'Mutation', 'rs121434569', (353, 358))	('SCLC', 'Disease', (334, 338))	('T790M', 'Var', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('patient', 'Species', '9606', (205, 212))	('ALK', 'Gene', '238', (271, 274))	('KRAS', 'Gene', '3845', (111, 115))	('ALK', 'Gene', (271, 274))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('T790M', 'Var', (353, 358))	('EGFR', 'Gene', (363, 367))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('patient', 'Species', '9606', (321, 328))	('G724S', 'Mutation', 'rs1051753269', (368, 373))	('KRAS', 'Gene', (111, 115))	('G12V', 'Mutation', 'rs121913529', (126, 130))	('SCLC', 'Disease', 'MESH:D018288', (334, 338))
23207	30073261	Patients developing loss of T790M were clinically similar to patients with maintained T790M aside from a female predominance in those with T790M maintained (eTable 2A).	('T790M', 'Mutation', 'rs121434569', (139, 144))	('loss', 'Var', (20, 24))	('patients', 'Species', '9606', (61, 69))	('Patients', 'Species', '9606', (0, 8))	('T790M', 'Mutation', 'rs121434569', (28, 33))	('T790M', 'Mutation', 'rs121434569', (86, 91))	('T790M', 'Var', (28, 33))
23208	30073261	We then explored the timing of osimertinib resistance, dividing patients based on maintained or lost EGFR T790M mutation in the resistance biopsy.	('patients', 'Species', '9606', (64, 72))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('osimertinib', 'Chemical', 'MESH:C000603933', (31, 42))	('EGFR', 'Gene', (101, 105))	('T790M', 'Mutation', 'rs121434569', (106, 111))	('T790M', 'Var', (106, 111))
23209	30073261	Patients with T790M loss had a median TTD of 6.1 months, shorter than the median TTD of 15.2 months in patients with maintained T790M (Figure 2), and the likelihood of T790M loss was lower for patients with a longer TTD (p = 0.003).	('T790M', 'Mutation', 'rs121434569', (128, 133))	('patients', 'Species', '9606', (193, 201))	('T790M', 'Mutation', 'rs121434569', (168, 173))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (103, 111))	('T790M', 'Var', (168, 173))	('T790M', 'Mutation', 'rs121434569', (14, 19))	('loss', 'NegReg', (20, 24))	('T790M', 'Var', (14, 19))
23210	30073261	In one patient with a prolonged TTD of 23.4 months, NGS of a resistance biopsy showed an exon 19 deletion at a low AF (5%) and no detectable T790M; however, plasma ddPCR detected the driver (47% AF) and both T790M (44% AF) and C797S (28% AF) mutations.	('AF', 'Disease', 'MESH:D001281', (219, 221))	('prolonged TTD', 'Phenotype', 'HP:0001657', (22, 35))	('T790M', 'Mutation', 'rs121434569', (208, 213))	('patient', 'Species', '9606', (7, 14))	('exon', 'Var', (89, 93))	('T790M', 'Var', (208, 213))	('C797S', 'Mutation', 'rs1057519861', (227, 232))	('AF', 'Disease', 'MESH:D001281', (115, 117))	('AF', 'Disease', 'MESH:D001281', (238, 240))	('T790M', 'Mutation', 'rs121434569', (141, 146))	('C797S', 'Var', (227, 232))	('deletion', 'Var', (97, 105))	('AF', 'Disease', 'MESH:D001281', (195, 197))
23211	30073261	To validate our finding of early resistance in patients developing loss of T790M, we performed a retrospective analysis of patients on the AURA trial (Figure 3A).	('T790M', 'Mutation', 'rs121434569', (75, 80))	('patients', 'Species', '9606', (47, 55))	('T790M', 'Var', (75, 80))	('patients', 'Species', '9606', (123, 131))	('loss', 'Var', (67, 71))
23212	30073261	Of 157 patients with plasma available after development of resistance, 110 had a driver EGFR mutation detected in plasma cfDNA and were deemed adequate for resistance analysis.	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('EGFR', 'Gene', '1956', (88, 92))	('mutation', 'Var', (93, 101))	('EGFR', 'Gene', (88, 92))	('patients', 'Species', '9606', (7, 15))
23213	30073261	52 patients (47%) had loss of T790M while 58 patients (53%) maintained the T790M mutation (eTable 2B), and 24 patients (22%) acquired EGFR C797S, all with maintained T790M.	('EGFR', 'Gene', '1956', (134, 138))	('EGFR', 'Gene', (134, 138))	('T790M', 'Mutation', 'rs121434569', (75, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('T790M', 'Var', (75, 80))	('T790M', 'Mutation', 'rs121434569', (30, 35))	('loss', 'NegReg', (22, 26))	('T790M', 'Var', (30, 35))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (45, 53))	('T790M', 'Mutation', 'rs121434569', (166, 171))	('patients', 'Species', '9606', (110, 118))	('C797S', 'Mutation', 'rs1057519861', (139, 144))
23214	30073261	Patients with loss of T790M had a shorter median TTD (5.5 months; Figure 3B) than patients with maintained T790M either without C797S (12.6 months) or with C797S (12.4 months), and odds of T790M loss was lower for patients with a longer TTD (p=0.001).	('loss', 'Var', (14, 18))	('patients', 'Species', '9606', (214, 222))	('C797S', 'Mutation', 'rs1057519861', (156, 161))	('T790M', 'Mutation', 'rs121434569', (22, 27))	('patients', 'Species', '9606', (82, 90))	('shorter', 'NegReg', (34, 41))	('T790M', 'Var', (22, 27))	('Patients', 'Species', '9606', (0, 8))	('T790M', 'Mutation', 'rs121434569', (189, 194))	('T790M', 'Mutation', 'rs121434569', (107, 112))	('T790M', 'Var', (189, 194))	('C797S', 'Mutation', 'rs1057519861', (128, 133))
23215	30073261	Patients with loss of T790M similarly had a shorter PFS.	('T790M', 'Mutation', 'rs121434569', (22, 27))	('T790M', 'Var', (22, 27))	('Patients', 'Species', '9606', (0, 8))	('PFS', 'MPA', (52, 55))	('shorter', 'NegReg', (44, 51))
23216	30073261	Dividing the cohort into tertiles, loss of T790M was seen in 26 of 38 patients (68%) with <=5.5-month TTD while maintained T790M was seen in 26 of 36 patients (72%) with >13-month TTD (Figure 3C).	('patients', 'Species', '9606', (70, 78))	('loss', 'NegReg', (35, 39))	('T790M', 'Mutation', 'rs121434569', (43, 48))	('T790M', 'Mutation', 'rs121434569', (123, 128))	('T790M', 'Var', (43, 48))	('patients', 'Species', '9606', (150, 158))
23221	30073261	Pre-osimertinib NGS for the patient with the BRAF fusion (eFigure 3) after osimertinib showed this fusion prior to therapy, co-existent with a T790M mutation (10% AF).	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('AF', 'Disease', 'MESH:D001281', (47, 49))	('osimertinib', 'Chemical', 'MESH:C000603933', (4, 15))	('AF', 'Disease', 'MESH:D001281', (163, 165))	('T790M', 'Mutation', 'rs121434569', (143, 148))	('patient', 'Species', '9606', (28, 35))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('T790M', 'Var', (143, 148))	('osimertinib', 'Chemical', 'MESH:C000603933', (75, 86))
23222	30073261	Separately, two patients with early osimertinib failure and T790M loss in tumor had T790M detected in plasma but not in tumor prior to osimertinib.	('T790M', 'Mutation', 'rs121434569', (84, 89))	('loss', 'NegReg', (66, 70))	('osimertinib failure', 'Disease', (36, 55))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('T790M', 'Var', (84, 89))	('T790M', 'Mutation', 'rs121434569', (60, 65))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('T790M', 'Var', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('osimertinib failure', 'Disease', 'MESH:D017093', (36, 55))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('osimertinib', 'Chemical', 'MESH:C000603933', (36, 47))	('osimertinib', 'Chemical', 'MESH:C000603933', (135, 146))	('tumor', 'Disease', (120, 125))
23224	30073261	TP53 mutational status was available for all 41 patients with resistance biopsies, and 26 had a pathogenic TP53 mutation or two-copy loss of TP53.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (112, 120))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (107, 111))	('TP53', 'Gene', (141, 145))	('loss', 'NegReg', (133, 137))	('patients', 'Species', '9606', (48, 56))
23225	30073261	While these mutations were more common in patients with T790M loss (71% versus 46%), the difference was not statistically significant (p=0.17).	('common', 'Reg', (32, 38))	('patients', 'Species', '9606', (42, 50))	('T790M loss', 'Var', (56, 66))	('T790M', 'Mutation', 'rs121434569', (56, 61))
23228	30073261	The relative AF of T790M as compared to the EGFR driver was calculated, as described previously, as a potential measure of T790M allelic prevalence.	('T790M', 'Mutation', 'rs121434569', (19, 24))	('AF', 'Disease', 'MESH:D001281', (13, 15))	('T790M', 'Var', (19, 24))	('T790M', 'Mutation', 'rs121434569', (123, 128))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('T790M', 'Var', (123, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
23230	30073261	However, studying this relationship in a dichotomous fashion, patients who develop T790M loss have only a slightly lower relative T790M AF pre-osimertinib (29% vs 38% median, p=0.06, Figure 4B).	('osimertinib', 'Chemical', 'MESH:C000603933', (143, 154))	('T790M', 'Mutation', 'rs121434569', (130, 135))	('loss', 'NegReg', (89, 93))	('pre', 'molecular_function', 'GO:0003904', ('139', '142'))	('T790M', 'Var', (130, 135))	('lower', 'NegReg', (115, 120))	('T790M', 'Mutation', 'rs121434569', (83, 88))	('patients', 'Species', '9606', (62, 70))	('AF', 'Disease', 'MESH:D001281', (136, 138))	('T790M', 'Var', (83, 88))
23231	30073261	Generation of a receiver operating curve (eFigure 4) reveals an AUC of 0.66, suggesting poor performance as a diagnostic test for predicting loss of T790M.	('T790M', 'Var', (149, 154))	('loss', 'Var', (141, 145))	('T790M', 'Mutation', 'rs121434569', (149, 154))
23234	30073261	Studying the relative change in plasma EGFR mutation concentration after 1-3 weeks on osimertinib, a dramatic decrease in plasma T790M levels (DeltaT790M) was seen both in patients with maintained T790M and T790M loss (median 100% decrease for both; Figure 4C).	('DeltaT790M', 'Mutation', 'c.790delT,M', (143, 153))	('T790M', 'Mutation', 'rs121434569', (129, 134))	('mutation', 'Var', (44, 52))	('T790M', 'Mutation', 'rs121434569', (207, 212))	('T790M', 'Mutation', 'rs121434569', (197, 202))	('T790M', 'Var', (207, 212))	('T790M', 'Var', (197, 202))	('plasma T790M levels', 'MPA', (122, 141))	('osimertinib', 'Chemical', 'MESH:C000603933', (86, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('decrease', 'NegReg', (110, 118))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('patients', 'Species', '9606', (172, 180))	('loss', 'NegReg', (213, 217))	('T790M', 'Mutation', 'rs121434569', (148, 153))
23235	30073261	Studying instead the relative change in EGFR driver levels (DeltaDriver), a larger decrease was seen for patients with maintained T790M versus those who lost T790M (median 100% decrease versus 83% decrease, p=0.01).	('decrease', 'NegReg', (177, 185))	('patients', 'Species', '9606', (105, 113))	('T790M', 'Mutation', 'rs121434569', (130, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('T790M', 'Var', (130, 135))	('EGFR', 'Gene', '1956', (40, 44))	('decrease', 'NegReg', (83, 91))	('EGFR', 'Gene', (40, 44))	('T790M', 'Mutation', 'rs121434569', (158, 163))
23236	30073261	We then studied the differential plasma response between the EGFR driver and T790M (DeltaDriver - DeltaT790M), and found this difference was significantly different comparing patients that went on to have T790M loss or T790M maintained at resistance (p=0.003; Figure 4D).	('T790M', 'Mutation', 'rs121434569', (205, 210))	('T790M', 'Mutation', 'rs121434569', (77, 82))	('T790M', 'Var', (205, 210))	('loss', 'NegReg', (211, 215))	('T790M', 'Mutation', 'rs121434569', (219, 224))	('DeltaT790M', 'Mutation', 'c.790delT,M', (98, 108))	('T790M', 'Mutation', 'rs121434569', (103, 108))	('patients', 'Species', '9606', (175, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('T790M', 'Var', (219, 224))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
23237	30073261	Eight of nine patients with a greater decrease in T790M than in driver EGFR mutation (DeltaDriver - DeltaT790M >1%) went on to develop loss of T790M at resistance.	('DeltaT790M', 'Mutation', 'c.790delT,M', (100, 110))	('T790M', 'Mutation', 'rs121434569', (105, 110))	('T790M', 'Mutation', 'rs121434569', (50, 55))	('loss', 'NegReg', (135, 139))	('T790M', 'Var', (50, 55))	('decrease', 'NegReg', (38, 46))	('T790M', 'Mutation', 'rs121434569', (143, 148))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', (71, 75))	('T790M', 'Var', (143, 148))
23240	30073261	Our data provide striking clinical evidence of the impact of heterogeneity on treatment outcomes with osimertinib and suggest there may be two types of T790M-positive resistance.	('T790M', 'Mutation', 'rs121434569', (152, 157))	('osimertinib', 'Gene', (102, 113))	('T790M-positive', 'Var', (152, 166))	('osimertinib', 'Chemical', 'MESH:C000603933', (102, 113))
23242	30073261	In patients with heterogeneous mechanisms of resistance, T790M-mutant subclones coexist with subclones harboring distinct resistance mechanisms; targeting T790M alone is likely to result in transient benefit.	('T790M', 'Var', (155, 160))	('T790M', 'Mutation', 'rs121434569', (57, 62))	('T790M-mutant', 'Var', (57, 69))	('patients', 'Species', '9606', (3, 11))	('T790M', 'Mutation', 'rs121434569', (155, 160))
23244	30073261	Some prior studies have found that quantification of the relative T790M AF is associated with degree of response to third-generation EGFR TKIs, though this relationship has not been consistent across published reports.	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('AF', 'Disease', 'MESH:D001281', (72, 74))	('EGFR', 'Gene', '1956', (133, 137))	('T790M', 'Mutation', 'rs121434569', (66, 71))	('response', 'MPA', (104, 112))	('EGFR', 'Gene', (133, 137))	('T790M', 'Var', (66, 71))
23245	30073261	In our analysis we studied whether such a calculation of relative T790M AF in plasma could predict for subsequent loss of T790M, and our data did not reveal a clear predictive ability.	('loss', 'NegReg', (114, 118))	('AF', 'Disease', 'MESH:D001281', (72, 74))	('T790M', 'Mutation', 'rs121434569', (122, 127))	('T790M', 'Var', (122, 127))	('T790M', 'Mutation', 'rs121434569', (66, 71))	('T790M', 'Var', (66, 71))
23248	30073261	The finding of multiple resistance mechanisms has been described previously - Yu et al identified multiple resistance mutations in 4% of 155 subjects with EGFR-mutant lung cancer and acquired resistance.	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('EGFR', 'Gene', '1956', (155, 159))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('mutations', 'Var', (118, 127))	('EGFR', 'Gene', (155, 159))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))
23251	30073261	T790M loss is a potentially confusing clinical state which could be misinterpreted as resensitization to first-line EGFR TKIs.	('loss', 'NegReg', (6, 10))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('T790M', 'Var', (0, 5))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
23252	30073261	Our data do not support this hypothesis - most of the time, loss of T790M is associated with development of alternate competing resistance mechanisms (Figure 5).	('T790M', 'Mutation', 'rs121434569', (68, 73))	('loss', 'Var', (60, 64))	('T790M', 'Var', (68, 73))
23254	30073261	However, we also have identified a novel finding of an acquired KRAS mutation, which was confirmed using tumor NGS and plasma ddPCR.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('KRAS', 'Gene', (64, 68))	('mutation', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('KRAS', 'Gene', '3845', (64, 68))	('tumor', 'Disease', (105, 110))
23255	30073261	The complex variety of resistance mutations seen in patients with loss of T790M, including several acquired fusion genes, highlights the need for better strategies to prevent or delay the emergence of resistance.	('T790M', 'Var', (74, 79))	('T790M', 'Mutation', 'rs121434569', (74, 79))	('patients', 'Species', '9606', (52, 60))	('loss', 'Var', (66, 70))
23256	30073261	Because loss of T790M is associated with early resistance, this phenomenon could be more evident in usual clinical care than prospective cohorts would suggest - indeed it was seen in 68% of patients in our post-hoc institutional cohort, but 47% of patients in the prospective AURA cohort (p = 0.03).	('T790M', 'Mutation', 'rs121434569', (16, 21))	('patients', 'Species', '9606', (190, 198))	('T790M', 'Var', (16, 21))	('loss', 'Var', (8, 12))	('patients', 'Species', '9606', (248, 256))	('early resistance', 'MPA', (41, 57))
23259	30073261	Patients who develop early resistance to osimertinib likely have competing resistance mechanisms in other tumor subclones, while patients who develop late resistance are more likely to have maintained T790M and acquired C797S - different targeted therapies could be considered for these biologically differing populations.	('T790M', 'Mutation', 'rs121434569', (201, 206))	('T790M', 'Var', (201, 206))	('patients', 'Species', '9606', (129, 137))	('C797S -', 'Var', (220, 227))	('osimertinib', 'Chemical', 'MESH:C000603933', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('C797S', 'Mutation', 'rs1057519861', (220, 225))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
23266	30073261	Interestingly, loss of T790M was more common in our institutional cohort as compared to the trial cohort - we suspect this is because a retrospective institutional cohort will enrich for patients presenting with early resistance, which is more often loss of T790M.	('patients', 'Species', '9606', (187, 195))	('T790M', 'Mutation', 'rs121434569', (23, 28))	('T790M', 'Var', (23, 28))	('loss', 'Var', (15, 19))	('T790M', 'Mutation', 'rs121434569', (258, 263))	('T790M', 'Var', (258, 263))	('loss', 'Var', (250, 254))
23267	30073261	Even the trial cohort may be falsely enriched for T790M loss because patients who are still on therapy without resistance may be enriched for C797S, which is seen more in late resistance.	('loss', 'NegReg', (56, 60))	('T790M', 'Mutation', 'rs121434569', (50, 55))	('T790M', 'Var', (50, 55))	('patients', 'Species', '9606', (69, 77))	('C797S', 'Mutation', 'rs1057519861', (142, 147))	('C797S', 'Var', (142, 147))
23268	30073261	The development of therapies targeting the EGFR C797S resistance mutation will need to consider possibility that this will be a late resistance mechanism on osimertinib, and extra time may be needed to identify these patients.	('C797S', 'Var', (48, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('osimertinib', 'Chemical', 'MESH:C000603933', (157, 168))	('EGFR', 'Gene', '1956', (43, 47))	('C797S', 'Mutation', 'rs1057519861', (48, 53))	('patients', 'Species', '9606', (217, 225))	('EGFR', 'Gene', (43, 47))
23269	30073261	In conclusion, our data indicate that EGFR T790M is a key biomarker not only for predicting osimertinib sensitivity, but also for understanding the biology of osimertinib resistance.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', (38, 42))	('T790M', 'Mutation', 'rs121434569', (43, 48))	('osimertinib', 'Chemical', 'MESH:C000603933', (159, 170))	('T790M', 'Var', (43, 48))	('osimertinib', 'Chemical', 'MESH:C000603933', (92, 103))
23270	30073261	Retesting for T790M after osimertinib failure is an important step for guiding patients to appropriate subsequent treatment strategies and relevant clinical trials.	('osimertinib failure', 'Disease', (26, 45))	('T790M', 'Mutation', 'rs121434569', (14, 19))	('osimertinib failure', 'Disease', 'MESH:D017093', (26, 45))	('patients', 'Species', '9606', (79, 87))	('T790M', 'Var', (14, 19))
23274	30073261	Findings: Loss of the EGFR T790M mutation is common upon resistance to osimertinib, and is associated with early treatment failure and development of a range of competing resistance mechanisms, some expected (MET amplification, small cell transformation) and some novel (acquired KRAS mutations, targetable gene fusions).	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('KRAS', 'Gene', (280, 284))	('KRAS', 'Gene', '3845', (280, 284))	('T790M', 'Mutation', 'rs121434569', (27, 32))	('Loss', 'NegReg', (10, 14))	('treatment failure', 'Disease', (113, 130))	('osimertinib', 'Chemical', 'MESH:C000603933', (71, 82))	('EGFR', 'Gene', '1956', (22, 26))	('treatment failure', 'Disease', 'MESH:D016609', (113, 130))	('T790M', 'Var', (27, 32))	('EGFR', 'Gene', (22, 26))	('associated', 'Reg', (91, 101))
23287	30112033	In the past decade, tyrosine-kinase inhibitors, immunotherapy and chemotherapy have been the primary treatments for lung cancer, resulting in a median progression-free survival time of ~6 months and a response rate of ~30%, which appears to have reached a plateau of effectiveness in improving survival.	('progression-free survival', 'CPA', (151, 176))	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('tyrosine-kinase', 'Var', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))
23329	30112033	The degree of Akt phosphorylation at Thr308 was significantly inhibited in the matrine-treated cells compared with in the control groups, whereas no significant change was observed in the total Akt levels.	('Akt', 'Gene', (14, 17))	('Akt', 'Gene', '207', (194, 197))	('matrine', 'Chemical', 'MESH:C034244', (79, 86))	('Thr308', 'Var', (37, 43))	('Akt', 'Gene', (194, 197))	('inhibited', 'NegReg', (62, 71))	('Thr308', 'Chemical', '-', (37, 43))	('Akt', 'Gene', '207', (14, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
23340	30112033	In the present study, the effect of matrine on the migration and invasion of lung cancer cells was evaluated using Transwell assays, and it was demonstrated that matrine could markedly inhibit cell mobility, as well as migration and invasion.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('matrine', 'Var', (162, 169))	('matrine', 'Chemical', 'MESH:C034244', (162, 169))	('matrine', 'Chemical', 'MESH:C034244', (36, 43))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('invasion', 'CPA', (233, 241))	('inhibit', 'NegReg', (185, 192))	('cell mobility', 'CPA', (193, 206))	('lung cancer', 'Disease', (77, 88))
23346	30112033	Deregulation of the Akt/GSK-3beta signaling pathways has been implicated in the initiation and progression of various human malignancies.	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('Deregulation', 'Var', (0, 12))	('malignancies', 'Disease', 'MESH:D009369', (124, 136))	('Akt', 'Gene', '207', (20, 23))	('malignancies', 'Disease', (124, 136))	('human', 'Species', '9606', (118, 123))	('implicated', 'Reg', (62, 72))	('Akt', 'Gene', (20, 23))	('GSK-3beta', 'Gene', '2932', (24, 33))	('GSK-3beta', 'Gene', (24, 33))
23350	30112033	In addition, a recent study demonstrated that matrine also modulates the Wnt/beta-catenin self-renewal pathway, further resulting in the increased phosphorylation of beta-catenin (Ser33/Ser37/Thr41), and that decreasing beta-catenin levels, as well as its target gene Cyclin D1, ultimately suppressed cancer proliferation.	('Thr41', 'Chemical', '-', (192, 197))	('beta-catenin', 'Gene', (166, 178))	('cancer', 'Disease', (301, 307))	('Ser', 'cellular_component', 'GO:0005790', ('180', '183'))	('Ser', 'cellular_component', 'GO:0005790', ('186', '189'))	('beta-catenin', 'Gene', '1499', (166, 178))	('increased', 'PosReg', (137, 146))	('Ser33', 'Chemical', '-', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('Cyclin D1', 'Gene', '595', (268, 277))	('beta-catenin', 'Gene', (220, 232))	('Cyclin D1', 'Gene', (268, 277))	('Cyclin', 'molecular_function', 'GO:0016538', ('268', '274'))	('modulates', 'Reg', (59, 68))	('beta-catenin', 'Gene', '1499', (220, 232))	('Ser37', 'Chemical', '-', (186, 191))	('Ser33/Ser37/Thr41', 'Var', (180, 197))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))	('suppressed', 'NegReg', (290, 300))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('phosphorylation', 'MPA', (147, 162))	('matrine', 'Chemical', 'MESH:C034244', (46, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))
23351	30112033	In the present study, the effects of matrine on non-epidermal growth factor receptor (EGFR) mutant A549 and H1299 cell lines originated from epithelial and mesenchymal lung adenocarcinomas was investigated, and it was observed that matrine was able to inhibit the Akt pathway and subsequent GSK-3beta activation, in order to ultimately inhibit proliferation and induce apoptosis in lung cancer cells.	('non-epidermal growth factor receptor', 'Gene', '1956', (48, 84))	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('mesenchymal lung adenocarcinomas', 'Disease', (156, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('GSK-3beta', 'Gene', (291, 300))	('matrine', 'Chemical', 'MESH:C034244', (37, 44))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('52', '75'))	('mesenchymal lung adenocarcinomas', 'Disease', 'MESH:D000077192', (156, 188))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (168, 188))	('inhibit', 'NegReg', (252, 259))	('EGFR', 'Gene', '1956', (86, 90))	('matrine', 'Chemical', 'MESH:C034244', (232, 239))	('lung cancer', 'Disease', 'MESH:D008175', (382, 393))	('apoptosis', 'biological_process', 'GO:0097194', ('369', '378'))	('apoptosis', 'biological_process', 'GO:0006915', ('369', '378'))	('lung cancer', 'Phenotype', 'HP:0100526', (382, 393))	('apoptosis', 'CPA', (369, 378))	('non-epidermal growth factor receptor', 'Gene', (48, 84))	('H1299', 'CellLine', 'CVCL:0060', (108, 113))	('activation', 'PosReg', (301, 311))	('GSK', 'molecular_function', 'GO:0050321', ('291', '294'))	('mutant', 'Var', (92, 98))	('Akt', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('proliferation', 'CPA', (344, 357))	('EGFR', 'Gene', (86, 90))	('induce', 'Reg', (362, 368))	('inhibit', 'NegReg', (336, 343))	('GSK-3beta', 'Gene', '2932', (291, 300))	('Akt', 'Gene', '207', (264, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung cancer', 'Disease', (382, 393))
23391	30013345	The cyclic arginine-glycine-aspartic acid-tyrosine-lysine c(RGDyK)-conjugated poly(trimethylene carbonate)-PEG micellar nanoparticle delivering paclitaxel was shown to enhance cytotoxic activity of the drug to integrin alphavbeta3-overexpressing human glioblastoma cells (U87MG) compared with non-targeted nanoparticles and free drugs (mean IC50: 0.022 microg/mL, 0.051 microg/mL, and 0.058 microg/mL, respectively).	('enhance', 'PosReg', (168, 175))	('glioblastoma', 'Disease', (252, 264))	('integrin alphavbeta3', 'Gene', '3685', (210, 230))	('PEG', 'Chemical', 'MESH:D011092', (107, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (252, 264))	('carbon', 'Chemical', 'MESH:D002244', (96, 102))	('mice', 'Species', '10090', (111, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (252, 264))	('aspartic acid', 'Chemical', 'MESH:D001224', (28, 41))	('human', 'Species', '9606', (246, 251))	('cyclic', 'Var', (4, 10))	('integrin alphavbeta3', 'Gene', (210, 230))	('U87MG', 'CellLine', 'CVCL:0022', (272, 277))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('arginine-glycine', 'Chemical', '-', (11, 27))	('cytotoxic activity', 'CPA', (176, 194))
23392	30013345	In addition, cellular drug uptake by U87MG cells was significantly increased.	('U87MG', 'CellLine', 'CVCL:0022', (37, 42))	('uptake', 'biological_process', 'GO:0098657', ('27', '33'))	('uptake', 'biological_process', 'GO:0098739', ('27', '33'))	('U87MG', 'Var', (37, 42))	('cellular drug uptake', 'CPA', (13, 33))	('increased', 'PosReg', (67, 76))
23403	30013345	Therefore, inhibition of the function of this receptor would be expected to benefit cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('benefit', 'PosReg', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('inhibition', 'Var', (11, 21))
23404	30013345	The NR7 peptide-conjugated PLGA-PEG nanoparticles exhibited higher cytotoxic activity against human ovarian carcinoma cells (SKOV3) compared with non-targeted nanoparticles (mean IC50: 0.05 microg/mL and 3.12 microg/mL, respectively).	('ovarian carcinoma', 'Disease', (100, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('higher', 'PosReg', (60, 66))	('PEG', 'Chemical', 'MESH:D011092', (32, 35))	('cytotoxic activity', 'CPA', (67, 85))	('human', 'Species', '9606', (94, 99))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (100, 117))	('NR7', 'Var', (4, 7))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (100, 117))	('SKOV3', 'CellLine', 'CVCL:0532', (125, 130))
23413	30013345	The HA-conjugated chitosan nanoparticle delivering cisplatin was shown to increase drug cellular uptake by CD44-positive human lung cancer cells (A549) and effectively enhance cytotoxic activity of the drug, compared with non-targeted nanoparticles.	('lung cancer', 'Disease', (127, 138))	('enhance', 'PosReg', (168, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('increase', 'PosReg', (74, 82))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('drug cellular uptake', 'CPA', (83, 103))	('chitosan', 'Chemical', 'MESH:D048271', (18, 26))	('human', 'Species', '9606', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('uptake', 'biological_process', 'GO:0098657', ('97', '103'))	('CD44', 'Gene', '960', (107, 111))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('cytotoxic activity', 'CPA', (176, 194))	('uptake', 'biological_process', 'GO:0098739', ('97', '103'))	('HA-conjugated', 'Var', (4, 17))	('CD44', 'Gene', (107, 111))
23439	30013345	For instance, nucleolin receptor is specific for AS14111 aptamer and EpCAM protein is specific for EpCAM aptamer.	('EpCAM', 'Gene', (69, 74))	('EpCAM', 'Gene', '4072', (99, 104))	('EpCAM', 'Gene', '4072', (69, 74))	('nucleolin', 'Gene', (14, 23))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('AS14111', 'Var', (49, 56))	('AS14111', 'Chemical', '-', (49, 56))	('EpCAM', 'Gene', (99, 104))	('nucleolin', 'Gene', '4691', (14, 23))
23440	30013345	The aptamer AS14111-conjugated PEG-PLGA nanoparticle delivering gemcitabine to target nucleolin receptor was shown to increase drug cellular uptake (36%) by nucleolin-overexpressing human lung cancer cells (A549) compared with non-targeted nanoparticles, with enhanced cytotoxic activity (IC50: 4.9 microg/mL and 28.9 microg/mL, respectively).	('increase', 'PosReg', (118, 126))	('nucleolin', 'Gene', (157, 166))	('drug cellular uptake', 'CPA', (127, 147))	('A549', 'CellLine', 'CVCL:0023', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('nucleolin', 'Gene', (86, 95))	('PEG', 'Chemical', 'MESH:D011092', (31, 34))	('lung cancer', 'Disease', (188, 199))	('nucleolin', 'Gene', '4691', (157, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))	('nucleolin', 'Gene', '4691', (86, 95))	('human', 'Species', '9606', (182, 187))	('uptake', 'biological_process', 'GO:0098657', ('141', '147'))	('lung cancer', 'Disease', 'MESH:D008175', (188, 199))	('AS14111', 'Chemical', '-', (12, 19))	('cytotoxic activity', 'CPA', (269, 287))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('enhanced', 'PosReg', (260, 268))	('uptake', 'biological_process', 'GO:0098739', ('141', '147'))	('AS14111-conjugated', 'Var', (12, 30))
23441	30013345	The AS14111-conjugated undecylenic acid modified, thermally hydrocarbonized porous silicon (UnTH-CPSi) nanoparticle delivering methotrexate was shown to increase drug cellular uptake by nucleolin-overexpressing human breast adenocarcinoma cells (MDA-MB-231) with enhanced cytotoxic activity compared with non-targeted nanoparticles and nucleolin-negative fibroblasts cells (NIH 3T3).	('cytotoxic activity', 'CPA', (272, 290))	('uptake', 'biological_process', 'GO:0098739', ('176', '182'))	('enhanced', 'PosReg', (263, 271))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (217, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('silicon', 'Chemical', 'MESH:D012825', (83, 90))	('nucleolin', 'Gene', (186, 195))	('breast adenocarcinoma', 'Disease', (217, 238))	('undecylenic acid', 'Chemical', 'MESH:C538763', (23, 39))	('nucleolin', 'Gene', (336, 345))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (217, 238))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (246, 256))	('drug cellular uptake', 'CPA', (162, 182))	('nucleolin', 'Gene', '4691', (186, 195))	('AS14111-conjugated', 'Var', (4, 22))	('carbon', 'Chemical', 'MESH:D002244', (65, 71))	('increase', 'PosReg', (153, 161))	('AS14111', 'Chemical', '-', (4, 11))	('uptake', 'biological_process', 'GO:0098657', ('176', '182'))	('nucleolin', 'Gene', '4691', (336, 345))	('human', 'Species', '9606', (211, 216))	('methotrexate', 'Chemical', 'MESH:D008727', (127, 139))
23442	30013345	The aptamer AS14111-conjugated polymersome delivering doxorubicin was shown to increase drug cellular uptake by nucleolin-overexpressing human breast adenocarcinoma cells (MCF-7) with enhanced cytotoxic activity compared with mutated aptamer-conjugated nanoparticles (mean IC50: 210.9 ng/mL and 369.4 ng/mL, respectively).	('increase', 'PosReg', (79, 87))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (143, 164))	('human', 'Species', '9606', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cytotoxic activity', 'CPA', (193, 211))	('breast adenocarcinoma', 'Disease', (143, 164))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('nucleolin', 'Gene', (112, 121))	('uptake', 'biological_process', 'GO:0098739', ('102', '108'))	('MCF-7', 'CellLine', 'CVCL:0031', (172, 177))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (143, 164))	('uptake', 'biological_process', 'GO:0098657', ('102', '108'))	('nucleolin', 'Gene', '4691', (112, 121))	('AS14111-conjugated', 'Var', (12, 30))	('enhanced', 'PosReg', (184, 192))	('drug', 'CPA', (88, 92))	('AS14111', 'Chemical', '-', (12, 19))
23488	29977547	Myositis-specific autoantibodies (MSA) such as anti-transcriptional intermediary factor-1 gamma (anti-TIF1 gamma), anti-nuclear matrix protein 2 (anti-NXP2) and anti-melanoma differentiation gene 5 (anti-MDA5) were reported to have an increased risk of malignancies in DM/PM patients.	('Myositis', 'Disease', (0, 8))	('patients', 'Species', '9606', (275, 283))	('TIF1 gamma', 'Gene', (102, 112))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('Myositis', 'Phenotype', 'HP:0100614', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('Myositis', 'Disease', 'MESH:D009220', (0, 8))	('DM', 'Disease', 'MESH:D009223', (269, 271))	('malignancies', 'Disease', 'MESH:D009369', (253, 265))	('NXP2', 'Gene', '23515', (151, 155))	('transcriptional intermediary factor-1 gamma', 'Gene', '51592', (52, 95))	('MDA5', 'Gene', '64135', (204, 208))	('NXP2', 'Gene', (151, 155))	('malignancies', 'Disease', (253, 265))	('anti-nuclear', 'Var', (115, 127))	('nuclear matrix', 'cellular_component', 'GO:0016363', ('120', '134'))	('transcriptional intermediary factor-1 gamma', 'Gene', (52, 95))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('TIF1 gamma', 'Gene', '51592', (102, 112))	('MDA5', 'Gene', (204, 208))
23506	29977547	Tumor markers evaluated in this study were serum CEA, CA125, CA19-9, CA15-3 and alpha-fetoprotein (AFP) on the first sample taken within 1 month after the diagnosis of DM/PM.	('CEA', 'Gene', (49, 52))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CA125', 'Gene', '94025', (54, 59))	('CEA', 'Gene', '1084', (49, 52))	('AFP', 'Gene', (99, 102))	('DM', 'Disease', 'MESH:D009223', (168, 170))	('CA19-9', 'Var', (61, 67))	('alpha-fetoprotein', 'Gene', '174', (80, 97))	('CA125', 'Gene', (54, 59))	('AFP', 'Gene', '174', (99, 102))	('CA15-3', 'Gene', '4582', (69, 75))	('CA19-9', 'Chemical', 'MESH:C086528', (61, 67))	('alpha-fetoprotein', 'Gene', (80, 97))	('CA15-3', 'Gene', (69, 75))
23508	29977547	The normal ranges for tumor markers were CEA < 5.0 ng/mL, CA125 < 35.0 U/mL, CA19-9 < 34.0 U/mL, CA15-3 < 25 U/mL and AFP < 12 ng/mL.	('CA15-3', 'Gene', (97, 103))	('AFP', 'Gene', '174', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('CEA', 'Gene', '1084', (41, 44))	('CA125', 'Gene', '94025', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CA19-9', 'Chemical', 'MESH:C086528', (77, 83))	('tumor', 'Disease', (22, 27))	('CEA', 'Gene', (41, 44))	('CA15-3', 'Gene', '4582', (97, 103))	('CA125', 'Gene', (58, 63))	('CA19-9 < 34.0', 'Var', (77, 90))	('AFP', 'Gene', (118, 121))
23510	29977547	Malignancies were identified using ICD-9-CM (140.x-172.x, 174.x-195.8 and 200.x-208.x).	('140.x-172.x', 'Var', (45, 56))	('Malignancies', 'Disease', 'MESH:D009369', (0, 12))	('174.x-195.8', 'Var', (58, 69))	('Malignancies', 'Disease', (0, 12))
23554	29977547	The employed monoclonal antibodies in CA15-3 assay recognized amino acids sequences on the central protein core of mucin-1.	('amino acids sequences', 'Var', (62, 83))	('core', 'cellular_component', 'GO:0019013', ('107', '111'))	('CA15-3', 'Gene', '4582', (38, 44))	('CA15-3', 'Gene', (38, 44))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('mucin-1', 'Gene', (115, 122))	('mucin-1', 'Gene', '4582', (115, 122))
23579	29483219	Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo.	('Knocking down', 'Var', (0, 13))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('attenuated colorectal liver and lung metastasis of colon cancer', 'Disease', 'MESH:D015179', (30, 93))	('PRPK', 'Gene', (14, 18))
23591	29483219	PRPK is phosphorylated at Ser250 by Akt/PBK and by the T-LAK cell-originated protein kinase (TOPK).	('Ser250', 'Var', (26, 32))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('PBK', 'Gene', (40, 43))	('PRPK', 'Protein', (0, 4))	('TOPK', 'Gene', '55872', (93, 97))	('T-LAK cell-originated protein kinase', 'Gene', '55872', (55, 91))	('Akt', 'Gene', (36, 39))	('T-LAK cell-originated protein kinase', 'Gene', (55, 91))	('TOPK', 'Gene', (93, 97))	('Ser250', 'Chemical', '-', (26, 32))	('PBK', 'Gene', '55872', (40, 43))	('Akt', 'Gene', '207', (36, 39))
23596	29483219	For example, the p53 protein is also phosphorylated at Ser15 by ATR and ATM.	('ATR', 'Gene', '545', (64, 67))	('ATR', 'Gene', (64, 67))	('ATM', 'Gene', '472', (72, 75))	('Ser15', 'Chemical', '-', (55, 60))	('Ser', 'cellular_component', 'GO:0005790', ('55', '58'))	('Ser15', 'Var', (55, 60))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('ATM', 'Gene', (72, 75))	('protein', 'Protein', (21, 28))
23599	29483219	Depletion of PRPK reportedly causes a p53-dependent and -independent increase in paclitaxel-induced caspase activation and p53 remains phosphorylated on Ser15 even after depletion of PRPK, suggesting that this is not a major role for PRPK in proliferating cells.	('increase', 'PosReg', (69, 77))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('caspase activation', 'biological_process', 'GO:0006919', ('100', '118'))	('paclitaxel-induced caspase', 'MPA', (81, 107))	('Depletion', 'Var', (0, 9))	('Ser', 'cellular_component', 'GO:0005790', ('153', '156'))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('p53', 'Gene', (123, 126))	('PRPK', 'Gene', (13, 17))	('Ser15', 'Chemical', '-', (153, 158))	('p53', 'Gene', '7157', (123, 126))	('activation', 'PosReg', (108, 118))
23609	29483219	Anti-phosphor-survivin (Thr34; D2E11), phosphor-p53 (Ser15) (16G8) anti-mouse antibody were from Cell Signaling Technology, Inc. (Beverly, MA).	('survivin', 'Gene', '11799', (14, 22))	('p53', 'Gene', (48, 51))	('Signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('Thr34', 'Chemical', '-', (24, 29))	('antibody', 'cellular_component', 'GO:0019814', ('78', '86'))	('antibody', 'molecular_function', 'GO:0003823', ('78', '86'))	('p53', 'Gene', '7157', (48, 51))	('mouse', 'Species', '10090', (72, 77))	('survivin', 'Gene', (14, 22))	('Ser', 'cellular_component', 'GO:0005790', ('53', '56'))	('Thr34', 'Var', (24, 29))	('antibody', 'cellular_component', 'GO:0042571', ('78', '86'))	('Ser15', 'Chemical', '-', (53, 58))	('antibody', 'cellular_component', 'GO:0019815', ('78', '86'))
23632	29483219	The colon adenocarcinoma tissue arrays (HCol-Ade180Sur-03) and (HCol-Ade180Sur-05) had survival data, including TNM and pathology grade, 90 cases and NAT, 90 cases.	('Ade180Sur', 'Chemical', '-', (69, 78))	('TNM', 'Gene', '10178', (112, 115))	('HCol', 'Chemical', '-', (64, 68))	('Ade180Sur', 'Chemical', '-', (45, 54))	('HCol-Ade180Sur-03', 'Var', (40, 57))	('HCol-Ade180Sur-05', 'Var', (64, 81))	('TNM', 'Gene', (112, 115))	('HCol', 'Chemical', '-', (40, 44))	('colon adenocarcinoma', 'Disease', (4, 24))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (4, 24))
23633	29483219	Immunostaining was performed on the tissue array using antibodies to detect p-PRPK (1:100) or mutant p53 (1:50).	('p53', 'Gene', '7157', (101, 104))	('p-PRPK', 'Var', (76, 82))	('mutant', 'Var', (94, 100))	('p53', 'Gene', (101, 104))
23643	29483219	Next, we determined the effect of knocking down PRPK levels with sh-RNA on the invasion abilities of invasive cancer cell lines such as HCT116 and HCT15.	('knocking', 'Var', (34, 42))	('invasive cancer', 'Disease', 'MESH:D009362', (101, 116))	('HCT116', 'CellLine', 'CVCL:0291', (136, 142))	('PRPK levels', 'Protein', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HCT15', 'CellLine', 'CVCL:0292', (147, 152))	('invasive cancer', 'Disease', (101, 116))	('RNA', 'cellular_component', 'GO:0005562', ('68', '71'))
23647	29483219	The area of liver metastasis from mice expressing shPRPK#1/HCT116 was significantly decreased compared to shMock (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (59, 65))	('decreased', 'NegReg', (84, 93))	('mice', 'Species', '10090', (34, 38))	('shPRPK#1/HCT116', 'Var', (50, 65))
23648	29483219	The metastatic nodules were completely absent in livers from mice expressing shPRPK#1/HCT15 compared to shMock (Fig.	('HCT15', 'CellLine', 'CVCL:0292', (86, 91))	('metastatic nodules', 'CPA', (4, 22))	('mice', 'Species', '10090', (61, 65))	('shPRPK#1/HCT15', 'Var', (77, 91))	('absent', 'NegReg', (39, 45))
23650	29483219	Migration and invasion were inhibited in CT26 mouse colon cancer cells stably expressing shPRPK, as compared to shMock (Supplementary Fig.	('colon cancer', 'Disease', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CT26', 'Gene', (41, 45))	('mouse', 'Species', '10090', (46, 51))	('inhibited', 'NegReg', (28, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('shPRPK', 'Var', (89, 95))	('CT26', 'Gene', '168400', (41, 45))
23652	29483219	The area of lung metastasis from mice expressing shMock in HCT116 cells (28 days) was greater compared to shPRPK#1 (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (59, 65))	('shMock', 'Var', (49, 55))	('lung metastasis', 'CPA', (12, 27))	('mice', 'Species', '10090', (33, 37))
23654	29483219	H&E staining of lungs with cells expressing shMock showed greater tumor metastasis compared with shPRPK (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('H&E', 'Chemical', '-', (0, 3))	('showed', 'PosReg', (51, 57))	('tumor metastasis', 'Disease', 'MESH:D009362', (66, 82))	('tumor metastasis', 'Disease', (66, 82))	('expressing', 'Var', (33, 43))
23656	29483219	2E) demonstrated that mice inoculated with shMock (n = 9, red line) exhibit dramatically decreased survival time compared to mice inoculated with shPRPK#1 (p = 0.0015).	('survival time', 'CPA', (99, 112))	('mice', 'Species', '10090', (125, 129))	('shMock', 'Var', (43, 49))	('mice', 'Species', '10090', (22, 26))	('decreased', 'NegReg', (89, 98))
23662	29483219	Mutation of survivin (Thr34Ala) can induce apoptosis and reduce angiogenesis, metastasis, and cell cycle progression.	('survivin', 'Gene', '11799', (12, 20))	('reduce', 'NegReg', (57, 63))	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('apoptosis', 'CPA', (43, 52))	('angiogenesis', 'CPA', (64, 76))	('cell cycle progression', 'CPA', (94, 116))	('Thr34Ala', 'SUBSTITUTION', 'None', (22, 30))	('Mutation', 'Var', (0, 8))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('survivin', 'Gene', (12, 20))	('Thr34Ala', 'Var', (22, 30))	('metastasis', 'CPA', (78, 88))	('induce', 'PosReg', (36, 42))
23663	29483219	Wild-type and mutant His-survivin (Thr34Ala) proteins were analyzed for phosphorylation by PRPK.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('Thr34Ala', 'SUBSTITUTION', 'None', (35, 43))	('survivin', 'Gene', (25, 33))	('mutant', 'Var', (14, 20))	('Thr34Ala', 'Var', (35, 43))	('phosphorylation', 'MPA', (72, 87))	('survivin', 'Gene', '11799', (25, 33))
23664	29483219	3B, right panel) results indicated that mutant T34A abrogated phosphorylation of survivin, confirming that PRPK phosphorylates survivin at Thr34.	('abrogated', 'NegReg', (52, 61))	('survivin', 'Gene', (127, 135))	('phosphorylation', 'MPA', (62, 77))	('survivin', 'Gene', '11799', (81, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))	('survivin', 'Gene', '11799', (127, 135))	('Thr34', 'Chemical', '-', (139, 144))	('T34A', 'Gene', (47, 51))	('mutant', 'Var', (40, 46))	('T34A', 'Mutation', 'rs752988925', (47, 51))	('survivin', 'Gene', (81, 89))
23669	29483219	We found that this was indeed the case, as phosphorylation of PRPK (Ser250) and survivin (Thr34) was induced in a dose- and time-dependent manner by EGF (Supplementary Fig.	('survivin', 'Gene', '11799', (80, 88))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('PRPK', 'Protein', (62, 66))	('Ser250', 'Chemical', '-', (68, 74))	('EGF', 'molecular_function', 'GO:0005154', ('149', '152'))	('Thr34', 'Chemical', '-', (90, 95))	('EGF', 'Var', (149, 152))	('induced', 'PosReg', (101, 108))	('survivin', 'Gene', (80, 88))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))
23680	29483219	Survivin phosphorylation induced by EGF was decreased by knockdown of PRPK (shPRPK#1) in HCT116 or HCT15 cells (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('Survivin', 'Gene', '11799', (0, 8))	('phosphorylation', 'MPA', (9, 24))	('EGF', 'molecular_function', 'GO:0005154', ('36', '39'))	('HCT116', 'CellLine', 'CVCL:0291', (89, 95))	('Survivin', 'Gene', (0, 8))	('knockdown', 'Var', (57, 66))	('HCT15', 'CellLine', 'CVCL:0292', (99, 104))	('decreased', 'NegReg', (44, 53))
23682	29483219	EGF regulates survivin stability and survivin is stabilized by Thr34 phosphorylation.	('EGF', 'molecular_function', 'GO:0005154', ('0', '3'))	('Thr34', 'Chemical', '-', (63, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('survivin', 'Gene', '11799', (37, 45))	('survivin', 'Gene', (14, 22))	('regulates', 'Reg', (4, 13))	('Thr34', 'Var', (63, 68))	('survivin', 'Gene', (37, 45))	('survivin', 'Gene', '11799', (14, 22))	('stability', 'MPA', (23, 32))
23685	29483219	3F, left panels), suggesting that phosphorylation of survivin by PRPK enhances its stability.	('PRPK', 'Gene', (65, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('stability', 'MPA', (83, 92))	('survivin', 'Gene', '11799', (53, 61))	('phosphorylation', 'Var', (34, 49))	('survivin', 'Gene', (53, 61))	('enhances', 'PosReg', (70, 78))
23686	29483219	Phosphorylation of survivin was almost absent in MutPRPK cells (Fig.	('survivin', 'Gene', '11799', (19, 27))	('MutPRPK', 'Var', (49, 56))	('Phosphorylation', 'MPA', (0, 15))	('absent', 'NegReg', (39, 45))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('survivin', 'Gene', (19, 27))
23687	29483219	These results demonstrate that mutation of PRPK markedly attenuates its phosphorylation of survivin.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('phosphorylation of', 'MPA', (72, 90))	('survivin', 'Gene', '11799', (91, 99))	('mutation', 'Var', (31, 39))	('PRPK', 'Gene', (43, 47))	('survivin', 'Gene', (91, 99))	('attenuates', 'NegReg', (57, 67))
23691	29483219	The mutation of survivin (Thr34Ala) induces apoptosis, thus we compared the level of cleaved caspase-3, a marker of apoptosis in cells expressing either mutant or wild-type PRPK (Supplementary Fig.	('Thr34Ala', 'Var', (26, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('apoptosis', 'CPA', (44, 53))	('survivin', 'Gene', '11799', (16, 24))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('mutation', 'Var', (4, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('Thr34Ala', 'SUBSTITUTION', 'None', (26, 34))	('survivin', 'Gene', (16, 24))	('induces', 'Reg', (36, 43))
23692	29483219	After 48 h of treatment with 5-FU, the level of cleaved caspase-3 was increased in cells expressing mutant PRPK, compared to cells expressing WT PRPK.	('level of cleaved caspase-3', 'MPA', (39, 65))	('PRPK', 'Gene', (107, 111))	('mutant', 'Var', (100, 106))	('increased', 'PosReg', (70, 79))	('5-FU', 'Chemical', 'MESH:D005472', (29, 33))
23693	29483219	This indicated that overexpression of the mutant PRPK induces apoptosis, and has a similar biological effect to the survivin T34A mutation.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('PRPK', 'Gene', (49, 53))	('mutant', 'Var', (42, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('T34A', 'Mutation', 'rs752988925', (125, 129))	('overexpression', 'PosReg', (20, 34))	('survivin', 'Gene', '11799', (116, 124))	('apoptosis', 'CPA', (62, 71))	('induces', 'Reg', (54, 61))	('survivin', 'Gene', (116, 124))
23694	29483219	Experiments were also performed with PRPK knockdown in HCT116 cells (Supplementary Figure 4F) and we did not observe dramatic differences in the levels of cleaved caspase 3 in cells with or without PRPK, thus apoptosis was not induced in the absence of 5-FU, which is consistent with our previous cell growth data.	('cell growth', 'biological_process', 'GO:0016049', ('297', '308'))	('apoptosis', 'biological_process', 'GO:0097194', ('209', '218'))	('PRPK', 'Gene', (37, 41))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('209', '218'))	('5-FU', 'Chemical', 'MESH:D005472', (253, 257))	('knockdown', 'Var', (42, 51))
23705	29483219	Computer modeling showed that FA fits into the ATP-binding pocket of PRPK and formed hydrogen bonds with Lys40, Ala45 or Lys60 and hydrophobic interactions with Val47/Val58 or Ile179/Ile182 of PRPK (Fig.	('fits', 'Disease', (33, 37))	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('Lys60', 'Chemical', '-', (121, 126))	('Ile179/Ile182', 'Var', (176, 189))	('formed', 'Reg', (78, 84))	('Ile179', 'Chemical', '-', (176, 182))	('Lys60', 'Var', (121, 126))	('Lys40', 'Chemical', '-', (105, 110))	('PRPK', 'Protein', (69, 73))	('hydrogen', 'Chemical', 'MESH:D006859', (85, 93))	('Ala45', 'Var', (112, 117))	('Lys40', 'Var', (105, 110))	('Val47/Val58', 'Var', (161, 172))	('Val58', 'Chemical', '-', (167, 172))	('Val47', 'Chemical', '-', (161, 166))	('PRPK', 'Protein', (193, 197))	('fits', 'Disease', 'MESH:D012640', (33, 37))	('hydrogen bonds', 'Interaction', (85, 99))	('hydrophobic', 'MPA', (131, 142))	('ATP-binding', 'molecular_function', 'GO:0005524', ('47', '58'))	('Ile182', 'Chemical', '-', (183, 189))	('Ala45', 'Chemical', '-', (112, 117))
23728	29483219	Results showed that p-survivin was dramatically decreased in lung tissues from groups treated with 5-FU or FA, as compared to the untreated group (Fig.	('5-FU', 'Chemical', 'MESH:D005472', (99, 103))	('survivin', 'Gene', '11799', (22, 30))	('decreased', 'NegReg', (48, 57))	('survivin', 'Gene', (22, 30))	('5-FU', 'Var', (99, 103))
23744	29483219	Next, we examined p-p53 or mutant p53 expression levels in the same tissue array with different tumor grades that we had used for the analysis of p-PRPK levels (Fig.	('p53', 'Gene', (20, 23))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p53', 'Gene', '7157', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutant', 'Var', (27, 33))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
23747	29483219	These results suggest that levels of mutated p53 are associated with colon cancer development in Stages I to II, but are not associated with colon metastasis (Stages III or IV).	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('colon metastasis', 'Disease', (141, 157))	('colon cancer', 'Disease', (69, 81))	('colon cancer', 'Disease', 'MESH:D015179', (69, 81))	('colon metastasis', 'Disease', 'MESH:D009362', (141, 157))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutated', 'Var', (37, 44))	('associated with', 'Reg', (53, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))
23756	29483219	The up-regulation of p53 activity suppresses cancer malignancy; however mutant p53 proteins not only lose their tumor suppressive activities, but often gain additional oncogenic functions.	('lose', 'NegReg', (101, 105))	('p53', 'Gene', (79, 82))	('proteins', 'Protein', (83, 91))	('p53', 'Gene', '7157', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutant', 'Var', (72, 78))	('cancer malignancy', 'Disease', 'MESH:D009369', (45, 62))	('p53', 'Gene', '7157', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('gain', 'PosReg', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer malignancy', 'Disease', (45, 62))	('oncogenic functions', 'CPA', (168, 187))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (21, 24))	('regulation', 'biological_process', 'GO:0065007', ('7', '17'))
23758	29483219	The cell lines HCT116 and DLD-1 express wild-type p53 and HCT15, HT-29 and WiDr cells express a mutant p53.	('mutant', 'Var', (96, 102))	('p53', 'Gene', '7157', (103, 106))	('p53', 'Gene', (103, 106))	('HT-29', 'CellLine', 'CVCL:0320', (65, 70))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('HCT15', 'CellLine', 'CVCL:0292', (58, 63))	('HCT116', 'CellLine', 'CVCL:0291', (15, 21))
23765	29483219	For experiments, we used HCT116 cells, which express wild-type p53, and HCT15 cells, which express a mutant p53.	('HCT15', 'CellLine', 'CVCL:0292', (72, 77))	('p53', 'Gene', (63, 66))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', '7157', (63, 66))	('HCT116', 'CellLine', 'CVCL:0291', (25, 31))	('mutant', 'Var', (101, 107))
23767	29483219	Knocking down PRPK expression prevented colorectal liver or lung metastasis of HCT116 and HCT15 colon cancer cells in vivo, and dramatically increased survival of mice.	('colorectal liver', 'Disease', (40, 56))	('HCT15', 'CellLine', 'CVCL:0292', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('prevented', 'NegReg', (30, 39))	('Knocking down', 'Var', (0, 13))	('increased', 'PosReg', (141, 150))	('survival', 'CPA', (151, 159))	('lung metastasis', 'CPA', (60, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('mice', 'Species', '10090', (163, 167))	('colon cancer', 'Disease', (96, 108))	('colorectal liver', 'Disease', 'MESH:D017093', (40, 56))	('PRPK', 'Gene', (14, 18))
23778	29483219	The phosphorylation of survivin at Thr34 is important for its therapeutic potential and its molecular mechanism of action.	('survivin', 'Gene', '11799', (23, 31))	('Thr34', 'Chemical', '-', (35, 40))	('Thr34', 'Var', (35, 40))	('survivin', 'Gene', (23, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))
23801	28913902	Consider where beta is the p-vector of unknown regression coefficients and epsilon = (epsilon1, ..., epsilonn)' is the vector of random errors.	('epsilonn', 'Var', (101, 109))	('eta', 'Gene', '1909', (16, 19))	('eta', 'Gene', (16, 19))
23827	28913902	Motivated by similar considerations, studies have been conducted, directly linking CNAs, methylation, microRNAs, and others with cancer outcomes.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('methylation', 'Var', (89, 100))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('CNAs', 'Var', (83, 87))
23851	28913902	Second, methylation and possibly other regulators may directly affect proteins and hence cancer outcomes not through GEs.	('affect', 'Reg', (63, 69))	('proteins', 'Protein', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('methylation', 'biological_process', 'GO:0032259', ('8', '19'))	('methylation', 'Var', (8, 19))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
23885	28913902	The PMSEs are 535.279 (Alt.1), 603.148 (Alt.2), 525.273 (Alt.3), 567.523 (Alt.4), 691.905 (Alt.5), and 481.051 (ARMI), respectively.	('691.905', 'Var', (82, 89))	('481.051', 'Var', (103, 110))	('Alt.1', 'Gene', '2875', (23, 28))	('Alt', 'molecular_function', 'GO:0004021', ('91', '94'))	('Alt.1', 'Gene', (23, 28))	('Alt', 'molecular_function', 'GO:0004021', ('74', '77'))	('Alt', 'molecular_function', 'GO:0004021', ('40', '43'))	('Alt.2', 'Gene', (40, 45))	('Alt.2', 'Gene', '84706', (40, 45))	('Alt', 'molecular_function', 'GO:0004021', ('57', '60'))	('Alt', 'molecular_function', 'GO:0004021', ('23', '26'))	('525.273', 'Var', (48, 55))	('567.523', 'Var', (65, 72))
23898	29511269	Using a mutant-allele tumor heterogeneity (MATH) score, we showed that CR cells are able to keep and maintain most of the intra-tumoral heterogeneity, suggesting oligoclonality of these cultures.	('intra-tumor', 'Disease', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutant-allele', 'Var', (8, 21))	('intra-tumor', 'Disease', 'MESH:D009369', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CR', 'Chemical', '-', (71, 73))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (128, 133))
23909	29511269	In order to address the capability of CR cells to maintain their tumor-derived heterogeneity, we carried out exome sequencing and single nucleotide variation calling from normal tissue, primary tumor and CR cells.	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('CR', 'Chemical', '-', (204, 206))	('primary tumor', 'Disease', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('primary tumor', 'Disease', 'MESH:D009369', (186, 199))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('CR', 'Chemical', '-', (38, 40))	('single nucleotide variation', 'Var', (130, 157))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
23917	29511269	We selected these cancer-specific SNVs panel because several malignant cells arise as a result of somatic changes in the cancer genes.	('result', 'Reg', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('changes', 'Var', (106, 113))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
23919	29511269	The genetic relationship between CR cells and primary tumor for cancer genes shows a good correlation (>90%), with the exception of G2204, presented as the Venn diagram in Fig.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('CR', 'Chemical', '-', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('primary tumor', 'Disease', (46, 59))	('G2204', 'Var', (132, 137))	('primary tumor', 'Disease', 'MESH:D009369', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
23924	29511269	Next, in order to evaluate if CR still keep the heterogeneity (ITH) from their respective primary tumors, we used the mutant-allele tumor heterogeneity (MATH) score.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutant-allele', 'Var', (118, 131))	('primary tumors', 'Disease', (90, 104))	('heterogeneity', 'MPA', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (132, 137))	('CR', 'Chemical', '-', (30, 32))	('primary tumors', 'Disease', 'MESH:D009369', (90, 104))	('tumor', 'Disease', (98, 103))
23928	29511269	We observed that all primary tumor samples (except G2204 and G2208) present higher MATH scores than their respective CR cells (Fig.	('G2208', 'Var', (61, 66))	('CR', 'Chemical', '-', (117, 119))	('primary tumor', 'Disease', (21, 34))	('MATH scores', 'CPA', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('primary tumor', 'Disease', 'MESH:D009369', (21, 34))	('G2204', 'Var', (51, 56))	('higher', 'PosReg', (76, 82))
23930	29511269	Interestingly, three primary tumors and their respective CR cells (G2200, G2202 and G2206), presented a very similar MATH score, suggesting that CR cells capture almost all of tumor ITH.	('primary tumors', 'Disease', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CR', 'Chemical', '-', (145, 147))	('primary tumors', 'Disease', 'MESH:D009369', (21, 35))	('tumor', 'Disease', (176, 181))	('G2202', 'Var', (74, 79))	('G2206', 'Var', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('CR', 'Chemical', '-', (57, 59))	('G2200', 'Var', (67, 72))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
23931	29511269	On the other hand, G2203 and G2205 CR cells presented a smaller MATH score than their primary tumor, indicating that CR cells were not able to capture all ITH from primary tumors although they are not clonal like standard cell lines.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('CR', 'Chemical', '-', (117, 119))	('primary tumors', 'Disease', (164, 178))	('CR', 'Chemical', '-', (35, 37))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('primary tumor', 'Disease', 'MESH:D009369', (164, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('G2205', 'Var', (29, 34))	('primary tumors', 'Disease', 'MESH:D009369', (164, 178))	('primary tumor', 'Disease', (86, 99))	('MATH score', 'MPA', (64, 74))	('G2203', 'Var', (19, 24))	('smaller', 'NegReg', (56, 63))	('primary tumor', 'Disease', 'MESH:D009369', (86, 99))
23932	29511269	Moreover, G2204 and G2208 had an unexpected higher MATH score than its corresponding tumor tissue.	('tumor', 'Disease', (85, 90))	('G2208', 'Var', (20, 25))	('G2204', 'Var', (10, 15))	('higher', 'PosReg', (44, 50))	('MATH score', 'CPA', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
23936	29511269	Copy number variation (CNV) is an important parameter for the intra-tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('intra-tumor', 'Disease', 'MESH:D009369', (62, 73))	('Copy number variation', 'Var', (0, 21))	('intra-tumor', 'Disease', (62, 73))
23940	29511269	2S, suggesting that this tumor CR culture (G2202) represents the primary tumor diversity for the CNV profile.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('CR', 'Chemical', '-', (31, 33))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('primary tumor', 'Disease', (65, 78))	('tumor', 'Disease', (25, 30))	('primary tumor', 'Disease', 'MESH:D009369', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('G2202', 'Var', (43, 48))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
23949	29511269	Recently it was shown that CR technology was successful in identifying low frequency high impact actionable mutations in primary breast cancer and liver metastasis patients.	('breast cancer', 'Disease', (129, 142))	('CR', 'Chemical', '-', (27, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('liver metastasis', 'Disease', 'MESH:D009362', (147, 163))	('liver metastasis', 'Disease', (147, 163))	('patients', 'Species', '9606', (164, 172))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('high impact', 'Var', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
23951	29511269	Similarly, CR cultures of liver metastasis identified several enriched mutations that were common among various cancer types irrespective of the primary site of tumor.	('CR', 'Chemical', '-', (11, 13))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mutations', 'Var', (71, 80))	('common', 'Reg', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('liver metastasis', 'Disease', 'MESH:D009362', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (161, 166))	('liver metastasis', 'Disease', (26, 42))
23974	29511269	To the ITH level estimation and enumeration of tumor cell subpopulations, we used the mutant-allele tumor heterogeneity (MATH) score.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('mutant-allele', 'Var', (86, 99))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (47, 52))
23990	29074535	The occurrence of early onset DNA lesions such as mutations in KRAS oncogene and molecular processes underlying tumor development are similar in humans and NNK-treated A/J mice.	('humans', 'Species', '9606', (145, 151))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('early onset DNA', 'Disease', (18, 33))	('mice', 'Species', '10090', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('KRAS oncogene', 'Gene', (63, 76))	('tumor', 'Disease', (112, 117))	('NNK', 'Chemical', 'MESH:C016583', (156, 159))
24052	29074535	The flaxseed-fed mice were slow to transition to their new diet, and consumed less food in the first two months compared to the control-fed mice (Fig.	('flaxseed-fed', 'Var', (4, 16))	('less', 'NegReg', (78, 82))	('mice', 'Species', '10090', (140, 144))	('mice', 'Species', '10090', (17, 21))
24061	29074535	Finally, tumor morphometry data showed flaxseed-fed mice had significantly decreased tumor burden as compared to control group mice (0.0-5.4 vs. 0.7-10.2 % of total lung area) (Fig.	('tumor', 'Disease', (85, 90))	('mice', 'Species', '10090', (127, 131))	('flaxseed-fed', 'Var', (39, 51))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('decreased tumor', 'Disease', 'MESH:D009369', (75, 90))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('decreased tumor', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
24114	29074535	Inhibition of AKT signaling may inhibit glycolysis and elevate reactive oxygen species, leading to preferential killing of cancer cells through oxidative stress.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('glycolysis', 'biological_process', 'GO:0006096', ('40', '50'))	('AKT signaling', 'biological_process', 'GO:0043491', ('14', '27'))	('inhibit', 'NegReg', (32, 39))	('AKT', 'Gene', (14, 17))	('AKT', 'Gene', '11651', (14, 17))	('glycolysis', 'MPA', (40, 50))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('reactive oxygen species', 'MPA', (63, 86))	('elevate', 'PosReg', (55, 62))	('cancer', 'Disease', (123, 129))	('Inhibition', 'Var', (0, 10))	('preferential', 'PosReg', (99, 111))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (63, 86))	('oxidative stress', 'MPA', (144, 160))
24115	29074535	In addition to AKT and ERK signaling pathways, de-regulation of another pivotal kinase, JNK, promotes development of tobacco smoke-induced lung tumors.	('de-regulation', 'Var', (47, 60))	('lung tumors', 'Phenotype', 'HP:0100526', (139, 150))	('JNK', 'Gene', (88, 91))	('ERK', 'molecular_function', 'GO:0004707', ('23', '26'))	('ERK', 'Gene', '26413', (23, 26))	('AKT', 'Gene', (15, 18))	('tobacco', 'Species', '4097', (117, 124))	('promotes', 'PosReg', (93, 101))	('JNK', 'Gene', '26419', (88, 91))	('lung tumors', 'Disease', (139, 150))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('AKT', 'Gene', '11651', (15, 18))	('regulation', 'biological_process', 'GO:0065007', ('50', '60'))	('development', 'CPA', (102, 113))	('JNK', 'molecular_function', 'GO:0004705', ('88', '91'))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('ERK', 'Gene', (23, 26))	('lung tumor', 'Phenotype', 'HP:0100526', (139, 149))	('lung tumors', 'Disease', 'MESH:D008175', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
24116	29074535	Genetic ablation of JNK1 alone is associated with reduced tobacco smoke-induced lung tumor multiplicity and size.	('lung tumor', 'Disease', (80, 90))	('JNK1', 'Gene', '26419', (20, 24))	('tobacco', 'Species', '4097', (58, 65))	('JNK', 'molecular_function', 'GO:0004705', ('20', '23'))	('lung tumor', 'Phenotype', 'HP:0100526', (80, 90))	('JNK1', 'Gene', (20, 24))	('Genetic ablation', 'Var', (0, 16))	('reduced', 'NegReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumor', 'Disease', 'MESH:D008175', (80, 90))
24118	29074535	These findings, together with our observations suggest that inhibiting AKT, ERK and JNK activity might be a valuable approach to suppress/delay the effects of NNK-induced lung tumorigenesis.	('JNK', 'Gene', '26419', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('AKT', 'Gene', '11651', (71, 74))	('ERK', 'Gene', (76, 79))	('suppress/delay', 'NegReg', (129, 143))	('JNK', 'molecular_function', 'GO:0004705', ('84', '87'))	('lung tumor', 'Phenotype', 'HP:0100526', (171, 181))	('lung tumor', 'Disease', (171, 181))	('JNK', 'Gene', (84, 87))	('activity', 'MPA', (88, 96))	('ERK', 'Gene', '26413', (76, 79))	('lung tumor', 'Disease', 'MESH:D008175', (171, 181))	('AKT', 'Gene', (71, 74))	('NNK', 'Chemical', 'MESH:C016583', (159, 162))	('inhibiting', 'Var', (60, 70))
24185	29291033	PAR-1 silencing and inhibiting thrombin decrease dissemination of metastatic melanoma cells.	('decrease', 'NegReg', (40, 48))	('thrombin', 'Gene', '2147', (31, 39))	('inhibiting', 'NegReg', (20, 30))	('PAR-1', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('inhibiting thrombin decrease', 'Phenotype', 'HP:0001976', (20, 48))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('silencing', 'Var', (6, 15))	('thrombin', 'Gene', (31, 39))
24186	29291033	PAR-1 siRNA mediated inhibition decreased MMP-2, IL-8 and VEGF, expression levels, subsequently vascular density.	('VEGF', 'Gene', (58, 62))	('MMP-2', 'Gene', (42, 47))	('IL-8', 'molecular_function', 'GO:0005153', ('49', '53'))	('PAR-1', 'Gene', (0, 5))	('VEGF', 'Gene', '7422', (58, 62))	('MMP-2', 'molecular_function', 'GO:0004228', ('42', '47'))	('inhibition', 'Var', (21, 31))	('vascular density', 'CPA', (96, 112))	('IL-8', 'Gene', '3576', (49, 53))	('MMP-2', 'Gene', '4313', (42, 47))	('expression levels', 'MPA', (64, 81))	('IL-8', 'Gene', (49, 53))	('decreased', 'NegReg', (32, 41))
24189	29291033	AA genotype of PAR-1 gene variant IVSn-14A> T was associated with an increased risk of RCC metastasis and a poorer prognosis.	('PAR-1', 'Gene', (15, 20))	('RCC metastasis', 'Disease', 'MESH:C538614', (87, 101))	('-14A> T', 'Mutation', 'rs168753', (38, 45))	('RCC metastasis', 'Disease', (87, 101))	('variant IVSn-14A> T', 'Var', (26, 45))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
24207	29291033	Activated PAR-1 also promotes colon cancer cell proliferation EGFR transactivation.	('EGFR', 'Gene', '1956', (62, 66))	('transactivation', 'biological_process', 'GO:2000144', ('67', '82'))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('EGFR', 'Gene', (62, 66))	('promotes', 'PosReg', (21, 29))	('Activated', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('colon cancer', 'Disease', (30, 42))	('PAR-1', 'Gene', (10, 15))	('rat', 'Species', '10116', (55, 58))
24210	29291033	According to a survey of 209 patients, PAR-1 polymorphism was associated with tumor stage and median OS (overall survival) of squamous cell lung cancer patients.	('squamous cell lung cancer', 'Disease', (126, 151))	('patients', 'Species', '9606', (29, 37))	('polymorphism', 'Var', (45, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('PAR-1', 'Gene', (39, 44))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (126, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (126, 151))	('median', 'CPA', (94, 100))	('tumor', 'Disease', (78, 83))	('patients', 'Species', '9606', (152, 160))
24214	29291033	Galphaq and Galpha13, coupled with PAR-1 as well as constitutively active GalphaqQL and Galpha12/13QL mutants to stimulate SCLC (small cell lung cancer) to connect autocrine bombesin (BBS).	('mutants', 'Var', (102, 109))	('small cell lung cancer', 'Disease', (129, 151))	('stimulate', 'PosReg', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SCLC', 'Disease', (123, 127))	('Galphaq', 'Gene', '2776', (74, 81))	('bombesin', 'Gene', (174, 182))	('Galphaq', 'Gene', (0, 7))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (129, 151))	('Galphaq', 'Gene', '2776', (0, 7))	('SCLC', 'Disease', 'MESH:D018288', (123, 127))	('Galpha13', 'Gene', '10672', (12, 20))	('Galpha12/13QL', 'Gene', (88, 101))	('Galpha13', 'Gene', (12, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('bombesin', 'Gene', '2922', (174, 182))	('small cell lung cancer', 'Disease', 'MESH:D055752', (129, 151))	('Galpha12/13QL', 'Gene', '2768', (88, 101))	('Galphaq', 'Gene', (74, 81))
24220	29291033	Unregulated PAR-1 expression in peritumoral stroma of prostate cancer patient is associated with biochemical recurrence.	('Unregulated', 'Var', (0, 11))	('stroma of prostate cancer', 'Disease', (44, 69))	('PAR-1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('stroma of prostate cancer', 'Disease', 'MESH:D011471', (44, 69))	('associated', 'Reg', (81, 91))	('biochemical recurrence', 'Disease', (97, 119))	('tumor', 'Disease', (36, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
24222	29291033	Tissue kallikrein (TK) promotes keratinocyte migration through activation of PAR-1 and transactivation of EGFR.	('TK', 'Gene', '3816', (19, 21))	('rat', 'Species', '10116', (48, 51))	('kallikrein', 'molecular_function', 'GO:0004293', ('7', '17'))	('promotes', 'PosReg', (23, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('PAR-1', 'Gene', (77, 82))	('transactivation', 'Var', (87, 102))	('Tissue kallikrein', 'Gene', '3816', (0, 17))	('Tissue kallikrein', 'Gene', (0, 17))	('EGFR', 'Gene', '1956', (106, 110))	('rat', 'Species', '10116', (34, 37))	('kallikrein', 'molecular_function', 'GO:0003807', ('7', '17'))	('keratinocyte migration', 'biological_process', 'GO:0051546', ('32', '54'))	('transactivation', 'biological_process', 'GO:2000144', ('87', '102'))	('keratinocyte migration', 'CPA', (32, 54))	('activation', 'PosReg', (63, 73))	('EGFR', 'Gene', (106, 110))
24229	29291033	Per HIF-alpha/VEGF pathway, PAR-1 maintains self-renewal and tumorigenicity of tumor-initiating progenitor cells (TPC) in gliomas, whilst inhibition of PAR-1 signaling slows down tumor progression.	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('PAR-1', 'Gene', (28, 33))	('inhibition', 'Var', (138, 148))	('self-renewal', 'CPA', (44, 56))	('VEGF', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('gliomas', 'Disease', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('maintains', 'PosReg', (34, 43))	('VEGF', 'Gene', '7422', (14, 18))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (179, 184))
24233	29291033	According to the experimental research mentioned above, PAR-1 inhibitors may have the effect of inhibiting tumor cell proliferation, reducing invasion and metastasis, and anti-tumor angiogenesis.	('rat', 'Species', '10116', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (176, 181))	('angiogenesis', 'biological_process', 'GO:0001525', ('182', '194'))	('inhibiting', 'NegReg', (96, 106))	('inhibitors', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PAR-1', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('reducing', 'NegReg', (133, 141))
24234	29291033	Currently, vorapaxar (SCH530348) and atopaxar (E5555) are the two clinical formulations of PAR-1 inhibitors,which have undergone extensive clinical development.	('E5555', 'Var', (47, 52))	('PAR-1', 'Gene', (91, 96))	('SCH530348', 'Var', (22, 31))	('vorapaxar', 'Chemical', 'MESH:C530299', (11, 20))	('SCH530348', 'Chemical', 'MESH:C530299', (22, 31))
24256	29291033	Although PAR-1 antagonists are known to be potent antiplatelet agents that are also complementary to other antiplatelet therapies, its role in clinical cancer treatment is still a mystery.	('PAR-1', 'Gene', (9, 14))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('antagonists', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
24259	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))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('EGFR', 'Gene', '1956', (89, 93))
24261	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))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('EGFR', 'Gene', '1956', (51, 55))
24262	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', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenosquamous lung carcinoma', 'Disease', (11, 39))
24265	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', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))	('aggressive malignancy', 'Disease', 'MESH:D009369', (35, 56))
24274	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))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('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))
24275	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', 'molecular_function', 'GO:0005006', ('76', '80'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (109, 113))	('improved', 'PosReg', (123, 131))	('mutations', 'Var', (17, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))
24276	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))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
24277	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', 'molecular_function', 'GO:0005006', ('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))
24278	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', 'molecular_function', 'GO:0005006', ('191', '195'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))
24286	27623437	EGFR mutations were detected in 27.4% (29/106) of 106 patients.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
24287	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))	('G719X', 'Mutation', 'p.G719X', (209, 214))	('patients', 'Species', '9606', (13, 21))	('del19', 'Mutation', 'c.del19', (69, 74))	('L858R', 'Mutation', 'rs121434568', (120, 125))	('G719X', 'Var', (209, 214))	('S768I', 'Mutation', 'rs121913465', (230, 235))	('G719X', 'Mutation', 'p.G719X', (155, 160))	('G719X', 'Var', (155, 160))
24298	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))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (92, 96))	('mutation', 'Var', (97, 105))	('adenosquamous lung carcinoma', 'Disease', (116, 144))	('NSE', 'Gene', '2026', (37, 40))	('CEA', 'Gene', (42, 45))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (116, 144))
24299	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))
24300	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', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('women', 'Species', '9606', (90, 95))
24303	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))
24309	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).	('patients', 'Species', '9606', (57, 65))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))
24310	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', 'molecular_function', 'GO:0005006', ('53', '57'))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('del19', 'Var', (115, 120))	('adenosquamous lung carcinoma', 'Disease', (10, 38))
24315	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))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('common', 'Reg', (24, 30))	('EGFR', 'Gene', '1956', (0, 4))
24316	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
24327	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', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
24328	27623437	Consistent with previous studies, we observed that EGFR mutation frequency was increased in never-smokers and in females.	('mutation', 'Var', (56, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
24330	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', 'molecular_function', 'GO:0005006', ('139', '143'))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', (139, 143))	('patients', 'Species', '9606', (110, 118))	('mutation', 'Var', (84, 92))
24331	27623437	In addition, a prior study showed an adenosquamous lung carcinoma patient harboring EGFR-sensitizing mutation had a remarkable response to gefitinib.	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('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))
24332	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', 'molecular_function', 'GO:0005006', ('10', '14'))	('EGFR', 'Gene', '1956', (164, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))
24345	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))
24346	27623437	In our study, elevated levels of neither Cyfra21-1 nor CEA were associated adenosquamous lung carcinoma patient prognosis.	('associated', 'Reg', (64, 74))	('CEA', 'Gene', (55, 58))	('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))
24351	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', 'molecular_function', 'GO:0005006', ('136', '140'))	('EGFR', 'Gene', (136, 140))
24352	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
24354	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))
24363	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))
24375	28195146	Autophagy was higher in CL1-5 and H1299 cells with lower AhR levels than in A549 cells.	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('CL1', 'Gene', (24, 27))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('CL1', 'Gene', '22859', (24, 27))	('lower', 'NegReg', (51, 56))	('H1299', 'Var', (34, 39))	('AhR levels', 'MPA', (57, 67))	('Autophagy', 'CPA', (0, 9))	('H1299', 'CellLine', 'CVCL:0060', (34, 39))	('higher', 'PosReg', (14, 20))
24377	28195146	AhR silencing in A549 cells also reduced BNIP3 ubiquitination.	('A549', 'CellLine', 'CVCL:0023', (17, 21))	('reduced', 'NegReg', (33, 40))	('BNIP3 ubiquitination', 'MPA', (41, 61))	('silencing', 'Var', (4, 13))
24393	28195146	Although aberrant EMT is known to contribute to cell motility during carcinoma progression, regulation of the molecular mechanisms involved has not been thoroughly investigated.	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('carcinoma', 'Disease', (69, 78))	('cell motility', 'CPA', (48, 61))	('contribute', 'Reg', (34, 44))	('cell motility', 'biological_process', 'GO:0048870', ('48', '61'))	('aberrant', 'Var', (9, 17))	('EMT', 'biological_process', 'GO:0001837', ('18', '21'))	('carcinoma', 'Disease', 'MESH:D002277', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
24417	28195146	In contrast to BafA1 treated group, treatment with ATG12 siRNA and BNIP3 knockdown in cells also impaired CL1-5 migration potential (Fig.	('BNIP3', 'Gene', (67, 72))	('impaired', 'NegReg', (97, 105))	('CL1', 'Gene', (106, 109))	('CL1', 'Gene', '22859', (106, 109))	('ATG12', 'Gene', '9140', (51, 56))	('BafA1', 'Chemical', 'MESH:C040929', (15, 20))	('ATG12', 'Gene', (51, 56))	('men', 'Species', '9606', (41, 44))	('knockdown', 'Var', (73, 82))
24422	28195146	wt-CL1-5 with low AhR protein expression showed highly metastatic spread to the lungs, which could be decreased by BafA1 treatment.	('men', 'Species', '9606', (126, 129))	('CL1', 'Gene', (3, 6))	('AhR protein', 'Protein', (18, 29))	('CL1', 'Gene', '22859', (3, 6))	('metastatic spread to the lungs', 'CPA', (55, 85))	('BafA1', 'Chemical', 'MESH:C040929', (115, 120))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('low', 'Var', (14, 17))
24428	28195146	In accordance with our above results, AhR knockdown increased the levels of BNIP3, LC3II/I, and ATG12-5 proteins.	('BNIP3', 'Protein', (76, 81))	('levels', 'MPA', (66, 72))	('increased', 'PosReg', (52, 61))	('LC3', 'Gene', '84557', (83, 86))	('ATG12', 'Gene', '9140', (96, 101))	('LC3', 'Gene', (83, 86))	('ATG12', 'Gene', (96, 101))	('knockdown', 'Var', (42, 51))	('AhR', 'Gene', (38, 41))
24429	28195146	p62 protein expression was dramatically decreased in AhR knockdown cells, indicating the potent induction of autophagy.	('autophagy', 'biological_process', 'GO:0016236', ('109', '118'))	('protein', 'Protein', (4, 11))	('p62', 'Gene', '8878', (0, 3))	('autophagy', 'biological_process', 'GO:0006914', ('109', '118'))	('induction', 'Reg', (96, 105))	('p62', 'Gene', (0, 3))	('knockdown', 'Var', (57, 66))	('autophagy', 'CPA', (109, 118))	('decreased', 'NegReg', (40, 49))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
24431	28195146	BafA1 treatment was used to confirm autophagy flux in AhR knockdown A549 cells compared to in wt-A549 cells.	('BafA1', 'Chemical', 'MESH:C040929', (0, 5))	('autophagy flux', 'CPA', (36, 50))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('knockdown', 'Var', (58, 67))	('men', 'Species', '9606', (11, 14))
24443	28195146	AhR-overexpressing CL1-5 cells showed a greater increase in BNIP3 accumulation following MG132 treatment compared to BafA1 treatment (Fig.	('CL1', 'Gene', '22859', (19, 22))	('MG132', 'Chemical', 'MESH:C072553', (89, 94))	('men', 'Species', '9606', (100, 103))	('BNIP3', 'Gene', (60, 65))	('BafA1', 'Chemical', 'MESH:C040929', (117, 122))	('men', 'Species', '9606', (128, 131))	('CL1', 'Gene', (19, 22))	('MG132 treatment', 'Var', (89, 104))	('increase', 'PosReg', (48, 56))
24445	28195146	Interestingly, wt-CL1-5 cells showed an inconsistent BNIP3 protein profile when compared to shAhR -A549 cells, particularly in the MG132-treated group.	('BNIP3 protein profile', 'MPA', (53, 74))	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('CL1', 'Gene', (18, 21))	('MG132-treated', 'Var', (131, 144))	('MG132', 'Chemical', 'MESH:C072553', (131, 136))	('CL1', 'Gene', '22859', (18, 21))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
24450	28195146	AhR knockdown clearly decreased BNIP3 ubiquitination in A549 cells.	('BNIP3', 'Protein', (32, 37))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('knockdown', 'Var', (4, 13))	('AhR', 'Gene', (0, 3))	('decreased', 'NegReg', (22, 31))
24459	28195146	Some studies have suggested both tumour suppressive and oncogenic functions for ligand-activated AhR; however, the other physiological functions of AhR remain unknown.	('AhR', 'Gene', (97, 100))	('oncogenic functions', 'CPA', (56, 75))	('tumour', 'Disease', (33, 39))	('ligand-activated', 'Var', (80, 96))	('ligand', 'molecular_function', 'GO:0005488', ('80', '86'))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
24469	28195146	3-MA is an inhibitor of phosphatidylinositol 3-kinases; several studies have revealed that inhibition of the phosphatidylinositol 3-kinases/AKT pathway suppresses cell migration and invasion.	('suppresses', 'NegReg', (152, 162))	('AKT', 'Gene', (140, 143))	('inhibition', 'Var', (91, 101))	('cell migration', 'CPA', (163, 177))	('AKT', 'Gene', '207', (140, 143))	('3-MA', 'Chemical', '-', (0, 4))	('cell migration', 'biological_process', 'GO:0016477', ('163', '177'))
24471	28195146	2b,c), ATG12 siRNA and BNIP3 shRNA also impaired cell migration in CL1-5 cells (Fig.	('cell migration', 'biological_process', 'GO:0016477', ('49', '63'))	('ATG12', 'Gene', '9140', (7, 12))	('BNIP3 shRNA', 'Var', (23, 34))	('impaired', 'NegReg', (40, 48))	('CL1', 'Gene', (67, 70))	('ATG12', 'Gene', (7, 12))	('CL1', 'Gene', '22859', (67, 70))
24474	28195146	On the other hand, our finding is consistent with previous studies, BNIP3 is required to maintain steady-state levels of intracellular complexes orchestrating the plasticity of the actin cytoskeleton, knockdown of BNIP3 could enhance melanoma cell migration.	('BNIP3', 'Gene', (214, 219))	('enhance', 'PosReg', (226, 233))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('181', '199'))	('knockdown', 'Var', (201, 210))	('cell migration', 'biological_process', 'GO:0016477', ('243', '257'))	('intracellular', 'cellular_component', 'GO:0005622', ('121', '134'))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))
24476	28195146	We found E-cadherin was downregulated while AhR knockdown in A549 cells.	('E-cadherin', 'Gene', '999', (9, 19))	('downregulated', 'NegReg', (24, 37))	('AhR', 'Gene', (44, 47))	('cadherin', 'molecular_function', 'GO:0008014', ('11', '19'))	('E-cadherin', 'Gene', (9, 19))	('A549', 'CellLine', 'CVCL:0023', (61, 65))	('knockdown', 'Var', (48, 57))
24498	28195146	In this study, we found that higher AhR protein expression contributed to BNIP3 accumulation following MG132 treatment.	('higher', 'PosReg', (29, 35))	('BNIP3', 'Gene', (74, 79))	('MG132', 'Chemical', 'MESH:C072553', (103, 108))	('men', 'Species', '9606', (114, 117))	('expression', 'MPA', (48, 58))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('MG132', 'Var', (103, 108))	('AhR protein', 'Protein', (36, 47))	('accumulation', 'PosReg', (80, 92))
24517	28195146	The membranes were then incubated overnight at 4  C with specific antibodies as follows: mouse monoclonal anti-AhR (sc-74571; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and anti-p62/SQSTM1 (sc-28359; Santa Cruz Biotechnology); rabbit monoclonal anti-LC3B (GTX127375; Genetex, Irvine, CA, USA), anti-ATG12-5 (GTX124181; Genetex), anti-ATG7 (GTX61647; Genetex), and anti-BNIP3 (ab109362; Abcam, Cambridge, UK), rabbit polyclonal anti-E-cadherin (GTX100443; Genetex) anti-vimentin (GTX100619; Genetex); and mouse monoclonal anti-beta-actin (A1978; Sigma).	('vimentin', 'cellular_component', 'GO:0045098', ('473', '481'))	('p62', 'Gene', '8878', (182, 185))	('p62', 'Gene', (182, 185))	('mouse', 'Species', '10090', (508, 513))	('ATG12', 'Gene', '9140', (303, 308))	('ATG7', 'Gene', '10533', (338, 342))	('beta-actin', 'Gene', '728378', (530, 540))	('cadherin', 'molecular_function', 'GO:0008014', ('438', '446'))	('vimentin', 'cellular_component', 'GO:0045099', ('473', '481'))	('SQSTM1', 'Gene', (186, 192))	('GTX100619', 'Var', (483, 492))	('LC3B', 'Gene', (254, 258))	('rabbit', 'Species', '9986', (413, 419))	('rabbit', 'Species', '9986', (231, 237))	('LC3B', 'Gene', '81631', (254, 258))	('E-cadherin', 'Gene', '999', (436, 446))	('ATG7', 'Gene', (338, 342))	('SQSTM1', 'Gene', '8878', (186, 192))	('vimentin', 'Gene', '7431', (473, 481))	('beta-actin', 'Gene', (530, 540))	('E-cadherin', 'Gene', (436, 446))	('vimentin', 'Gene', (473, 481))	('ATG12', 'Gene', (303, 308))	('mouse', 'Species', '10090', (89, 94))
24594	33568752	These variations activate the nonenzymatic Maillard reaction, leading to the formation of glycation products and AGEs.	('nonenzymatic Maillard reaction', 'Enzyme', (30, 60))	('formation of glycation products', 'MPA', (77, 108))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('activate', 'PosReg', (17, 25))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('variations', 'Var', (6, 16))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('AGEs', 'MPA', (113, 117))	('leading to', 'Reg', (62, 72))
24614	33568752	Activation of these proteins usually increases oxidative stress and inflammation that, in turn, promotes RAGE expression in a positive feed-forward loop, contributing to chronic disease development.	('RAGE expression in a positive feed-forward loop', 'MPA', (105, 152))	('n', 'Chemical', 'MESH:D009584', (156, 157))	('inflammation', 'biological_process', 'GO:0006954', ('68', '80'))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('chronic disease', 'Disease', (170, 185))	('oxidative stress', 'Phenotype', 'HP:0025464', (47, 63))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('Activation', 'Var', (0, 10))	('inflammation', 'Disease', (68, 80))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('promotes', 'PosReg', (96, 104))	('n', 'Chemical', 'MESH:D009584', (174, 175))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('contributing to', 'Reg', (154, 169))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('oxidative stress', 'MPA', (47, 63))	('increases', 'PosReg', (37, 46))	('chronic disease', 'Disease', 'MESH:D002908', (170, 185))	('n', 'Chemical', 'MESH:D009584', (69, 70))
24617	33568752	These AGE cell surface receptors include AGE-R1, AGE-R2, AGE-R3, and scavenger receptors such as macrophage scavenger receptors, scavenger receptor class B type I and II (SR-BI, SR-BII), and cluster of differentiation 36 (CD36).	('CD36', 'Species', '42374', (222, 226))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('AGE-R2', 'Var', (49, 55))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('AGE-R1', 'Gene', '1650', (41, 47))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('CD36', 'Gene', (222, 226))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('cell surface', 'cellular_component', 'GO:0009986', ('10', '22'))	('n', 'Chemical', 'MESH:D009584', (216, 217))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('cell surface receptor', 'Gene', (10, 31))	('AGE-R1', 'Gene', (41, 47))	('cell surface receptor', 'Gene', '57126', (10, 31))
24620	33568752	Consequently, these changes lead to increased oxidative stress, insulin resistance, inflammation, pancreatic beta-cell dysfunction with apoptosis, and eventually diabetic complications, including retinopathy, neuropathy, cardiomyopathy, microvascular complications, and nephropathy.	('n', 'Chemical', 'MESH:D009584', (148, 149))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (221, 235))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('cardiomyopathy', 'Disease', 'MESH:D009202', (221, 235))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('insulin', 'molecular_function', 'GO:0016088', ('64', '71'))	('retinopathy', 'Disease', (196, 207))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('nephropathy', 'Disease', (270, 281))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('neuropathy', 'Disease', 'MESH:D009422', (209, 219))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('oxidative stress', 'Phenotype', 'HP:0025464', (46, 62))	('microvascular complications', 'Disease', (237, 264))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (36, 62))	('beta-cell dysfunction', 'Phenotype', 'HP:0006279', (109, 130))	('diabetic complications', 'Disease', (162, 184))	('nephropathy', 'Disease', 'MESH:D007674', (270, 281))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('diabetic complications', 'Disease', 'MESH:D048909', (162, 184))	('inflammation', 'Disease', (84, 96))	('n', 'Chemical', 'MESH:D009584', (262, 263))	('increased', 'PosReg', (36, 45))	('insulin', 'Gene', '3630', (64, 71))	('retinopathy', 'Disease', 'MESH:D012164', (196, 207))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('lead', 'Reg', (28, 32))	('changes', 'Var', (20, 27))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('retinopathy', 'Phenotype', 'HP:0000488', (196, 207))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (270, 271))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('cardiomyopathy', 'Disease', (221, 235))	('pancreatic beta-cell dysfunction', 'Disease', 'MESH:D010182', (98, 130))	('nephropathy', 'Phenotype', 'HP:0000112', (270, 281))	('pancreatic beta-cell dysfunction', 'Disease', (98, 130))	('n', 'Chemical', 'MESH:D009584', (267, 268))	('neuropathy', 'Phenotype', 'HP:0009830', (209, 219))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('oxidative stress', 'MPA', (46, 62))	('apoptosis', 'CPA', (136, 145))	('neuropathy', 'Disease', (209, 219))	('insulin', 'Gene', (64, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('insulin resistance', 'Phenotype', 'HP:0000855', (64, 82))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (187, 188))
24625	33568752	AGEs play important roles in diabetic microvascular complications by cross-linking with extracellular matrix proteins, thereby altering vascular elasticity, structure, and function.	('structure', 'MPA', (157, 166))	('extracellular', 'Protein', (88, 101))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('cross-linking', 'Var', (69, 82))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (174, 175))	('diabetic microvascular complications', 'Disease', (29, 65))	('altering', 'Reg', (127, 135))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('88', '108'))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('vascular', 'MPA', (136, 144))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('function', 'MPA', (172, 180))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('diabetic microvascular complications', 'Disease', 'MESH:D048909', (29, 65))
24677	33568752	In the brain, AGEs can be produced as a result of elevated oxidative stress during aging or chronic exposure to toxic agents such as alcohol (ethanol), n-6 fatty acid-containing high-fat Western diets, and sugary soft drinks.	('n-6', 'Var', (152, 155))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('oxidative stress', 'MPA', (59, 75))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('ethanol', 'Chemical', 'MESH:D000431', (142, 149))	('elevated', 'PosReg', (50, 58))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('alcohol', 'Chemical', 'MESH:D000438', (133, 140))	('sugar', 'Chemical', 'MESH:D000073893', (206, 211))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('aging', 'biological_process', 'GO:0007568', ('83', '88'))	('n', 'Chemical', 'MESH:D009584', (203, 204))	('n-6 fatty acid', 'Chemical', 'MESH:D043371', (152, 166))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (146, 147))
24692	33568752	Furthermore, AGEs cross-linked with Abeta can also decrease the ability of microglia to clear plaques.	('Abeta', 'Gene', (36, 41))	('cross-linked', 'Var', (18, 30))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('decrease', 'NegReg', (51, 59))	('Abeta', 'Gene', '351', (36, 41))
24707	33568752	Accumulated AGEs and AGE-RAGE interactions in these cells augment the generation of ROS and the activation of MAPK and NF-kappaB pathways, leading to inflammatory cell death in the parenchyma and tissue remodeling processes during fibrosis.	('interactions', 'Var', (30, 42))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (211, 212))	('n', 'Chemical', 'MESH:D009584', (185, 186))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('MAPK', 'Gene', '5595;5594;5595', (110, 114))	('NF-kappaB', 'Gene', (119, 128))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('ROS', 'Chemical', '-', (84, 87))	('fibrosis', 'Disease', 'MESH:D005355', (231, 239))	('fibrosis', 'Disease', (231, 239))	('RAGE interaction', 'Phenotype', 'HP:0000718', (25, 41))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('NF-kappaB', 'Gene', '4790', (119, 128))	('MAPK', 'Gene', (110, 114))	('inflammatory cell death', 'CPA', (150, 173))	('ROS', 'MPA', (84, 87))	('cell death', 'biological_process', 'GO:0008219', ('163', '173'))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('tissue remodeling processes', 'CPA', (196, 223))	('RAGE interactions', 'Phenotype', 'HP:0000718', (25, 42))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('augment', 'PosReg', (58, 65))	('leading to', 'Reg', (139, 149))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('rat', 'Species', '10116', (74, 77))	('tissue remodeling', 'biological_process', 'GO:0048771', ('196', '213'))	('MAPK', 'molecular_function', 'GO:0004707', ('110', '114'))
24717	33568752	Catalase present in peroxisomes may participate in ethanol oxidation in the presence of H2O2, although this enzyme appears to play no major role in hepatic ethanol metabolism under physiological conditions due to the limited supply of H2O2.	('Catalase', 'Gene', (0, 8))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('ethanol oxidation', 'MPA', (51, 68))	('H2O2', 'Chemical', 'MESH:D006861', (235, 239))	('ethanol oxidation', 'biological_process', 'GO:0006069', ('51', '68'))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('n', 'Chemical', 'MESH:D009584', (176, 177))	('Catalase', 'Gene', '847', (0, 8))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('ethanol', 'Chemical', 'MESH:D000431', (156, 163))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('H2O2', 'Chemical', 'MESH:D006861', (88, 92))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('ethanol metabolism', 'biological_process', 'GO:0006067', ('156', '174'))	('ethanol', 'Chemical', 'MESH:D000431', (51, 58))	('participate', 'Reg', (36, 47))	('n', 'Chemical', 'MESH:D009584', (197, 198))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (203, 204))	('H2O2', 'Var', (88, 92))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('n', 'Chemical', 'MESH:D009584', (131, 132))
24734	33568752	Free amino acid residues of proteins, lipids, nucleic acids, and nucleophilic molecules are major targets of adduct formation or covalent binding with reactive molecules such as acetaldehyde, acrolein, crotonaldehyde, formaldehyde, malondialdehyde, 4-hydroxynonenal, 8-hydroxydeoxyguanosine, N2-((furan-2-yl)methyl)-2'-deoxyguanosine, and N2-ethyl-2'-deoxyguanosine.	('8-hydroxydeoxyguanosine', 'MPA', (267, 290))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (336, 337))	('n', 'Chemical', 'MESH:D009584', (327, 328))	('8-hydroxydeoxyguanosine', 'Chemical', 'MESH:C067134', (267, 290))	('n', 'Chemical', 'MESH:D009584', (359, 360))	('formaldehyde', 'Chemical', 'MESH:D005557', (218, 230))	('n', 'Chemical', 'MESH:D009584', (288, 289))	('acetaldehyde', 'Chemical', 'MESH:D000079', (178, 190))	('crotonaldehyde', 'Chemical', 'MESH:C012796', (202, 216))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('acrolein', 'Chemical', 'MESH:D000171', (192, 200))	('binding', 'Interaction', (138, 145))	('n', 'Chemical', 'MESH:D009584', (262, 263))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('n', 'Chemical', 'MESH:D009584', (207, 208))	("N2-ethyl-2'-deoxyguanosine", 'Var', (339, 365))	('n', 'Chemical', 'MESH:D009584', (301, 302))	('malondialdehyde', 'Chemical', 'MESH:D008315', (232, 247))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))	('n', 'Chemical', 'MESH:D009584', (331, 332))	('n', 'Chemical', 'MESH:D009584', (236, 237))	("N2-((furan-2-yl)methyl)-2'-deoxyguanosine", 'Chemical', '-', (292, 333))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('n', 'Chemical', 'MESH:D009584', (284, 285))	('n', 'Chemical', 'MESH:D009584', (140, 141))	('n', 'Chemical', 'MESH:D009584', (260, 261))	('n', 'Chemical', 'MESH:D009584', (363, 364))	("N2-ethyl-2'-deoxyguanosine", 'Chemical', 'MESH:C492934', (339, 365))	('n', 'Chemical', 'MESH:D009584', (258, 259))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (249, 265))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('lipids', 'Chemical', 'MESH:D008055', (38, 44))
24768	33568752	These findings suggest a critical role for AA-protein adducts in promoting brain damage and pathophysiology associated with chronic alcohol consumption.	('promoting', 'PosReg', (65, 74))	('chronic alcohol consumption', 'Phenotype', 'HP:0030955', (124, 151))	('n', 'Chemical', 'MESH:D009584', (128, 129))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('brain damage', 'Disease', 'MESH:D001925', (75, 87))	('AA', 'Gene', '351', (43, 45))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('brain damage', 'Disease', (75, 87))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('adducts', 'Var', (54, 61))
24771	33568752	The dual mechanisms of simultaneously elevated AA-DNA adducts and suppressed DNA repair systems following alcohol intake may contribute to genetic instability and DNA mutations, promoting neurological pathologies.	('n', 'Chemical', 'MESH:D009584', (148, 149))	('n', 'Chemical', 'MESH:D009584', (185, 186))	('mutations', 'Var', (167, 176))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('DNA repair', 'biological_process', 'GO:0006281', ('77', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('DNA repair systems', 'Enzyme', (77, 95))	('promoting', 'PosReg', (178, 187))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('n', 'Chemical', 'MESH:D009584', (174, 175))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('neurological pathologies', 'Disease', (188, 212))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('alcohol', 'Chemical', 'MESH:D000438', (106, 113))	('DNA', 'Gene', (163, 166))	('suppressed', 'NegReg', (66, 76))	('AA', 'Gene', '351', (47, 49))	('elevated', 'PosReg', (38, 46))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('contribute', 'Reg', (125, 135))
24775	33568752	These effects can be prevented by treatment with the antioxidant N-acetylcysteine (NAC) or a neutralizing anti-AA-AGE antibody, suggesting a direct role for AA-AGE adducts in generating oxidative stress-induced neurotoxicity.	('n', 'Chemical', 'MESH:D009584', (211, 212))	('antibody', 'molecular_function', 'GO:0003823', ('118', '126'))	('n', 'Chemical', 'MESH:D009584', (177, 178))	('antibody', 'cellular_component', 'GO:0042571', ('118', '126'))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('NAC', 'Chemical', 'MESH:D000111', (83, 86))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('adducts', 'Var', (164, 171))	('neurotoxicity', 'Disease', (211, 224))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('antibody', 'cellular_component', 'GO:0019815', ('118', '126'))	('rat', 'Species', '10116', (179, 182))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('oxidative stress', 'Phenotype', 'HP:0025464', (186, 202))	('neurotoxicity', 'Disease', 'MESH:D020258', (211, 224))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (204, 205))	('NAC', 'cellular_component', 'GO:0005854', ('83', '86'))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('AA', 'Gene', '351', (111, 113))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (65, 81))	('AA', 'Gene', '351', (157, 159))	('antibody', 'cellular_component', 'GO:0019814', ('118', '126'))	('n', 'Chemical', 'MESH:D009584', (107, 108))
24777	33568752	Accumulated AGE-albumin adducts increase the expression of RAGE and activate the MAPK (JNK and p38K)-dependent cell death pathway to promote inflammation, apoptosis, and neuronal damage, which are significantly attenuated by treatment with soluble RAGE and chemical AGE inhibitors.	('p38', 'Gene', '5594', (95, 98))	('inflammation', 'Disease', 'MESH:D007249', (141, 153))	('inflammation', 'biological_process', 'GO:0006954', ('141', '153'))	('RAGE', 'Gene', (59, 63))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('activate', 'PosReg', (68, 76))	('JNK', 'Gene', (87, 90))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('MAPK', 'Gene', '5595;5594;5595', (81, 85))	('n', 'Chemical', 'MESH:D009584', (232, 233))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('inflammation', 'Disease', (141, 153))	('JNK', 'Gene', '5599', (87, 90))	('n', 'Chemical', 'MESH:D009584', (254, 255))	('n', 'Chemical', 'MESH:D009584', (271, 272))	('adducts', 'Var', (24, 31))	('JNK', 'molecular_function', 'GO:0004705', ('87', '90'))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('apoptosis', 'CPA', (155, 164))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('MAPK', 'Gene', (81, 85))	('n', 'Chemical', 'MESH:D009584', (215, 216))	('promote', 'PosReg', (133, 140))	('p38', 'Gene', (95, 98))	('n', 'Chemical', 'MESH:D009584', (206, 207))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('neuronal damage', 'Disease', (170, 185))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('increase', 'PosReg', (32, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('cell death', 'biological_process', 'GO:0008219', ('111', '121'))	('soluble', 'cellular_component', 'GO:0005625', ('240', '247'))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('expression', 'MPA', (45, 55))	('neuronal damage', 'Disease', 'MESH:D009410', (170, 185))	('n', 'Chemical', 'MESH:D009584', (108, 109))	('n', 'Chemical', 'MESH:D009584', (170, 171))
24787	33568752	The presence of MAA adducts in these cells can induce proinflammatory cytokines such as TNF-alpha, IL-12, IL-18, and macrophage migration inhibitory factor (MIF).	('macrophage migration', 'biological_process', 'GO:1905517', ('117', '137'))	('IL-18', 'molecular_function', 'GO:0045515', ('106', '111'))	('MIF', 'Gene', '4282', (157, 160))	('IL-18', 'Gene', '3606', (106, 111))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('MAA', 'Chemical', '-', (16, 19))	('proinflammatory cytokines', 'MPA', (54, 79))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('IL-12', 'molecular_function', 'GO:0005143', ('99', '104'))	('MIF', 'Gene', (157, 160))	('induce', 'PosReg', (47, 53))	('macrophage migration inhibitory factor', 'Gene', (117, 155))	('TNF-alpha', 'Gene', '7124', (88, 97))	('macrophage migration inhibitory factor', 'Gene', '4282', (117, 155))	('TNF-alpha', 'Gene', (88, 97))	('IL-18', 'Gene', (106, 111))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('adducts', 'Var', (20, 27))	('IL-12', 'MPA', (99, 104))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (139, 140))
24789	33568752	These findings indicate a contributing role of MAA and 4-HNE adducts in promoting the hepatic immune response associated with ALD development.	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('hepatic immune response', 'biological_process', 'GO:0002384', ('86', '109'))	('ALD', 'Disease', 'MESH:D000326', (126, 129))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('4-HNE', 'Chemical', 'MESH:C027576', (55, 60))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('hepatic immune response', 'MPA', (86, 109))	('ALD', 'Disease', (126, 129))	('MAA', 'Chemical', '-', (47, 50))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('promoting', 'PosReg', (72, 81))	('adducts', 'Var', (61, 68))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (139, 140))
24795	33568752	These findings suggest a role for AA-AGE adducts in the pathogenesis of AFLD.	('n', 'Chemical', 'MESH:D009584', (50, 51))	('AFLD', 'Disease', 'None', (72, 76))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('adducts', 'Var', (41, 48))	('AA', 'Gene', '351', (34, 36))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('AFLD', 'Disease', (72, 76))
24798	33568752	Additionally, AGE-protein adducts can accumulate as aggregated proteins in the cells, leading to the activation of Kupffer and HSCs in the liver and microglial cells in the brain followed by parenchymal cell death (e.g., hepatocytes and neurons, respectively), suggesting the involvement of AGEs in the progression of ALD and alcohol-mediated multiorgan injury.	('n', 'Chemical', 'MESH:D009584', (297, 298))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (242, 243))	('ALD', 'Disease', 'MESH:D000326', (318, 321))	('adducts', 'Var', (26, 33))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('activation', 'PosReg', (101, 111))	('alcohol', 'Chemical', 'MESH:D000438', (326, 333))	('n', 'Chemical', 'MESH:D009584', (352, 353))	('n', 'Chemical', 'MESH:D009584', (177, 178))	('ALD', 'Disease', (318, 321))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('n', 'Chemical', 'MESH:D009584', (277, 278))	('cell death', 'biological_process', 'GO:0008219', ('203', '213'))	('n', 'Chemical', 'MESH:D009584', (237, 238))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (323, 324))	('n', 'Chemical', 'MESH:D009584', (285, 286))	('n', 'Chemical', 'MESH:D009584', (355, 356))	('n', 'Chemical', 'MESH:D009584', (269, 270))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('n', 'Chemical', 'MESH:D009584', (234, 235))	('n', 'Chemical', 'MESH:D009584', (313, 314))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('n', 'Chemical', 'MESH:D009584', (146, 147))
24799	33568752	Although more detailed studies need to be conducted, the involvement of AGEs - alcohol -adducts in different cells/tissues is presented as follows: Chronic and/or excessive alcohol intake can cause acute respiratory distress syndrome (ARDS) and other types of pulmonary dysfunction characterized by reduced air exchange rates with increased lung epithelial barrier dysfunction, possibly through increased oxidative stress and MDA and 4-HNE adducts.	('excessive alcohol', 'Phenotype', 'HP:0030955', (163, 180))	('pulmonary dysfunction', 'Disease', (260, 281))	('n', 'Chemical', 'MESH:D009584', (242, 243))	('increased', 'PosReg', (331, 340))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('air', 'MPA', (307, 310))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('oxidative stress', 'Phenotype', 'HP:0025464', (405, 421))	('cause', 'Reg', (192, 197))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (423, 424))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (265, 266))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('acute respiratory distress syndrome', 'Disease', (198, 233))	('n', 'Chemical', 'MESH:D009584', (375, 376))	('alcohol', 'Chemical', 'MESH:D000438', (173, 180))	('n', 'Chemical', 'MESH:D009584', (131, 132))	('n', 'Chemical', 'MESH:D009584', (280, 281))	('n', 'Chemical', 'MESH:D009584', (431, 432))	('n', 'Chemical', 'MESH:D009584', (343, 344))	('respiratory distress', 'Phenotype', 'HP:0002098', (204, 224))	('n', 'Chemical', 'MESH:D009584', (396, 397))	('ARDS', 'Disease', (235, 239))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('4-HNE', 'Chemical', 'MESH:C027576', (434, 439))	('n', 'Chemical', 'MESH:D009584', (332, 333))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('rat', 'Species', '10116', (209, 212))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('ARDS', 'Disease', 'MESH:D012128', (235, 239))	('pulmonary dysfunction', 'Disease', 'MESH:D011660', (260, 281))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (316, 317))	('rat', 'Species', '10116', (320, 323))	('excessive', 'Var', (163, 172))	('reduced', 'NegReg', (299, 306))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (395, 421))	('n', 'Chemical', 'MESH:D009584', (370, 371))	('n', 'Chemical', 'MESH:D009584', (227, 228))	('n', 'Chemical', 'MESH:D009584', (275, 276))	('acute respiratory distress syndrome', 'Disease', 'MESH:D012128', (198, 233))	('MDA', 'Chemical', 'MESH:D008315', (426, 429))	('acute respiratory distress', 'Phenotype', 'HP:0011948', (198, 224))
24810	33568752	Excessive alcohol intake is known to cause leaky gut with increased intestinal cell permeability and endotoxemia, possibly via increased CYP2E1 and oxidative stress.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('Excessive alcohol', 'Phenotype', 'HP:0030955', (0, 17))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('endotoxemia', 'Disease', 'MESH:D019446', (101, 112))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('CYP2E1', 'Gene', '1571', (137, 143))	('oxidative stress', 'Phenotype', 'HP:0025464', (148, 164))	('cause', 'Reg', (37, 42))	('n', 'Chemical', 'MESH:D009584', (128, 129))	('increased', 'PosReg', (58, 67))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('intestinal cell permeability', 'MPA', (68, 96))	('gut', 'Gene', (49, 52))	('gut', 'Gene', '110006', (49, 52))	('Excessive alcohol', 'Var', (0, 17))	('CYP2E1', 'Gene', (137, 143))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('endotoxemia', 'Disease', (101, 112))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('increased', 'PosReg', (127, 136))
24815	33568752	Since CYP2E1 and ALDH2 are also expressed in the pancreas, future study of the opposite regulation of CYP2E1 (i.e., induction) and ALDH2 (i.e., inactivation) during the production of MDA and/or 4-HNE adducts and the subsequent damage may be important for understanding the pathogenesis mechanisms of alcohol-mediated pancreatitis and dysfunction.	('ALDH2', 'Gene', (131, 136))	('pancreatitis', 'Phenotype', 'HP:0001733', (317, 329))	('n', 'Chemical', 'MESH:D009584', (266, 267))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('ALDH', 'molecular_function', 'GO:0004030', ('131', '135'))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (248, 249))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('alcohol', 'Chemical', 'MESH:D000438', (300, 307))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('CYP2E1', 'Gene', '1571', (6, 12))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('n', 'Chemical', 'MESH:D009584', (263, 264))	('CYP2E1', 'Gene', (102, 108))	('adducts', 'Var', (200, 207))	('n', 'Chemical', 'MESH:D009584', (344, 345))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('n', 'Chemical', 'MESH:D009584', (280, 281))	('n', 'Chemical', 'MESH:D009584', (256, 257))	('CYP2E1', 'Gene', (6, 12))	('pathogenesis', 'biological_process', 'GO:0009405', ('273', '285'))	('n', 'Chemical', 'MESH:D009584', (319, 320))	('ALDH2', 'Gene', (17, 22))	('n', 'Chemical', 'MESH:D009584', (224, 225))	('ALDH2', 'Gene', '217', (131, 136))	('n', 'Chemical', 'MESH:D009584', (128, 129))	('MDA', 'Chemical', 'MESH:D008315', (183, 186))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (331, 332))	('4-HNE', 'Chemical', 'MESH:C027576', (194, 199))	('ALDH2', 'Gene', '217', (17, 22))	('n', 'Chemical', 'MESH:D009584', (291, 292))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('n', 'Chemical', 'MESH:D009584', (339, 340))	('CYP2E1', 'Gene', '1571', (102, 108))	('regulation', 'biological_process', 'GO:0065007', ('88', '98'))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('pancreatitis and dysfunction', 'Disease', 'MESH:D010195', (317, 345))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (155, 156))	('ALDH', 'molecular_function', 'GO:0004030', ('17', '21'))
24847	33568752	Furthermore, soluble RAGE, inhibitors of the RAGE signaling pathway, neutralizing antibodies against RAGE or AA-AGE adduct, and other AGE-degrading compound(s), such as pyridoxamine and ALT-711, lipoic acid, synthetic compounds OPB-9195, and nitrothiadiazolo[3,2-alpha]pyrimidines, have been reported to decrease AGE adduct formation.	('n', 'Chemical', 'MESH:D009584', (242, 243))	('n', 'Chemical', 'MESH:D009584', (290, 291))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('neutralizing', 'Var', (69, 81))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (210, 211))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('lipoic acid', 'Chemical', 'MESH:D008063', (195, 206))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('soluble', 'cellular_component', 'GO:0005625', ('13', '20'))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (224, 225))	('decrease', 'NegReg', (304, 312))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('formation', 'biological_process', 'GO:0009058', ('324', '333'))	('n', 'Chemical', 'MESH:D009584', (332, 333))	('n', 'Chemical', 'MESH:D009584', (277, 278))	('n', 'Chemical', 'MESH:D009584', (239, 240))	('AGE adduct formation', 'MPA', (313, 333))	('ALT', 'molecular_function', 'GO:0004021', ('186', '189'))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('signaling pathway', 'biological_process', 'GO:0007165', ('50', '67'))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('pyridoxamine', 'Chemical', 'MESH:D011733', (169, 181))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('AA', 'Gene', '351', (109, 111))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('OPB', 'Chemical', '-', (228, 231))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('nitrothiadiazolo[3,2-alpha]pyrimidines', 'Chemical', '-', (242, 280))
24881	33731858	Genomic instability triggers chronic inflammatory signalling from tumour cells themselves, which has recently emerged as a pervasive driver of metastases.	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('Genomic instability', 'Var', (0, 19))	('triggers', 'Reg', (20, 28))	('metastases', 'Disease', (143, 153))	('tumour', 'Disease', (66, 72))	('signalling', 'biological_process', 'GO:0023052', ('50', '60'))
24894	33731858	Over the past few years, however, genomic instability as a result of ongoing errors during mitosis (described below) has emerged as a chronic and tumour cell-intrinsic source of inflammatory signalling that can drive metastasis.	('drive', 'PosReg', (211, 216))	('tumour', 'Disease', (146, 152))	('signalling', 'biological_process', 'GO:0023052', ('191', '201'))	('mitosis', 'Disease', (91, 98))	('genomic instability', 'MPA', (34, 53))	('mitosis', 'Disease', 'None', (91, 98))	('mitosis', 'biological_process', 'GO:0000278', ('91', '98'))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('errors', 'Var', (77, 83))	('metastasis', 'CPA', (217, 227))
24911	33731858	Genomic instability is a tumour cell-intrinsic source of chronic inflammation that has been linked to aggressive features of cancer such as therapeutic resistance and metastasis.	('inflammation', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('linked', 'Reg', (92, 98))	('therapeutic resistance', 'Disease', (140, 162))	('Genomic instability', 'Var', (0, 19))	('inflammation', 'biological_process', 'GO:0006954', ('65', '77'))	('metastasis', 'Disease', (167, 177))	('cancer', 'Disease', (125, 131))	('inflammation', 'Disease', 'MESH:D007249', (65, 77))	('tumour', 'Disease', (25, 31))
24928	33731858	showed that a single point mutation in STING (S365A) specifically abrogates IFN signalling to promote immune evasion.	('IFN', 'Gene', (76, 79))	('immune evasion', 'MPA', (102, 116))	('immune evasion', 'biological_process', 'GO:0042783', ('102', '116'))	('single point mutation', 'Var', (14, 35))	('STING', 'Gene', (39, 44))	('S365A', 'Mutation', 'p.S365A', (46, 51))	('immune evasion', 'biological_process', 'GO:0051842', ('102', '116'))	('signalling', 'biological_process', 'GO:0023052', ('80', '90'))	('promote', 'PosReg', (94, 101))	('IFN', 'Gene', '3439', (76, 79))	('abrogates', 'NegReg', (66, 75))
24932	33731858	Although NKG2D ligands are typically upregulated in non-tumour cells by genotoxic stress and stalled DNA replication, it remains unclear whether NK activating ligands are regulated by genomic instability.	('upregulated', 'PosReg', (37, 48))	('DNA replication', 'biological_process', 'GO:0006260', ('101', '116'))	('NKG2D', 'Gene', '22914', (9, 14))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('stalled DNA', 'Var', (93, 104))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('NKG2D', 'Gene', (9, 14))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))
24937	33731858	This may indicate why inactivating mutations in the cGAS-STING pathway are rarely observed in cancer as a mode of immune evasion despite its role in primary tumour surveillance.	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cGAS-STING', 'Gene', (52, 62))	('inactivating mutations', 'Var', (22, 44))	('tumour', 'Disease', (157, 163))	('immune evasion', 'biological_process', 'GO:0042783', ('114', '128'))	('immune evasion', 'biological_process', 'GO:0051842', ('114', '128'))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
24939	33731858	Maintaining NF-kappaB signalling is relevant in cancer cells, as its expression has been shown to promote metastasis through induction of TWIST and the epithelial-mesenchymal transition (EMT).	('TWIST', 'Gene', (138, 143))	('promote', 'PosReg', (98, 105))	('NF-kappaB', 'Gene', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('152', '185'))	('signalling', 'biological_process', 'GO:0023052', ('22', '32'))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('induction', 'PosReg', (125, 134))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('epithelial-mesenchymal transition', 'CPA', (152, 185))	('TWIST', 'Gene', '7291', (138, 143))	('metastasis', 'CPA', (106, 116))	('NF-kappaB', 'Gene', '4790', (12, 21))	('expression', 'Var', (69, 79))
24954	33731858	As outlined above, chromosomally unstable cancer cells show increased activation of the non-canonical pathway, which is slow and persistent:in stark contrast to the rapid and transient canonical response.	('chromosomally unstable', 'Var', (19, 41))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('non-canonical pathway', 'Pathway', (88, 109))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('activation', 'PosReg', (70, 80))
24982	33731858	Altered Toll-like receptor (TLR) signalling may also contribute to NF-kappaB activity and the responsiveness of stem-like cancer cells to inflammation.	('NF-kappaB', 'Gene', '4790', (67, 76))	('TLR', 'Gene', (28, 31))	('inflammation', 'Disease', (138, 150))	('NF-kappaB', 'Gene', (67, 76))	('contribute', 'Reg', (53, 63))	('signalling', 'biological_process', 'GO:0023052', ('33', '43'))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('TLR', 'Gene', '7098', (28, 31))	('Altered', 'Var', (0, 7))	('inflammation', 'biological_process', 'GO:0006954', ('138', '150'))	('activity', 'MPA', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inflammation', 'Disease', 'MESH:D007249', (138, 150))
24989	33731858	Indeed, the expression of SOX2 has been associated with increased motility, metastasis and chemotherapy resistance in cancer, and the stable knockdown of SOX2 reduces micro-metastatic seeding in our model of delayed lung cancer metastasis.	('knockdown', 'Var', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('motility', 'CPA', (66, 74))	('SOX2', 'Gene', '6657', (154, 158))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('chemotherapy resistance', 'CPA', (91, 114))	('delayed lung', 'Phenotype', 'HP:0002089', (208, 220))	('SOX2', 'Gene', (154, 158))	('expression', 'Var', (12, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('reduces', 'NegReg', (159, 166))	('SOX2', 'Gene', '6657', (26, 30))	('SOX2', 'Gene', (26, 30))	('metastasis', 'CPA', (76, 86))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('increased', 'PosReg', (56, 65))	('lung cancer', 'Disease', (216, 227))	('micro-metastatic seeding', 'CPA', (167, 191))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
24996	33731858	In line with these observations, inhibition of TGF-beta enhances the cytotoxic T cell response against tumour metastasis.	('inhibition', 'Var', (33, 43))	('TGF-beta', 'Gene', '7039', (47, 55))	('tumour metastasis', 'Disease', (103, 120))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('TGF-beta', 'Gene', (47, 55))	('enhances', 'PosReg', (56, 64))	('tumour metastasis', 'Disease', 'MESH:D009362', (103, 120))
24998	33731858	The mechanisms underlying the shift of TGF-beta from tumour suppressive to promoting roles are not well understood, but is thought to involve mutations in the mediators of TGF-beta and changes to the TME that lead to dose-dependent effects of TGF-beta.	('TGF-beta', 'Gene', '7039', (39, 47))	('mutations', 'Var', (142, 151))	('TGF-beta', 'Gene', '7039', (243, 251))	('TGF-beta', 'Gene', (172, 180))	('tumour', 'Disease', (53, 59))	('TME', 'MPA', (200, 203))	('effects', 'Reg', (232, 239))	('TGF-beta', 'Gene', '7039', (172, 180))	('changes', 'Reg', (185, 192))	('TGF-beta', 'Gene', (243, 251))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('TGF-beta', 'Gene', (39, 47))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
25015	33731858	Depletion of NK cells facilitated the emergence of diverse cancer cell subpopulations during metastasis, including the outgrowth of phenotypic states that were otherwise suppressed.	('metastasis', 'CPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Depletion', 'Var', (0, 9))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
25017	33731858	Perturbation of epithelial status directly altered the expression of NK ligands by tumour cells and increased susceptibility to NK cell killing.	('tumour', 'Disease', (83, 89))	('increased', 'PosReg', (100, 109))	('cell killing', 'biological_process', 'GO:0001906', ('131', '143'))	('expression', 'MPA', (55, 65))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('susceptibility', 'CPA', (110, 124))	('Perturbation', 'Var', (0, 12))	('altered', 'Reg', (43, 50))
25036	33731858	Dysfunction in the wound healing response leads to the accumulation of ECM, which prevents proper lung function and can ultimately lead to respiratory failure.	('wound healing response', 'CPA', (19, 41))	('Dysfunction', 'Var', (0, 11))	('respiratory failure', 'Disease', (139, 158))	('prevents', 'NegReg', (82, 90))	('respiratory failure', 'Disease', 'MESH:D012131', (139, 158))	('proper lung function', 'CPA', (91, 111))	('respiratory failure', 'Phenotype', 'HP:0002878', (139, 158))	('wound healing', 'biological_process', 'GO:0042060', ('19', '32'))	('lead to', 'Reg', (131, 138))
25038	33731858	Delaying the production of chemokines and cytokines in wounds is a common source of chronic inflammation that can lead to non-resolving wounds.	('Delaying', 'Var', (0, 8))	('non-resolving wounds', 'Disease', (122, 142))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('inflammation', 'biological_process', 'GO:0006954', ('92', '104'))	('production of chemokines', 'MPA', (13, 37))	('inflammation', 'Disease', (92, 104))	('lead to', 'Reg', (114, 121))
25054	33731858	Disrupted macrophage dynamics leads to chronic inflammation and resumes the wound healing cycle in an amplifying feed-forward loop of inflammation and regeneration that the wound or tumour cannot resolve.	('leads to', 'Reg', (30, 38))	('wound healing cycle', 'CPA', (76, 95))	('inflammation', 'biological_process', 'GO:0006954', ('134', '146'))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('resumes', 'PosReg', (64, 71))	('regeneration', 'biological_process', 'GO:0031099', ('151', '163'))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('wound healing', 'biological_process', 'GO:0042060', ('76', '89'))	('inflammation', 'Disease', 'MESH:D007249', (47, 59))	('inflammation', 'Disease', (47, 59))	('inflammation', 'Disease', 'MESH:D007249', (134, 146))	('tumour', 'Disease', (182, 188))	('inflammation', 'biological_process', 'GO:0006954', ('47', '59'))	('inflammation', 'Disease', (134, 146))	('Disrupted', 'Var', (0, 9))
25056	33731858	Inflammatory signalling generated from within tumour cells themselves results in the chronic engagement of various aspects of the wound healing process:disrupting this interplay to create an unchecked positive feedback loop that has profound consequences on the dissemination, immune surveillance and propagation of metastasis-initiating stem cells to promote cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('consequences', 'Reg', (242, 254))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('wound healing', 'biological_process', 'GO:0042060', ('130', '143'))	('tumour', 'Disease', (46, 52))	('cancer', 'Disease', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('disrupting', 'Var', (152, 162))	('promote', 'PosReg', (352, 359))	('signalling', 'biological_process', 'GO:0023052', ('13', '23'))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
25107	33523599	Then, membranes were incubated with primary antibodies of caspase-3 (1:500 dilutions; a190437, Abcam), MMP-2 (1:500 dilutions; ab97779, Abcam) and MMP-9 (1:500 dilutions; ab38898, Abcam) for 12 hours at cold temperature.	('MMP-2', 'molecular_function', 'GO:0004228', ('103', '108'))	('a190437', 'Var', (86, 93))	('MMP-9', 'Gene', (147, 152))	('caspase-3', 'Gene', '836', (58, 67))	('MMP-9', 'molecular_function', 'GO:0004229', ('147', '152'))	('caspase-3', 'Gene', (58, 67))	('MMP-9', 'Gene', '4318', (147, 152))
25110	33523599	Then, cells were treated primary antibodies of caspase-3 (a190437, Abcam), MMP-2 (ab97779, Abcam) and MMP-9 (ab38898, Abcam) for 12 hours at cold temperature.	('a190437', 'Var', (58, 65))	('ab97779', 'Var', (82, 89))	('caspase-3', 'Gene', (47, 56))	('MMP-2', 'molecular_function', 'GO:0004228', ('75', '80'))	('MMP-9', 'Gene', '4318', (102, 107))	('MMP-9', 'molecular_function', 'GO:0004229', ('102', '107'))	('caspase-3', 'Gene', '836', (47, 56))	('MMP-9', 'Gene', (102, 107))
25151	33523599	Jang et al 38  have reported that the simvastatin induces the activation and nuclear translocation of Nrf2 in cancer cells and simvastatin-activated Nrf2 induces the expression of various anti-oxidant enzymes in tumour cells leading to inhibition of tumour progression.	('Nrf2', 'Gene', (149, 153))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('activation', 'MPA', (62, 72))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('tumour', 'Disease', (212, 218))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('nuclear translocation', 'MPA', (77, 98))	('tumour', 'Disease', 'MESH:D009369', (250, 256))	('tumour', 'Disease', (250, 256))	('Nrf2', 'Gene', '4780', (102, 106))	('cancer', 'Disease', (110, 116))	('induces', 'Reg', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Nrf2', 'Gene', '4780', (149, 153))	('simvastatin-activated', 'Var', (127, 148))	('expression', 'MPA', (166, 176))	('simvastatin', 'Chemical', 'MESH:D019821', (38, 49))	('simvastatin', 'Chemical', 'MESH:D019821', (127, 138))	('Nrf2', 'Gene', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
25180	33556194	4  Here, the breakpoints of SMPD3-ALK fusion were located in the Intron 1 of SMPD3 and the Intron 19 of ALK that preserves the intact kinase domain of the ALK and may lead to the activation of ALK kinase.	('ALK', 'Gene', '238', (34, 37))	('ALK', 'Gene', '238', (155, 158))	('SMPD3', 'Gene', '55512', (77, 82))	('fusion', 'Var', (38, 44))	('lead to', 'Reg', (167, 174))	('ALK', 'Gene', '238', (104, 107))	('SMPD3', 'Gene', (77, 82))	('SMPD3', 'Gene', '55512', (28, 33))	('ALK', 'Gene', '238', (193, 196))	('ALK', 'Gene', (34, 37))	('ALK', 'Gene', (104, 107))	('activation', 'PosReg', (179, 189))	('kinase domain', 'MPA', (134, 147))	('ALK', 'Gene', (155, 158))	('ALK', 'Gene', (193, 196))	('SMPD3', 'Gene', (28, 33))
25181	33556194	Similarly, EML4-ALK fusion with similar breakpoints occurring in the Intron 19 of ALK activates the downstream RAS/MAPK, PI3K/Akt, and JAK signaling pathways.	('RAS/MAPK', 'Pathway', (111, 119))	('fusion', 'Var', (20, 26))	('activates', 'PosReg', (86, 95))	('ALK', 'Gene', (82, 85))	('JAK signaling pathways', 'Pathway', (135, 157))	('Akt', 'Gene', '207', (126, 129))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('EML4', 'Gene', (11, 15))	('JAK', 'molecular_function', 'GO:0004713', ('135', '138'))	('ALK', 'Gene', '238', (16, 19))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('ALK', 'Gene', '238', (82, 85))	('EML4', 'Gene', '27436', (11, 15))	('ALK', 'Gene', (16, 19))	('Akt', 'Gene', (126, 129))
25261	33053604	Transcriptomic analyses have suggested that disruption in oxidative phosphorylation and lipid accumulation may contribute to myosteatosis, as observed in abdominal skeletal muscle biopsies of patients with pancreatic or periampullary cancer and with significantly low radiological attenuation of skeletal muscle on computed tomography scan.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('myosteatosis', 'Disease', (125, 137))	('disruption', 'Var', (44, 54))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('58', '83'))	('patients', 'Species', '9606', (192, 200))	('myosteatosis', 'Disease', 'None', (125, 137))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('lipid accumulation', 'MPA', (88, 106))	('lipid', 'Chemical', 'MESH:D008055', (88, 93))	('contribute', 'Reg', (111, 121))	('cancer', 'Disease', (234, 240))	('pancreatic', 'Disease', 'MESH:D010195', (206, 216))	('pancreatic', 'Disease', (206, 216))	('oxidative phosphorylation', 'MPA', (58, 83))
25262	33053604	93  Genetic and transcriptomic studies of skeletal muscle biopsies obtained from cachectic patients (mainly gastrointestinal cancers) have identified single nucleotide polymorphism 69  and miRNA 70  involved in lipid biosynthesis (Table  1 ).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('miRNA', 'Var', (189, 194))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('patients', 'Species', '9606', (91, 99))	('single nucleotide polymorphism 69', 'Var', (150, 183))	('cancers', 'Disease', (125, 132))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (108, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lipid biosynthesis', 'biological_process', 'GO:0008610', ('211', '229'))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (108, 131))	('gastrointestinal cancer', 'Disease', (108, 131))	('lipid', 'Chemical', 'MESH:D008055', (211, 216))
25280	33053604	These alterations may affect the structure of muscle fibres, the different pathways involved in proteolysis and protein synthesis, lipid metabolism (myosteatosis), and mitochondrial metabolism (i.e.	('lipid metabolism', 'MPA', (131, 147))	('alterations', 'Var', (6, 17))	('metabolism', 'biological_process', 'GO:0008152', ('182', '192'))	('myosteatosis', 'Disease', (149, 161))	('lipid metabolism', 'biological_process', 'GO:0006629', ('131', '147'))	('affect', 'Reg', (22, 28))	('myosteatosis', 'Disease', 'None', (149, 161))	('lipid', 'Chemical', 'MESH:D008055', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('proteolysis', 'biological_process', 'GO:0006508', ('96', '107'))	('structure', 'MPA', (33, 42))	('mitochondrial metabolism', 'MPA', (168, 192))	('rat', 'Species', '10116', (10, 13))	('protein synthesis', 'biological_process', 'GO:0006412', ('112', '129'))
25308	33053604	Even if there are discrepancies in the results of clinical studies, this review suggests the presence of defects in the structure of muscle fibres, increase in proteolysis, decrease in protein synthesis, alterations in lipid metabolism (myosteatosis), and dysfunctions in mitochondrial structure and metabolism (mitochondrial surface and dynamics and mitochondrial DNA) (Table  1 ).	('rat', 'Species', '10116', (208, 211))	('alterations', 'Reg', (204, 215))	('lipid', 'Chemical', 'MESH:D008055', (219, 224))	('proteolysis', 'MPA', (160, 171))	('decrease', 'NegReg', (173, 181))	('myosteatosis', 'Disease', (237, 249))	('myosteatosis', 'Disease', 'None', (237, 249))	('metabolism', 'biological_process', 'GO:0008152', ('300', '310'))	('increase', 'PosReg', (148, 156))	('dysfunctions', 'Var', (256, 268))	('mitochondrial structure', 'MPA', (272, 295))	('lipid metabolism', 'biological_process', 'GO:0006629', ('219', '235'))	('dynamics', 'MPA', (338, 346))	('protein synthesis', 'MPA', (185, 202))	('lipid metabolism', 'MPA', (219, 235))	('metabolism', 'MPA', (300, 310))	('structure', 'MPA', (120, 129))	('protein synthesis', 'biological_process', 'GO:0006412', ('185', '202'))	('mitochondrial DNA', 'MPA', (351, 368))	('proteolysis', 'biological_process', 'GO:0006508', ('160', '171'))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('defects', 'NegReg', (105, 112))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('351', '368'))
25320	33053604	136  Conversely, alterations in mitochondrial metabolism could limit fatty acid beta-oxidation, accentuate the accumulation of lipid droplets, and thereby create a vicious circle.	('fatty acid', 'Chemical', 'MESH:D005227', (69, 79))	('limit', 'NegReg', (63, 68))	('lipid', 'Chemical', 'MESH:D008055', (127, 132))	('create', 'Reg', (155, 161))	('mitochondrial metabolism', 'MPA', (32, 56))	('metabolism', 'biological_process', 'GO:0008152', ('46', '56'))	('vicious circle', 'MPA', (164, 178))	('fatty acid beta-oxidation', 'biological_process', 'GO:0006635', ('69', '94'))	('accentuate', 'PosReg', (96, 106))	('rat', 'Species', '10116', (21, 24))	('fatty acid beta-oxidation', 'MPA', (69, 94))	('accumulation of lipid droplets', 'MPA', (111, 141))	('alterations', 'Var', (17, 28))
25321	33053604	Deterioration of mitochondrial metabolism may also actively participate in muscle wasting via the production of reactive oxygen species.	('Deterioration of mitochondrial metabolism', 'Phenotype', 'HP:0003287', (0, 41))	('muscle wasting', 'Phenotype', 'HP:0003202', (75, 89))	('metabolism', 'biological_process', 'GO:0008152', ('31', '41'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (112, 135))	('participate', 'Reg', (60, 71))	('rat', 'Species', '10116', (7, 10))	('Deterioration', 'Var', (0, 13))	('mitochondrial metabolism', 'MPA', (17, 41))	('muscle wasting', 'Disease', (75, 89))
25340	33053604	demonstrated that excess weight is associated with increased ER stress marker levels in human vastus lateralis.	('excess weight', 'Var', (18, 31))	('ER stress marker levels', 'MPA', (61, 84))	('increased', 'PosReg', (51, 60))	('rat', 'Species', '10116', (7, 10))	('human', 'Species', '9606', (88, 93))
25343	33053604	158   The overall result of clinical studies suggests the presence of alterations in skeletal muscle from cachectic cancer patients, and these alterations could affect myofibers structure, proteolysis, and protein synthesis pathways, as well as lipid and mitochondrial metabolisms.	('proteolysis', 'MPA', (189, 200))	('protein synthesis', 'biological_process', 'GO:0006412', ('206', '223'))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('rat', 'Species', '10116', (74, 77))	('patients', 'Species', '9606', (123, 131))	('mitochondrial metabolisms', 'MPA', (255, 280))	('proteolysis', 'biological_process', 'GO:0006508', ('189', '200'))	('rat', 'Species', '10116', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('protein', 'Pathway', (206, 213))	('lipid', 'Chemical', 'MESH:D008055', (245, 250))	('myofibers structure', 'CPA', (168, 187))	('alterations', 'Var', (143, 154))	('affect', 'Reg', (161, 167))
25352	33174014	Mechanistically, FEZF1-AS1 expression was influenced by N6-methyladenosine (m6A) modification.	('modification', 'Var', (81, 93))	('AS1', 'Gene', '5729', (23, 26))	('AS1', 'Gene', (23, 26))	('expression', 'MPA', (27, 37))	('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))
25362	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('gastric cancer', 'Disease', (3, 17))	('FEZF1', 'Gene', (24, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
25363	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))	('signaling pathway', 'biological_process', 'GO:0007165', ('90', '107'))	('FEZF1', 'Gene', '389549', (31, 36))	('p-catenin', 'Chemical', '-', (80, 89))	('Wnt/p-catenin signaling pathway', 'Pathway', (76, 107))
25418	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))
25419	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))	('miR-516b-5p', 'Var', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ITGA11', 'Gene', '22801', (70, 76))	('FEZF1', 'Gene', (59, 64))	('AS1', 'Gene', '5729', (65, 68))	('AS1', 'Gene', (65, 68))	('ITGA11', 'Gene', (70, 76))
25428	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))
25435	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))
25438	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))	('AS1', 'Gene', (73, 76))	('m6A', 'Var', (108, 111))	('expression', 'MPA', (77, 87))	('FEZF1', 'Gene', '389549', (67, 72))	('regulated', 'Reg', (95, 104))	('FEZF1', 'Gene', (67, 72))
25445	33174014	The present results suggested that the high expression levels of FEZF1-AS1 in NSCLC cells was positively regulated by m6A methylation.	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('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))	('FEZF1', 'Gene', (65, 70))	('NSCLC', 'Disease', (78, 83))	('expression levels', 'MPA', (44, 61))
25451	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))
25453	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))	('H1299', 'CellLine', 'CVCL:0060', (121, 126))	('FEZF1', 'Gene', '389549', (98, 103))	('AS1', 'Gene', '5729', (104, 107))	('H520', 'CellLine', 'CVCL:1566', (131, 135))	('FEZF1', 'Gene', (98, 103))	('ITGA11', 'Gene', '22801', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('decreased', 'NegReg', (78, 87))	('AS1', 'Gene', (104, 107))
25457	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))	('gene ontology', 'biological_process', 'GO:0003673', ('48', '61'))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('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))
25458	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))
25459	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))
25460	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))
25462	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))
25463	33174014	Subsequently, it was examined whether miR-516b-5p-mediated ITGA11 regulation occurred through direct targeting of miRNA-binding sites in the ITGA11 sequence.	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('miRNA-binding', 'Protein', (114, 127))	('ITGA11', 'Gene', '22801', (141, 147))	('ITGA11', 'Gene', (59, 65))	('miRNA-binding', 'molecular_function', 'GO:0035198', ('114', '127'))	('ITGA11', 'Gene', '22801', (59, 65))	('miR-516b-5p', 'Chemical', '-', (38, 49))	('ITGA11', 'Gene', (141, 147))	('miR-516b-5p-mediated', 'Var', (38, 58))	('regulation', 'MPA', (66, 76))
25465	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))
25466	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))
25467	33174014	This repressive effect was abolished by directed mutagenesis of the miR-516b-5p binding seed region in ITGA11.	('mutagenesis', 'biological_process', 'GO:0006280', ('49', '60'))	('ITGA11', 'Gene', '22801', (103, 109))	('miR-516b-5p', 'Chemical', '-', (68, 79))	('abolished', 'NegReg', (27, 36))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('ITGA11', 'Gene', (103, 109))	('miR-516b-5p', 'Var', (68, 79))
25469	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))
25470	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', 'Chemical', '-', (72, 80))	('miR-516b-5p', 'Chemical', '-', (197, 208))	('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', '22801', (236, 242))	('ITGA11', 'Gene', (101, 107))	('miR-516b', 'Chemical', '-', (260, 268))	('expression', 'MPA', (108, 118))	('suppressed', 'NegReg', (90, 100))
25477	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))
25479	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))
25481	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))
25483	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))	('NSCLC', 'Disease', (84, 89))	('miR-516b-5p', 'Var', (48, 59))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('miR-516b-5p', 'Chemical', '-', (48, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))
25484	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))
25485	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('inhibited', 'NegReg', (80, 89))	('miR-516b-5p', 'Var', (68, 79))
25488	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))
25495	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))
25498	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))
25502	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))
25506	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))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('AS1', 'Gene', '5729', (102, 105))	('AS1', 'Gene', (102, 105))	('miR-516b-5p', 'Chemical', '-', (0, 11))	('FEZF1', 'Gene', '389549', (96, 101))	('ITGA11', 'Gene', '22801', (110, 116))	('FEZF1', 'Gene', (96, 101))
25507	33174014	Low miR-516 expression can significantly improve OS in patients with lung squamous cell carcinoma.	('miR-516', 'Chemical', '-', (4, 11))	('miR-516', 'Protein', (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))	('Low', 'Var', (0, 3))
25508	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))
25509	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))	('ITGA11', 'Gene', '22801', (27, 33))	('AS1', 'Gene', (186, 189))	('FEZF1', 'Gene', (180, 185))	('involved', 'Reg', (55, 63))	('AS1', 'Gene', '5729', (186, 189))	('miR-516b-5p', 'Chemical', '-', (38, 49))	('tumor', 'Disease', (159, 164))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('FEZF1', 'Gene', '389549', (180, 185))	('cell proliferation', 'CPA', (67, 85))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('ITGA11', 'Gene', (27, 33))	('invasion', 'CPA', (101, 109))	('miR-516b-5p', 'Var', (38, 49))
25511	33174014	Additionally, ITGA11 expression was decreased following miR-516b overexpression.	('miR-516b', 'Chemical', '-', (56, 64))	('miR-516b', 'Var', (56, 64))	('ITGA11', 'Gene', '22801', (14, 20))	('expression', 'MPA', (21, 31))	('ITGA11', 'Gene', (14, 20))	('decreased', 'NegReg', (36, 45))
25512	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))
25513	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.	('binding', 'molecular_function', 'GO:0005488', ('166', '173'))	('RIP', 'Gene', (8, 11))	('AS1', 'Gene', '5729', (101, 104))	('AS1', 'Gene', (101, 104))	('RIP', 'Gene', '3267', (8, 11))	('miR-516b-5p', 'Chemical', '-', (67, 78))	('AS1', 'Gene', (150, 153))	('FEZF1', 'Gene', '389549', (95, 100))	('miR-516b-5p', 'Var', (128, 139))	('FEZF1', 'Gene', '389549', (144, 149))	('binding', 'Interaction', (166, 173))	('AS1', 'Gene', '5729', (150, 153))	('FEZF1', 'Gene', (95, 100))	('FEZF1', 'Gene', (144, 149))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('miR-516b-5p', 'Chemical', '-', (128, 139))
25514	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))
25601	32486257	MoDCs can promote CD4+ T cell polarization within inflammatory contexts.	('C', 'Chemical', 'MESH:D002244', (3, 4))	('CD4+ T cell', 'MPA', (18, 29))	('T cell polarization', 'biological_process', 'GO:0001768', ('23', '42'))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('MoDCs', 'Var', (0, 5))	('promote', 'PosReg', (10, 17))
25610	32486257	The critical role of cDC1s in antitumor immune defense was demonstrated by the genetic model of Batf3 deficient mice, where cDC1 depletion led to the inability to reject transplantable immunogenic tumors and to sustain immunotherapies based on adoptive T cell transfer or immune checkpoint inhibition.	('Batf3', 'Gene', (96, 101))	('tumor', 'Disease', (34, 39))	('depletion', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cDC1', 'Gene', (124, 128))	('inability', 'Disease', (150, 159))	('immunogenic tumors', 'Disease', 'MESH:D009369', (185, 203))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('Batf3', 'Gene', '381319', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mice', 'Species', '10090', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('immunogenic tumors', 'Disease', (185, 203))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('inability', 'Disease', 'MESH:D007319', (150, 159))
25635	32486257	Depletion of T regulatory (Treg) cells was shown to enhance their migration and ability to prime proinflammatory CD4+ T cells for IFN-gamma production and tumor rejection.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('migration', 'CPA', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('Depletion', 'Var', (0, 9))	('Treg', 'Chemical', '-', (27, 31))	('enhance', 'PosReg', (52, 59))	('IFN-gamma', 'Gene', '3458', (130, 139))	('IFN-gamma', 'Gene', (130, 139))
25658	32486257	IL-10 receptor blockade, in combination with CSF-1 inhibition, was shown to reduce metastatic burden and to improve the efficacy of paclitaxel therapy.	('blockade', 'Var', (15, 23))	('metastatic burden', 'CPA', (83, 100))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('IL-10', 'Gene', (0, 5))	('CSF-1', 'Gene', '1435', (45, 50))	('IL-10', 'molecular_function', 'GO:0005141', ('0', '5'))	('improve', 'PosReg', (108, 115))	('reduce', 'NegReg', (76, 82))	('IL-10', 'Gene', '3586', (0, 5))	('CSF-1', 'molecular_function', 'GO:0005011', ('45', '50'))	('CSF-1', 'Gene', (45, 50))
25730	32486257	By using public datasets of gene expression profiles of whole tumor tissues, the presence of tumor infiltrating cDC1s has emerged to correlate with a better clinical outcome in a variety of different solid tumors.	('gene expression', 'biological_process', 'GO:0010467', ('28', '43'))	('cDC1s', 'Gene', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (93, 98))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('presence', 'Var', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
25746	32486257	Consistent with this finding, infiltration of DC-LAMP+ cells in the TME of ovarian cancer patients and cutaneous malignant melanoma were associated with better overall survival.	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (103, 131))	('cutaneous malignant melanoma', 'Disease', (103, 131))	('DC-LAMP', 'Gene', '27074', (46, 53))	('TME of ovarian cancer', 'Disease', (68, 89))	('infiltration', 'Var', (30, 42))	('TME of ovarian cancer', 'Disease', 'MESH:D010051', (68, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DC-LAMP', 'Gene', (46, 53))	('overall', 'MPA', (160, 167))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('better', 'PosReg', (153, 159))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (103, 131))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('patients', 'Species', '9606', (90, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('malignant melanoma', 'Phenotype', 'HP:0002861', (113, 131))
25751	32486257	PDCs can also induce lymphangiogenesis and neo-angiogenesis through the production of VEGF-C, TNF-alpha and IL-8 which are hallmarks of poor prognosis associated with multifocal intra-peritoneal dissemination.	('neo-angiogenesis', 'CPA', (43, 59))	('IL-8', 'molecular_function', 'GO:0005153', ('108', '112'))	('VEGF-C', 'Gene', (86, 92))	('TNF-alpha', 'Gene', '7124', (94, 103))	('angiogenesis', 'biological_process', 'GO:0001525', ('47', '59'))	('VEGF-C', 'Gene', '7424', (86, 92))	('induce', 'PosReg', (14, 20))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('PDCs', 'Var', (0, 4))	('TNF-alpha', 'Gene', (94, 103))	('IL-8', 'Gene', '3576', (108, 112))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('21', '38'))	('IL-8', 'Gene', (108, 112))	('lymphangiogenesis', 'CPA', (21, 38))
25754	32486257	MoDCs were detected in melanoma nodules in lung and colon carcinoma both in mice and patients, and in ascites from ovarian and breast cancer patients with negative prognostic value.	('C', 'Chemical', 'MESH:D002244', (3, 4))	('detected', 'Reg', (11, 19))	('colon carcinoma', 'Disease', 'MESH:D003110', (52, 67))	('melanoma nodules', 'Disease', (23, 39))	('ascites', 'Phenotype', 'HP:0001541', (102, 109))	('ascites from ovarian and breast cancer', 'Disease', 'MESH:D001201', (102, 140))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('MoDCs', 'Var', (0, 5))	('patients', 'Species', '9606', (85, 93))	('mice', 'Species', '10090', (76, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('colon carcinoma', 'Disease', (52, 67))	('melanoma nodules', 'Disease', 'MESH:D008545', (23, 39))	('lung', 'Disease', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('patients', 'Species', '9606', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
25764	32486257	Considering that all DC subsets can generate an anti-tumor response, several clinical trials were conducted and some are still ongoing (NCT02574377, NCT02692976, NCT02993315), using autologous primary cDC2s and pDCs.	('cDC2', 'Gene', '983', (201, 205))	('NCT02993315', 'Var', (162, 173))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('cDC2', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('tumor', 'Disease', (53, 58))	('C', 'Chemical', 'MESH:D002244', (150, 151))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (137, 138))	('C', 'Chemical', 'MESH:D002244', (213, 214))	('C', 'Chemical', 'MESH:D002244', (203, 204))
25774	32486257	For example, moDCs pulsed with autologous oxidized whole tumor lysates led to prolonged patient survival in a personalized ovarian cancer clinical trial.	('moDCs', 'Var', (13, 18))	('patient', 'Species', '9606', (88, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ovarian cancer', 'Disease', (123, 137))	('patient survival', 'CPA', (88, 104))	('tumor', 'Disease', (57, 62))	('prolonged', 'PosReg', (78, 87))
25776	32486257	Antigen processing and cross-presentation can be improved through the regulation of proteolysis of internalized antigens as recently demonstrated by the genetic deletion of molecules involved in the vesicular trafficking machinery, such as SEC22B and YTHDF1.	('cross-presentation', 'biological_process', 'GO:0002480', ('23', '41'))	('regulation of proteolysis', 'biological_process', 'GO:0030162', ('70', '95'))	('regulation', 'MPA', (70, 80))	('improved', 'PosReg', (49, 57))	('Antigen processing', 'biological_process', 'GO:0019882', ('0', '18'))	('Antigen processing', 'MPA', (0, 18))	('cross-presentation', 'biological_process', 'GO:0042590', ('23', '41'))	('proteolysis', 'MPA', (84, 95))	('genetic deletion', 'Var', (153, 169))	('cross-presentation', 'biological_process', 'GO:0002479', ('23', '41'))	('YTHDF1', 'Gene', '54915', (251, 257))	('YTHDF1', 'Gene', (251, 257))	('SEC22B', 'Gene', (240, 246))	('cross-presentation', 'MPA', (23, 41))	('SEC22B', 'Gene', '9554', (240, 246))
25777	32486257	Another strategy that can be used to improve T cell priming is the silencing of cDC1-intrinsic immunosuppressive signals, by the use of small interfering RNA (siRNA) to delete PD-L1 and PD-L2 as already shown for moDCs.	('PD-L2', 'Gene', (186, 191))	('PD-L2', 'Gene', '80380', (186, 191))	('C', 'Chemical', 'MESH:D002244', (216, 217))	('silencing', 'NegReg', (67, 76))	('delete', 'Var', (169, 175))	('PD-L1', 'Gene', '29126', (176, 181))	('RNA', 'cellular_component', 'GO:0005562', ('154', '157'))	('cDC1-intrinsic immunosuppressive signals', 'MPA', (80, 120))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('PD-L1', 'Gene', (176, 181))
25784	32486257	The knowledge on how to induce CCR7 upregulation generated with moDCs, such as adenoviral transduction, immune adjuvant targeting micelles, and epigenetic regulation, should now be extended to cDC1-based vaccines.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('mice', 'Species', '10090', (130, 134))	('upregulation', 'PosReg', (36, 48))	('transduction', 'biological_process', 'GO:0009293', ('90', '102'))	('CCR', 'molecular_function', 'GO:0043880', ('31', '34'))	('CCR7', 'Gene', (31, 35))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('regulation', 'biological_process', 'GO:0065007', ('155', '165'))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('C', 'Chemical', 'MESH:D002244', (195, 196))	('epigenetic regulation', 'Var', (144, 165))
25790	32486257	The usage of XCL1 variants engineered to enhance receptor stability and chemotactic activity was reported to further improve anti-tumor immune response and could provide a rational for future translational developments.	('XCL1', 'Gene', '6375', (13, 17))	('enhance', 'PosReg', (41, 48))	('variants', 'Var', (18, 26))	('XCL1', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('immune response', 'biological_process', 'GO:0006955', ('136', '151'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('improve', 'PosReg', (117, 124))	('tumor', 'Disease', (130, 135))
25794	32486257	Based on their specialized ability to cross-present tumor antigens to CD8 T cells and to their homing characteristics, cDC1s are emerging as the DC subset endowed with the highest potential to activate an anti-tumor response, both in mouse and human settings.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('C', 'Chemical', 'MESH:D002244', (121, 122))	('human', 'Species', '9606', (244, 249))	('mouse', 'Species', '10090', (234, 239))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('tumor', 'Disease', (52, 57))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cDC1s', 'Var', (119, 124))	('tumor', 'Disease', (210, 215))	('activate', 'PosReg', (193, 201))	('CD8', 'Gene', (70, 73))	('CD8', 'Gene', '925', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
25800	32486257	Additionally, radiotherapy can enhance response to immunotherapy and can promote immune-mediated tumor clearance by a mechanism apparently associated with radiation-induced cytosolic DNA, which stimulates the secretion of IFN-beta by cancer cells.	('stimulates', 'PosReg', (194, 204))	('radiotherapy', 'Var', (14, 26))	('response to', 'CPA', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('IFN-beta', 'Gene', '3439', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('enhance', 'PosReg', (31, 38))	('IFN-beta', 'Gene', (222, 230))	('tumor', 'Disease', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('promote', 'PosReg', (73, 80))	('secretion', 'biological_process', 'GO:0046903', ('209', '218'))
25824	32384792	There is evidence that the dysregulation of iR-200b contributes to oncogenesis and metastasis in some cancers, such as breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('iR-200b', 'Gene', (44, 51))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('metastasis', 'CPA', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('oncogenesis', 'biological_process', 'GO:0007048', ('67', '78'))	('contributes', 'Reg', (52, 63))	('dysregulation', 'Var', (27, 40))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('oncogenesis', 'CPA', (67, 78))
25835	32384792	Disturbance to this equilibrium results in increased angiogenesis, and thus uncontrollable tumour overgrowth.	('tumour overgrowth', 'Disease', 'MESH:D009369', (91, 108))	('angiogenesis', 'CPA', (53, 65))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('tumour overgrowth', 'Disease', (91, 108))	('Disturbance', 'Var', (0, 11))	('increased', 'PosReg', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('overgrowth', 'Phenotype', 'HP:0001548', (98, 108))
25849	32384792	Animal studies showed that removing NRP1 was associated with increased infiltration of TME with antitumoural CD8 T cells, with a reduction in tumour growth.	('tumour', 'Disease', (142, 148))	('CD8', 'Gene', (109, 112))	('removing', 'Var', (27, 35))	('CD8', 'Gene', '925', (109, 112))	('rat', 'Species', '10116', (77, 80))	('reduction', 'NegReg', (129, 138))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour growth', 'Disease', (142, 155))	('infiltration', 'CPA', (71, 83))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('increased', 'PosReg', (61, 70))	('tumour growth', 'Disease', 'MESH:D006130', (142, 155))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('NRP', 'biological_process', 'GO:0085015', ('36', '39'))	('tumour', 'Disease', (100, 106))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('NRP1', 'Gene', '8829', (36, 40))	('NRP1', 'Gene', (36, 40))
25860	32384792	The proangiogenic imbalance often occurs at the gene level due to the activation of oncogenes or inactivation of tumour suppressor genes, all the way to cell environmental factors such as hypoxia, hypoglycaemia, cellular nutrient deficiency and metabolic acidosis.	('hypoglycaemia', 'Disease', (197, 210))	('hypoglycaemia', 'Phenotype', 'HP:0001943', (197, 210))	('deficiency', 'Disease', (230, 240))	('imbalance', 'Phenotype', 'HP:0002172', (18, 27))	('metabolic acidosis', 'Phenotype', 'HP:0001942', (245, 263))	('oncogenes', 'Gene', (84, 93))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('deficiency', 'Disease', 'MESH:D007153', (230, 240))	('hypoxia', 'Disease', (188, 195))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('tumour', 'Disease', (113, 119))	('inactivation', 'Var', (97, 109))	('metabolic acidosis', 'Disease', 'MESH:D000138', (245, 263))	('hypoglycaemia', 'Disease', 'None', (197, 210))	('acidosis', 'Phenotype', 'HP:0001941', (255, 263))	('activation', 'PosReg', (70, 80))	('metabolic acidosis', 'Disease', (245, 263))
25869	32384792	In contrast, inhibiting VEGF-A resulted in suppressing angiogenic switch and tumour growth.	('tumour growth', 'Disease', 'MESH:D006130', (77, 90))	('suppressing', 'NegReg', (43, 54))	('VEGF-A', 'Gene', (24, 30))	('angiogenic switch', 'CPA', (55, 72))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('inhibiting', 'Var', (13, 23))	('tumour growth', 'Disease', (77, 90))
25909	32384792	Other immune modulated strategies that have been studied include: inhibition of Cyclooxygenase-2 (COX-2) expression by COX-2 inhibitors in pancreatic and cervical cancer and Lenalidomide (an immunomodulatory drug) in advanced renal cancer, with benefits in phase two trials but no additional advantage in combination with standard cytotoxic protocols.	('pancreatic and cervical cancer', 'Disease', 'MESH:D010190', (139, 169))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('COX-2', 'Gene', (119, 124))	('expression', 'MPA', (105, 115))	('renal cancer', 'Disease', (226, 238))	('died', 'Disease', (52, 56))	('renal cancer', 'Phenotype', 'HP:0009726', (226, 238))	('Cyclooxygenase-2', 'Gene', '5743', (80, 96))	('inhibitors', 'Var', (125, 135))	('COX-2', 'Gene', '5743', (119, 124))	('Cyclooxygenase-2', 'Gene', (80, 96))	('Lenalidomide', 'Chemical', 'MESH:D000077269', (174, 186))	('renal cancer', 'Disease', 'MESH:D007680', (226, 238))	('COX-2', 'Gene', (98, 103))	('inhibition', 'NegReg', (66, 76))	('died', 'Disease', 'MESH:D003643', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('COX-2', 'Gene', '5743', (98, 103))	('rat', 'Species', '10116', (25, 28))
25912	32384792	Several studies showed that arteriol formation and tortuosity, as well as venous dilation, are increased through VEGF expression.	('expression', 'Var', (118, 128))	('venous dilation', 'Disease', 'MESH:D002311', (74, 89))	('VEGF', 'Gene', (113, 117))	('formation', 'biological_process', 'GO:0009058', ('37', '46'))	('arteriol formation', 'CPA', (28, 46))	('tortuosity', 'CPA', (51, 61))	('venous dilation', 'Disease', (74, 89))	('VEGF', 'Gene', '7422', (113, 117))	('increased', 'PosReg', (95, 104))
25915	32384792	For example, Aflibercept, a decoy receptor that binds VEGF-A, induces the rapid collapse of mother vessels (MV) to glomeruloid microvascular proliferations (GMP).	('mother vessels', 'CPA', (92, 106))	('VEGF-A', 'Gene', (54, 60))	('rat', 'Species', '10116', (148, 151))	('GMP', 'Chemical', '-', (157, 160))	('decoy receptor', 'molecular_function', 'GO:0140319', ('28', '42'))	('collapse', 'NegReg', (80, 88))	('Aflibercept', 'Var', (13, 24))
25949	32384792	Furthermore, genomic instability would enable cancer cells to bypass the VEGF/VEGFR axis and stimulate new blood vessel growth using alternative signaling pathways.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('bypass', 'NegReg', (62, 68))	('cancer', 'Disease', (46, 52))	('VEGFR', 'Gene', (78, 83))	('genomic instability', 'Var', (13, 32))	('VEGF', 'Gene', (78, 82))	('VEGF', 'Gene', '7422', (73, 77))	('new blood vessel growth', 'Phenotype', 'HP:0011496', (103, 126))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('stimulate', 'PosReg', (93, 102))	('new blood vessel growth', 'CPA', (103, 126))	('VEGFR', 'Gene', '3791', (78, 83))	('VEGF', 'Gene', '7422', (78, 82))	('VEGF', 'Gene', (73, 77))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
25957	32384792	Cancer cells are shown to readily uptake nano-particles, and therefore the anti-tumoural activity of endostatin is enhanced when delivered via nano-particles.	('tumour', 'Disease', (80, 86))	('uptake', 'biological_process', 'GO:0098739', ('34', '40'))	('nano-particles', 'Var', (143, 157))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('enhanced', 'PosReg', (115, 123))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('uptake', 'biological_process', 'GO:0098657', ('34', '40'))
25977	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))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('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))
25982	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))
26003	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))
26025	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))
26029	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).	('DSS', 'Chemical', '-', (94, 97))	('longer DSS', 'Disease', (87, 97))	('highly expressed', 'Var', (60, 76))	('STAT1', 'Gene', (77, 82))
26030	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))
26031	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))
26048	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))
26054	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.	('tumor', 'Disease', (4, 9))	('STAT1-deficient', 'Gene', (94, 109))	('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))
26055	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))
26056	32426049	However, on the other hand, two studies have identified high STAT1 mRNA levels associated with poor prognosis, tumor progression, and worse survival in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('tumor', 'Disease', (111, 116))	('STAT1 mRNA levels', 'MPA', (61, 78))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('high', 'Var', (56, 60))
26059	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))
26061	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))
26069	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))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('cell cycle', 'CPA', (35, 45))	('cyclin D1', 'Gene', '595', (102, 111))	('IFNgamma', 'Gene', (61, 69))	('CDK4', 'Gene', (116, 120))	('CDK4', 'Gene', '1019', (116, 120))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('cyclin D1', 'Gene', (102, 111))	('IFNgamma', 'Gene', '3458', (61, 69))	('interaction', 'Interaction', (85, 96))	('STAT1', 'Var', (14, 19))	('cyclin', 'molecular_function', 'GO:0016538', ('102', '108'))	('cell cycle', 'biological_process', 'GO:0007049', ('35', '45'))
26075	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.	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('Ser727', 'Var', (145, 151))	('Ser727', 'Chemical', '-', (145, 151))	('Tyr701', 'Chemical', '-', (134, 140))	('Ser', 'cellular_component', 'GO:0005790', ('145', '148'))	('Tyr701', 'Var', (134, 140))
26076	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))	('death', 'Disease', 'MESH:D003643', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('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))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('impact', 'Reg', (94, 100))
26078	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))	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('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))
26088	32269623	In the present study, using NGS, it was demonstrated that 93 patients (86%) harbored EGFR mutations and 62 patients possessed mutations in EGFR exons 18-21, which are targets of available treatment agents.	('EGFR', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('patients', 'Species', '9606', (61, 69))	('men', 'Species', '9606', (193, 196))	('EGFR', 'Gene', '1956', (139, 143))	('harbored', 'Reg', (76, 84))	('EGFR', 'Gene', (139, 143))	('EGFR', 'Gene', '1956', (85, 89))	('patients', 'Species', '9606', (107, 115))
26089	32269623	EGFR L858R and exon 19 indel mutations were the most frequently observed alterations, with frequencies of 31 and 25%, respectively.	('L858R', 'Mutation', 'rs121434568', (5, 10))	('EGFR', 'Gene', (0, 4))	('exon 19 indel', 'Var', (15, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('L858R', 'Var', (5, 10))	('EGFR', 'Gene', '1956', (0, 4))
26090	32269623	In 1 patient, an EGFR amplification was identified and 6 patients possessed a T790M mutation.	('patient', 'Species', '9606', (5, 12))	('patient', 'Species', '9606', (57, 64))	('T790M', 'Mutation', 'rs121434569', (78, 83))	('patients', 'Species', '9606', (57, 65))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('T790M', 'Var', (78, 83))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
26092	32269623	In 4 patients, significant KRAS mutations (G12D, G12S, G13C and A146T) were observed, which are associated with resistance to afatinib, icotinib, erlotinib and gefitinib.	('G13C', 'Mutation', 'rs121913535', (55, 59))	('afatinib', 'Chemical', 'MESH:D000077716', (126, 134))	('A146T', 'Mutation', 'rs121913527', (64, 69))	('KRAS', 'Gene', '3845', (27, 31))	('patients', 'Species', '9606', (5, 13))	('erlotinib', 'Chemical', 'MESH:D000069347', (146, 155))	('G12D', 'Var', (43, 47))	('associated', 'Reg', (96, 106))	('icotinib', 'Chemical', 'MESH:C531470', (136, 144))	('G12S', 'Var', (49, 53))	('A146T', 'Var', (64, 69))	('G12D', 'Mutation', 'rs121913529', (43, 47))	('gefitinib', 'Chemical', 'MESH:D000077156', (160, 169))	('G12S', 'Mutation', 'rs121913530', (49, 53))	('G13C', 'Var', (55, 59))	('KRAS', 'Gene', (27, 31))
26093	32269623	There were 83 patients with ERBB2 mutations, but only two of these mutations were targets of available treatments.	('men', 'Species', '9606', (108, 111))	('ERBB2', 'Gene', '2064', (28, 33))	('ERBB2', 'Gene', (28, 33))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (34, 43))
26099	32269623	In NSCLCs, mutant oncogenes drive proliferation and tumor maintenance, particularly in adenocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('proliferation', 'CPA', (34, 47))	('mutant', 'Var', (11, 17))	('NSCLCs', 'Disease', 'MESH:D002289', (3, 9))	('tumor', 'Disease', (52, 57))	('adenocarcinomas', 'Disease', 'MESH:D000230', (87, 102))	('drive', 'PosReg', (28, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('adenocarcinomas', 'Disease', (87, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('NSCLCs', 'Disease', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('oncogenes', 'Gene', (18, 27))
26100	32269623	Tumors may be heavily dependent on these driver mutations for survival rather than multiple downstream genetic and epigenetic abnormalities.	('epigenetic abnormalities', 'Disease', (115, 139))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic abnormalities', 'Disease', 'MESH:D018376', (115, 139))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (48, 57))
26101	32269623	Mutations in EGFR and gene fusion of EML4-anaplastic lymphoma kinase (ALK) are the best studied and actionable genes in lung adenocarcinomas and have been observed in 15-60 and 3-5% of lung cancer cases, respectively.	('ALK', 'Gene', '238', (70, 73))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (42, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('ALK', 'Gene', (70, 73))	('EGFR', 'Gene', '1956', (13, 17))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (120, 140))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('EML4-anaplastic lymphoma kinase', 'Gene', (37, 68))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('lung adenocarcinomas', 'Disease', (120, 140))	('observed', 'Reg', (155, 163))	('gene fusion', 'Var', (22, 33))	('EML4-anaplastic lymphoma kinase', 'Gene', '238', (37, 68))	('EGFR', 'Gene', (13, 17))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('lung cancer', 'Disease', (185, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (120, 140))
26102	32269623	Other reported oncogenic driver mutations include KRAS, ROS1, BRAF, ERBB2 and MET.	('ERBB2', 'Gene', '2064', (68, 73))	('KRAS', 'Gene', (50, 54))	('ERBB2', 'Gene', (68, 73))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', '3845', (50, 54))	('ROS1', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('ROS1', 'Gene', '6098', (56, 60))	('MET', 'Disease', (78, 81))
26103	32269623	The presence of EGFR mutations and ALK gene fusions in lung cancer are associated with longer median survival times compared with the wild type status (>24 months vs. 5-9 months).	('ALK', 'Gene', '238', (35, 38))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('lung cancer', 'Disease', (55, 66))	('EGFR', 'Gene', '1956', (16, 20))	('median survival times', 'CPA', (94, 115))	('ALK', 'Gene', (35, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('longer', 'PosReg', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
26113	32269623	In 2014, Akamatsu et al examined genetic alterations in 84 patients with pleural effusions using pyro-sequencing and/or capillary electrophoresis, and reverse-transcription polymerase chain reaction (RT-PCR) and their results showed that 24 patients (28.5%) possessed EGFR mutations, including EGFR G719C/S, G719A, exon 19 deletion, T790M, exon 20 insertion, L858R and L861Q mutations, and 4 patients (4.7%) possessed fusion of ALK-EML4.	('ALK', 'Gene', (428, 431))	('L861Q mutations', 'Var', (369, 384))	('T790M', 'Var', (333, 338))	('G719A', 'Var', (308, 313))	('EGFR', 'Gene', '1956', (268, 272))	('EML4', 'Gene', (432, 436))	('exon 19 deletion', 'Var', (315, 331))	('EML4', 'Gene', '27436', (432, 436))	('pleural effusion', 'Phenotype', 'HP:0002202', (73, 89))	('pleural effusions', 'Disease', (73, 90))	('patients', 'Species', '9606', (59, 67))	('G719C', 'SUBSTITUTION', 'None', (299, 304))	('L858R', 'Mutation', 'rs121434568', (359, 364))	('EGFR', 'Gene', (294, 298))	('patients', 'Species', '9606', (392, 400))	('L861Q', 'Mutation', 'rs121913444', (369, 374))	('G719C', 'Var', (299, 304))	('EGFR', 'molecular_function', 'GO:0005006', ('268', '272'))	('pleural effusions', 'Disease', 'MESH:D010996', (73, 90))	('reverse-transcription', 'biological_process', 'GO:0001171', ('151', '172'))	('patients', 'Species', '9606', (241, 249))	('EGFR', 'molecular_function', 'GO:0005006', ('294', '298'))	('T790M', 'Mutation', 'rs121434569', (333, 338))	('EGFR', 'Gene', (268, 272))	('exon 20 insertion', 'Var', (340, 357))	('L858R', 'Var', (359, 364))	('EGFR', 'Gene', '1956', (294, 298))	('G719A', 'Mutation', 'rs121913428', (308, 313))	('ALK', 'Gene', '238', (428, 431))	('pleural effusions', 'Phenotype', 'HP:0002202', (73, 90))
26114	32269623	Other studies have used direct sequencing methods, reporting an EGFR mutation rate between 25-68%.	('EGFR', 'Gene', (64, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', '1956', (64, 68))
26115	32269623	The use of high resolution melting (HRM) analysis has demonstrated a 50% EGFR mutation rate in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('EGFR', 'Gene', '1956', (73, 77))	('mutation', 'Var', (78, 86))	('EGFR', 'Gene', (73, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('NSCLC', 'Disease', (95, 100))
26116	32269623	Peptide nucleic acid (PNA) clamping methods have reported an EGFR mutation rate between 39-72% in NSCLC.	('nucleic acid', 'cellular_component', 'GO:0005561', ('8', '20'))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('mutation', 'Var', (66, 74))	('NSCLC', 'Disease', (98, 103))	('EGFR', 'Gene', '1956', (61, 65))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('EGFR', 'Gene', (61, 65))
26117	32269623	Buttitta et al conducted next generation pyrosequencing in bronchoalveolar lavage, and pleural fluid patients, demonstrating an EGFR mutation rate of 80.5%.	('patients', 'Species', '9606', (101, 109))	('mutation', 'Var', (133, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('pleural fluid', 'Phenotype', 'HP:0002202', (87, 100))
26119	32269623	This detection method has the power to identify new single nucleotide variations (SNVs) or indel mutations, and chromosomal rearrangements.	('single nucleotide variations', 'Var', (52, 80))	('men', 'Species', '9606', (133, 136))	('indel mutations', 'Var', (91, 106))
26120	32269623	Liu et al evaluated the molecular profiling of lung adenocarcinoma using MPE specimens utilizing NGS, illustrating 22 cases of EGFR mutations within 30 patients (73%), including L858R, G719S, exon 20 insertion and exon 19 deletion, with an average sequencing depth on target of 359X.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('exon 19 deletion', 'Var', (214, 230))	('L858R', 'Var', (178, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('mutations', 'Var', (132, 141))	('exon 20 insertion', 'Var', (192, 209))	('G719S', 'Var', (185, 190))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('L858R', 'Mutation', 'rs121434568', (178, 183))	('G719S', 'Mutation', 'rs28929495', (185, 190))	('lung adenocarcinoma', 'Disease', (47, 66))	('EGFR', 'Gene', '1956', (127, 131))	('men', 'Species', '9606', (82, 85))	('EGFR', 'Gene', (127, 131))	('patients', 'Species', '9606', (152, 160))
26121	32269623	In the present study, multiple oncogene mutations were detected, including 17 genes closely associated with advanced lung cancer induction in 108 MPE samples using deep sequencing methods.	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
26146	32269623	Among the 108 MPE samples, there were only 2 cases (females aged 89 and 62 years old) with insertion of AYVM in M774_A775 in the ERBB2 amino acid sequence, which is sensitive to trastuzumab (Herceptin), ado-trastuzumab emtansine (Kadcyla), and afatinib dimaleate (Gilotrif) treatment.	('ERBB2', 'Gene', (129, 134))	('ERBB2', 'Gene', '2064', (129, 134))	('men', 'Species', '9606', (279, 282))	('M774_A775', 'Var', (112, 121))	('afatinib', 'Chemical', 'MESH:D000077716', (244, 252))	('AYVM', 'Gene', (104, 108))
26147	32269623	Special ERBB2 mutations are noted in Fig.	('ERBB2', 'Gene', '2064', (8, 13))	('mutations', 'Var', (14, 23))	('ERBB2', 'Gene', (8, 13))
26148	32269623	In addition to these two cases of ERBB2 alterations, 83 patients (76.8%) were identified as harboring other ERBB2 mutations of unknown present significance, annotated as 'ERBB2 other mutations' in Fig.	('patients', 'Species', '9606', (56, 64))	('mutations', 'Var', (114, 123))	('ERBB2', 'Gene', (171, 176))	('ERBB2', 'Gene', '2064', (171, 176))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))	('ERBB2', 'Gene', '2064', (108, 113))	('ERBB2', 'Gene', (108, 113))
26149	32269623	EGFR mutations were first identified as NSCLC driver oncogenes by three independent groups in 2004.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('NSCLC', 'Disease', (40, 45))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
26150	32269623	In the present study, analysis of 108 patients with MPE, demonstrated that 93 patients (86%) harbored EGFR mutations, the breakdown by type of which is shown in Fig.	('breakdown', 'biological_process', 'GO:0009056', ('122', '131'))	('mutations', 'Var', (107, 116))	('patients', 'Species', '9606', (78, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('patients', 'Species', '9606', (38, 46))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
26151	32269623	In particularly, 16 patients harbored mutations in EGFR exon 18, among which, only two women possessed the G719A/G719S alterations.	('G719A', 'Var', (107, 112))	('EGFR', 'Gene', (51, 55))	('G719S', 'Mutation', 'rs28929495', (113, 118))	('G719A', 'SUBSTITUTION', 'None', (107, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('patients', 'Species', '9606', (20, 28))	('women', 'Species', '9606', (87, 92))	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (51, 55))
26152	32269623	A total of 28 patients (30%) were found to harbor exon 19 alterations, 24 of which were deletion mutations, primarily in the KELREATS sequence, whereas only one deletion was observed in the TSPKANKE sequence.	('deletion', 'Var', (88, 96))	('patients', 'Species', '9606', (14, 22))	('exon', 'Var', (50, 54))	('alterations', 'Var', (58, 69))
26153	32269623	A total of 3 patients exhibited a E746_S752>V mutation and 1 patient had a L747_P753>S alteration on exon 19 of EGFR.	('EGFR', 'Gene', (112, 116))	('P753>S', 'Mutation', 'rs121913231', (80, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('patient', 'Species', '9606', (61, 68))	('L747_P753>S', 'Var', (75, 86))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('S752>V', 'Mutation', 'p.S752V', (39, 45))	('exhibited', 'Reg', (22, 31))	('EGFR', 'Gene', '1956', (112, 116))	('E746_S752>V', 'Var', (34, 45))
26154	32269623	A total of 18 abnormalities on exon 20 of EGFR were identified, among which, 1 patient had a L798I mutation, one had a T790M/C797S double alteration (cis relationship), six had a T790M mutation and only one had an insertion of threonine between D770 and N771.	('L798I', 'Mutation', 'p.L798I', (93, 98))	('EGFR', 'Gene', '1956', (42, 46))	('threonine', 'Chemical', 'MESH:D013912', (227, 236))	('T790M', 'SUBSTITUTION', 'None', (119, 124))	('EGFR', 'Gene', (42, 46))	('L798I', 'Var', (93, 98))	('T790M', 'Mutation', 'rs121434569', (119, 124))	('T790M', 'SUBSTITUTION', 'None', (179, 184))	('T790M', 'Mutation', 'rs121434569', (179, 184))	('T790M', 'Var', (119, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('patient', 'Species', '9606', (79, 86))	('T790M', 'Var', (179, 184))	('C797S', 'SUBSTITUTION', 'None', (125, 130))	('C797S', 'Var', (125, 130))
26155	32269623	A total of 33 patients (35.5%) harbored mutations on exon 21, including L858R (n=29) and L861Q (n=4).	('L858R', 'Var', (72, 77))	('L861Q', 'Mutation', 'rs121913444', (89, 94))	('L858R', 'Mutation', 'rs121434568', (72, 77))	('patients', 'Species', '9606', (14, 22))	('L861Q', 'Var', (89, 94))
26156	32269623	There was only one case of EGFR amplification that simultaneously harbored a L858R mutation.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('L858R', 'Mutation', 'rs121434568', (77, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('L858R', 'Var', (77, 82))
26157	32269623	Altogether, 62 patients (66.7%) had EGFR mutations that are associated with sensitivity to certain agents, such as icotinib, gefitinib, erlotinib, afatinib and osimertinib.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('gefitinib', 'Chemical', 'MESH:D000077156', (125, 134))	('EGFR', 'Gene', '1956', (36, 40))	('erlotinib', 'Chemical', 'MESH:D000069347', (136, 145))	('EGFR', 'Gene', (36, 40))	('icotinib', 'Chemical', 'MESH:C531470', (115, 123))	('associated', 'Reg', (60, 70))	('afatinib', 'Chemical', 'MESH:D000077716', (147, 155))
26158	32269623	In addition to these mutations, 31 patients (33.3%) possessed EGFR alterations outside of exons 18-21 which do not currently have an available targeted therapy (Fig.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('alterations', 'Var', (67, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('patients', 'Species', '9606', (35, 43))
26161	32269623	An E17K mutation of AKT1 is associated with AKT1 sensitivity to the inhibitor, uprosertib.	('uprosertib', 'Chemical', 'MESH:C000595149', (79, 89))	('AKT1', 'Gene', '207', (20, 24))	('sensitivity to the inhibitor', 'MPA', (49, 77))	('AKT1', 'Gene', (20, 24))	('associated', 'Reg', (28, 38))	('E17K', 'Var', (3, 7))	('AKT1', 'Gene', '207', (44, 48))	('E17K', 'Mutation', 'rs121434592', (3, 7))	('AKT1', 'Gene', (44, 48))
26164	32269623	A total of 45 patients (41.7%) harbored TP53 gene mutations, including SNVs and frameshifts (Fig.	('SNVs', 'Disease', (71, 75))	('frameshifts', 'Var', (80, 91))	('harbored', 'Reg', (31, 39))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('patients', 'Species', '9606', (14, 22))
26169	32269623	In the present study, 23 patients (21.3%) harbored BRAF mutations, including two cases of the N581I mutations, which are sensitive to Solafini.	('mutations', 'Var', (56, 65))	('N581I', 'Mutation', 'p.N581I', (94, 99))	('Solafini', 'Chemical', '-', (134, 142))	('BRAF', 'Gene', '673', (51, 55))	('patients', 'Species', '9606', (25, 33))	('BRAF', 'Gene', (51, 55))
26170	32269623	In 6 patients, KRAS mutations were observed, four of whom had different mutations; G12D, G12S, G13C and A146T.	('patients', 'Species', '9606', (5, 13))	('G12S', 'Var', (89, 93))	('KRAS', 'Gene', (15, 19))	('G13C', 'Var', (95, 99))	('G12S', 'Mutation', 'rs121913530', (89, 93))	('A146T', 'Mutation', 'rs121913527', (104, 109))	('KRAS', 'Gene', '3845', (15, 19))	('G13C', 'Mutation', 'rs121913535', (95, 99))	('G12D', 'Var', (83, 87))	('A146T', 'Var', (104, 109))	('G12D', 'Mutation', 'rs121913529', (83, 87))
26173	32269623	The present study demonstrated that 21 patients (19.4%) harbored PIK3CA mutations, but only one patient harbored a E545K mutation, which is sensitive to Sirolimus and Ivimos (Fig.	('mutations', 'Var', (72, 81))	('patient', 'Species', '9606', (39, 46))	('patients', 'Species', '9606', (39, 47))	('patient', 'Species', '9606', (96, 103))	('PIK3CA', 'Gene', (65, 71))	('harbored', 'Reg', (56, 64))	('Sirolimus', 'Chemical', 'MESH:D020123', (153, 162))	('E545K', 'Mutation', 'rs104886003', (115, 120))	('Ivimos', 'Chemical', '-', (167, 173))	('PIK3CA', 'Gene', '5290', (65, 71))
26174	32269623	PTEN acts as a tumor suppressor gene through its phosphatase activity, and in the present study, 23 patients (21.3%) exhibited PTEN mutations (Fig.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('phosphatase activity', 'MPA', (49, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('49', '69'))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', (15, 20))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (127, 131))	('PTEN', 'Gene', '5728', (0, 4))
26176	32269623	In the present study, 2 patients harbored DDR2 mutations (Fig.	('DDR2', 'Gene', (42, 46))	('DDR2', 'Gene', '4921', (42, 46))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (24, 32))
26177	32269623	No amplifications of the FGFR1 gene were observed, but 20 patients (18.5%) possessed SNVs in this gene (Fig.	('patients', 'Species', '9606', (58, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR1', 'Gene', (25, 30))	('SNVs', 'Var', (85, 89))	('FGFR1', 'Gene', '2260', (25, 30))
26182	32269623	Overall, 6 cases (5.6%) of ALK-EML4 fusions, in 1 man and 5 women, were observed.	('women', 'Species', '9606', (60, 65))	('fusions', 'Var', (36, 43))	('ALK', 'Gene', (27, 30))	('EML4', 'Gene', (31, 35))	('EML4', 'Gene', '27436', (31, 35))	('ALK', 'Gene', '238', (27, 30))
26183	32269623	Table SIII shows the corresponding sequences, in particularly, a man (77 years old) demonstrated gene fusion between ALK exon 20, and EML4 intron 13.	('ALK', 'Gene', '238', (117, 120))	('EML4', 'Gene', (134, 138))	('EML4', 'Gene', '27436', (134, 138))	('gene fusion', 'Var', (97, 108))	('ALK', 'Gene', (117, 120))
26184	32269623	Meanwhile, 5 women possessed gene fusion between ALK intron 19, and different EML4 introns (three cases of intron 6, one case of intron 2, and one case of intron 20).	('ALK', 'Gene', '238', (49, 52))	('EML4', 'Gene', '27436', (78, 82))	('women', 'Species', '9606', (13, 18))	('ALK', 'Gene', (49, 52))	('gene fusion', 'Var', (29, 40))	('EML4', 'Gene', (78, 82))
26185	32269623	A total of 51 patients (47.2%) possessed SNVs in the ALK gene, which have no known significance at present.	('SNVs', 'Var', (41, 45))	('patients', 'Species', '9606', (14, 22))	('ALK', 'Gene', '238', (53, 56))	('ALK', 'Gene', (53, 56))
26186	32269623	Among MPE samples from 108 patients, there was only one person without sex or age information, and this patient had mutations of E746_A750 deletion, and T790M in the EGFR gene, as well as TP53 abnormalities (Table SII).	('T790M', 'Mutation', 'rs121434569', (153, 158))	('T790M', 'Var', (153, 158))	('EGFR', 'Gene', '1956', (166, 170))	('E746_A750 deletion', 'Var', (129, 147))	('EGFR', 'Gene', (166, 170))	('patient', 'Species', '9606', (27, 34))	('patients', 'Species', '9606', (27, 35))	('patient', 'Species', '9606', (104, 111))	('TP53', 'Gene', '7157', (188, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('TP53', 'Gene', (188, 192))
26188	32269623	The mutation rate in females was higher than in males in the ERBB2 special mutations, EGFR exon 18 special mutations, EGFR exon 19 special mutations, ALK fusions, ROS1 fusions, and PIK3CA special mutations.	('ALK', 'Gene', (150, 153))	('ERBB2', 'Gene', (61, 66))	('mutation', 'MPA', (4, 12))	('mutations', 'Var', (107, 116))	('higher', 'Reg', (33, 39))	('EGFR', 'Gene', '1956', (86, 90))	('ERBB2', 'Gene', '2064', (61, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('PIK3CA', 'Gene', (181, 187))	('EGFR', 'Gene', (86, 90))	('ALK', 'Gene', '238', (150, 153))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('mutations', 'Var', (75, 84))	('PIK3CA', 'Gene', '5290', (181, 187))	('ROS1', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('ROS1', 'Gene', '6098', (163, 167))
26189	32269623	The abnormalities in males which were higher compared with females were EGFR exon 21 special mutations, BIM, TP53 mutations, and BRAF special mutations.	('BIM', 'Gene', '10018', (104, 107))	('BIM', 'Gene', (104, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('mutations', 'Var', (114, 123))	('EGFR', 'Gene', '1956', (72, 76))	('TP53', 'Gene', '7157', (109, 113))	('EGFR', 'Gene', (72, 76))	('TP53', 'Gene', (109, 113))
26191	32269623	In particular, there were 36 female patients (64.3%) harboring EGFR mutations with known significance, higher than in males (50.9%).	('EGFR', 'Gene', '1956', (63, 67))	('patients', 'Species', '9606', (36, 44))	('EGFR', 'Gene', (63, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('harboring', 'Reg', (53, 62))	('mutations', 'Var', (68, 77))
26192	32269623	As mentioned above, one patient without age or sex information harbored an E746_A750 deletion, and T790M mutations in the EGFR gene and TP53 abnormalities.	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('T790M', 'Mutation', 'rs121434569', (99, 104))	('E746_A750 deletion', 'Var', (75, 93))	('patient', 'Species', '9606', (24, 31))	('T790M mutations', 'Var', (99, 114))	('TP53', 'Gene', '7157', (136, 140))	('EGFR', 'Gene', '1956', (122, 126))	('TP53', 'Gene', (136, 140))	('EGFR', 'Gene', (122, 126))	('men', 'Species', '9606', (3, 6))
26194	32269623	These results demonstrate that some mutation rates increased with age, including ERBB2 special mutations, PIK3CA special mutations, BRAF special mutations, EGFR exon 21 mutations, EGFR exon 21 special mutations, PTEN mutations, FGFR1 other mutations, EGFR exon 18 mutations, EGFR exon 18 special mutations, BIM mutations, KRAS mutations, and KRAS special mutations.	('mutations', 'Var', (264, 273))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('mutations', 'Var', (121, 130))	('ERBB2', 'Gene', (81, 86))	('mutations', 'Var', (169, 178))	('FGFR1', 'Gene', '2260', (228, 233))	('mutations', 'Var', (145, 154))	('PIK3CA', 'Gene', '5290', (106, 112))	('KRAS', 'Gene', (322, 326))	('PTEN', 'Gene', '5728', (212, 216))	('EGFR', 'Gene', '1956', (251, 255))	('EGFR', 'Gene', '1956', (275, 279))	('ERBB2', 'Gene', '2064', (81, 86))	('mutations', 'Var', (240, 249))	('EGFR', 'Gene', '1956', (156, 160))	('FGFR', 'molecular_function', 'GO:0005007', ('228', '232'))	('EGFR', 'Gene', '1956', (180, 184))	('mutations', 'Var', (95, 104))	('BRAF', 'Gene', '673', (132, 136))	('KRAS', 'Gene', '3845', (342, 346))	('FGFR1', 'Gene', (228, 233))	('BRAF', 'Gene', (132, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('251', '255'))	('EGFR', 'molecular_function', 'GO:0005006', ('275', '279'))	('increased', 'PosReg', (51, 60))	('PIK3CA', 'Gene', (106, 112))	('KRAS', 'Gene', (342, 346))	('BIM', 'Gene', (307, 310))	('EGFR', 'Gene', (275, 279))	('EGFR', 'Gene', (251, 255))	('mutation', 'MPA', (36, 44))	('EGFR', 'Gene', (180, 184))	('EGFR', 'Gene', (156, 160))	('PTEN', 'Gene', (212, 216))	('KRAS', 'Gene', '3845', (322, 326))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('mutations', 'Var', (296, 305))	('BIM', 'Gene', '10018', (307, 310))
26195	32269623	In contrast, other mutation frequencies decreased with age, for example the PIK3CA mutations, EGFR exon 20 special mutations and ROS1 fusions.	('mutations', 'Var', (83, 92))	('ROS1', 'Gene', '6098', (129, 133))	('PIK3CA', 'Gene', '5290', (76, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (94, 98))	('PIK3CA', 'Gene', (76, 82))	('ROS1', 'Gene', (129, 133))
26200	32269623	Stathopoulos et al found that nuclear factor-kappaB affected tumor progression in a mouse model of MPE by injecting Lewis lung cancer cells directly into the pleural space of syngeneic C57B/6 mice.	('mice', 'Species', '10090', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('MPE', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mouse', 'Species', '10090', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('affected', 'Reg', (52, 60))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('C57B', 'SUBSTITUTION', 'None', (185, 189))	('C57B', 'Var', (185, 189))	('tumor', 'Disease', (61, 66))
26211	32269623	These studies showed that EGFR mutation frequency was 80% (29/36 patients) and 73% (22/30 patients).	('EGFR', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', '1956', (26, 30))	('patients', 'Species', '9606', (90, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
26215	32269623	Activating mutations in EGFR are the most well-known among lung adenocarcinomas, which are associated with therapeutic agents, and have been described in 15-60% of lung cancer cases in different studies.	('EGFR', 'Gene', '1956', (24, 28))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (59, 79))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (59, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('lung cancer', 'Disease', (164, 175))	('described', 'Reg', (141, 150))	('Activating mutations', 'Var', (0, 20))	('EGFR', 'Gene', (24, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('lung adenocarcinomas', 'Disease', (59, 79))
26216	32269623	The two most common mutations of EGFR in lung cancer are exon 19 deletions (60%) and the L858R point mutation (35%).	('L858R', 'Mutation', 'rs121434568', (89, 94))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('EGFR', 'Gene', (33, 37))	('L858R point mutation', 'Var', (89, 109))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
26217	32269623	A retrospective single-center study reported that the frequency of these specific EGFR mutations was higher in patients with MPE compared with those without MPE in patients with stage IV lung cancer.	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', (82, 86))	('MPE', 'Disease', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('higher', 'Reg', (101, 107))	('EGFR', 'Gene', '1956', (82, 86))	('patients', 'Species', '9606', (164, 172))	('lung cancer', 'Disease', (187, 198))	('mutations', 'Var', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (111, 119))
26218	32269623	In the present study, 93 patients (86%) with MPE harbored EGFR mutations (Table SII), and molecular profiling of the mutation distribution within these 93 EGFR-positive patients is shown in Fig.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('patients', 'Species', '9606', (169, 177))	('EGFR', 'Gene', '1956', (155, 159))	('EGFR', 'Gene', (58, 62))	('EGFR', 'Gene', (155, 159))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('patients', 'Species', '9606', (25, 33))
26219	32269623	Among these 93 patients, 31 (33.3%) presented with mutations holding no known significance, including the rare mutations within exons 18-21 and mutations outside exons 18-21.	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (15, 23))	('presented', 'Reg', (36, 45))
26223	32269623	Other studies demonstrated that the EGFR exon 19 deletion in lung cancer cell lines resulted in high basal levels of MYC and HIF-1alpha expression, which contributed to tumor angiogenesis and may increase the probability of MPE formation.	('HIF-1alpha', 'Gene', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('angiogenesis', 'biological_process', 'GO:0001525', ('175', '187'))	('formation', 'biological_process', 'GO:0009058', ('228', '237'))	('increase', 'PosReg', (196, 204))	('MYC', 'Gene', '4609', (117, 120))	('lung cancer', 'Disease', (61, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('contributed', 'Reg', (154, 165))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('HIF-1alpha', 'Gene', '3091', (125, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('MPE formation', 'CPA', (224, 237))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('MYC', 'Gene', (117, 120))	('deletion', 'Var', (49, 57))	('EGFR', 'Gene', (36, 40))
26224	32269623	The results of the present study indicate that higher EGFR mutation frequency was associated with increased tendency for MPE.	('MPE', 'Disease', (121, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('EGFR', 'Gene', '1956', (54, 58))	('mutation', 'Var', (59, 67))	('EGFR', 'Gene', (54, 58))
26225	32269623	Overall, in the present study, 62 patients exhibited mutations within EGFR exons 18-21, who were treated with TKIs.	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('mutations', 'Var', (53, 62))	('EGFR', 'Gene', (70, 74))	('patients', 'Species', '9606', (34, 42))
26226	32269623	Rearrangements involving the ALK gene are critical events in NSCLC.	('ALK', 'Gene', (29, 32))	('Rearrangements', 'Var', (0, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('men', 'Species', '9606', (9, 12))	('NSCLC', 'Disease', (61, 66))	('ALK', 'Gene', '238', (29, 32))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
26232	32269623	The analysis of the present study identified 6 patients harboring KRAS mutations, only four of whom exhibited mutations of glycine or alanine, for which there are available treatment agents.	('KRAS', 'Gene', '3845', (66, 70))	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (71, 80))	('KRAS', 'Gene', (66, 70))	('alanine', 'Chemical', 'MESH:D000409', (134, 141))	('men', 'Species', '9606', (178, 181))	('glycine', 'Chemical', 'MESH:D005998', (123, 130))
26235	32269623	Several studies have reported that the BIM deletion polymorphism confers intrinsic resistance to EGFR-TKIs in cell lines.	('intrinsic resistance', 'MPA', (73, 93))	('EGFR', 'Gene', '1956', (97, 101))	('deletion polymorphism', 'Var', (43, 64))	('EGFR', 'Gene', (97, 101))	('BIM', 'Gene', '10018', (39, 42))	('BIM', 'Gene', (39, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
26236	32269623	However, other studies have reported that the BIM deletion polymorphism did not account for intrinsic resistance to EGFR-TKIs, notably for MPE in patients with lung adenocarcinoma.	('deletion polymorphism', 'Var', (50, 71))	('EGFR', 'Gene', '1956', (116, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (160, 179))	('BIM', 'Gene', '10018', (46, 49))	('BIM', 'Gene', (46, 49))	('lung adenocarcinoma', 'Disease', (160, 179))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (160, 179))	('patients', 'Species', '9606', (146, 154))	('EGFR', 'Gene', (116, 120))
26238	32269623	NGS analysis in the present study of MPE samples demonstrated that 10 patients (9.2%) possessed the BIM polymorphism, but the role of this mutation in the development or treatment of lung cancer remains unclear.	('BIM', 'Gene', (100, 103))	('patients', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('polymorphism', 'Var', (104, 116))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('men', 'Species', '9606', (162, 165))	('lung cancer', 'Disease', (183, 194))	('BIM', 'Gene', '10018', (100, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('men', 'Species', '9606', (175, 178))
26239	32269623	In patients with lung cancer, there is a consensus among studies that EGFR mutations are more frequent in female than in male patients.	('frequent', 'Reg', (94, 102))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (75, 84))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))
26240	32269623	In the present study, the EGFR mutant frequency in female patients was 64.3% (36/56 patients), higher than in male patients, 50.9% (26/51 patients).	('EGFR', 'Gene', (26, 30))	('patients', 'Species', '9606', (115, 123))	('mutant', 'Var', (31, 37))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('EGFR', 'Gene', '1956', (26, 30))	('patients', 'Species', '9606', (138, 146))
26241	32269623	This was consistent with previous studies, but EGFR exon 21 special mutations, BIM mutations, TP53 and BRAF special mutations were higher in males than in females in the present study.	('higher', 'Reg', (131, 137))	('TP53', 'Gene', '7157', (94, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('TP53', 'Gene', (94, 98))	('mutations', 'Var', (116, 125))	('EGFR', 'Gene', '1956', (47, 51))	('BRAF', 'Gene', '673', (103, 107))	('BIM', 'Gene', '10018', (79, 82))	('BIM', 'Gene', (79, 82))	('EGFR', 'Gene', (47, 51))	('BRAF', 'Gene', (103, 107))
26245	32269623	Such mechanisms include the role of genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, decreased nutrient sensing and altered metabolism, but also cellular senescence and stem cell function.	('telomere', 'cellular_component', 'GO:0000781', ('57', '65'))	('decreased', 'NegReg', (119, 128))	('epigenetic changes', 'Var', (77, 95))	('loss', 'NegReg', (97, 101))	('proteostasis', 'Disease', (105, 117))	('telomere attrition', 'CPA', (57, 75))	('stem cell function', 'CPA', (203, 221))	('genomic', 'Var', (36, 43))	('proteostasis', 'Disease', 'MESH:D057165', (105, 117))	('telomere', 'cellular_component', 'GO:0005696', ('57', '65'))	('metabolism', 'biological_process', 'GO:0008152', ('158', '168'))	('cellular senescence', 'CPA', (179, 198))	('cellular senescence', 'biological_process', 'GO:0090398', ('179', '198'))	('nutrient sensing', 'biological_process', 'GO:0009594', ('129', '145'))	('metabolism', 'MPA', (158, 168))	('altered', 'Reg', (150, 157))	('nutrient sensing', 'MPA', (129, 145))
26246	32269623	Cancer cells and aged cells are also fundamentally different, as cancer cells can be thought of as hyperactive cells with advantageous mutations, rapid cell division and increased energy consumption, whereas aged cells are hypoactive with accumulated disadvantageous mutations, cell division inability and a decreased ability for energy production and consumption.	('energy consumption', 'MPA', (180, 198))	('inability', 'Disease', 'MESH:D007319', (292, 301))	('men', 'Species', '9606', (42, 45))	('ability', 'MPA', (318, 325))	('cell division', 'biological_process', 'GO:0051301', ('152', '165'))	('mutations', 'Var', (135, 144))	('increased', 'PosReg', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell division', 'biological_process', 'GO:0051301', ('278', '291'))	('decreased', 'NegReg', (308, 317))	('inability', 'Disease', (292, 301))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cell division', 'CPA', (278, 291))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
26247	32269623	A previous study investigating MPE from lung adenocarcinoma demonstrated that fewer Asian patients aged <=50 years possessed EGFR mutations, but the EGFR mutation types observed were more uncommon.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', (125, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('lung adenocarcinoma', 'Disease', (40, 59))	('mutations', 'Var', (130, 139))	('EGFR', 'Gene', (149, 153))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('patients', 'Species', '9606', (90, 98))
26255	32010261	LncRNA MALAT1 prevents the protective effects of miR-125b-5p against acute myocardial infarction through positive regulation of NLRC5 Acute myocardial infarction (AMI), as the first manifestation of ischemic heart disease, is the most common cause of death in developed countries.	('myocardial infarction', 'Disease', 'MESH:D009203', (140, 161))	('MALAT1', 'Gene', '72289', (7, 13))	('myocardial infarction', 'Disease', (140, 161))	('NLRC5', 'Gene', (128, 133))	('MALAT1', 'Gene', (7, 13))	('myocardial infarction', 'Phenotype', 'HP:0001658', (75, 96))	('ischemic heart disease', 'Disease', 'MESH:D017202', (199, 221))	('miR-125b-5p', 'Var', (49, 60))	('ischemic heart disease', 'Disease', (199, 221))	('death', 'Disease', (251, 256))	('death', 'Disease', 'MESH:D003643', (251, 256))	('regulation', 'biological_process', 'GO:0065007', ('114', '124'))	('positive regulation', 'PosReg', (105, 124))	('myocardial infarction', 'Phenotype', 'HP:0001658', (140, 161))	('myocardial infarction', 'Disease', 'MESH:D009203', (75, 96))	('myocardial infarction', 'Disease', (75, 96))
26260	32010261	Overexpression of miR-125b-5p significantly reduced hypoxia/reperfusion-induced apoptosis of HL-1 cells, an effect that could be blocked by NLCR5 overexpression.	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('miR-125b-5p', 'Var', (18, 29))	('HL-1', 'CellLine', 'CVCL:0303', (93, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('reduced', 'NegReg', (44, 51))	('hypoxia', 'Disease', (52, 59))
26277	32010261	This led to the hypothesis that the effect of MALAT1 on AMI-induced heart damage may be associated with NLRC5 and miR-125b-5p.	('AMI-induced', 'Disease', (56, 67))	('heart damage', 'Disease', (68, 80))	('miR-125b-5p', 'Var', (114, 125))	('associated', 'Reg', (88, 98))	('MALAT1', 'Gene', (46, 52))	('heart damage', 'Disease', 'MESH:D006331', (68, 80))
26283	32010261	Rats were divided into four groups (sham NC-siRNA, sham MALAT1-siRNA, AMI NC-siRNA and AMI MALAT-siRNA, 8 rats per each group) and housed at room temperature (22-26 C), humidity 50-70% on a 12-h light/dark cycle.	('rats', 'Species', '10116', (106, 110))	('Rats', 'Species', '10116', (0, 4))	('AMI MALAT-siRNA', 'Var', (87, 102))	('rat', 'Species', '10116', (106, 109))	('rat', 'Species', '10116', (151, 154))	('AMI NC-siRNA', 'Var', (70, 82))
26341	32010261	Interestingly, knockdown of MALAT1 strongly decreased the myocardial infarction area in AMI rats as compared with the NC-siRNA group (Fig.	('rats', 'Species', '10116', (92, 96))	('myocardial infarction', 'Disease', (58, 79))	('myocardial infarction', 'Disease', 'MESH:D009203', (58, 79))	('knockdown', 'Var', (15, 24))	('MALAT1', 'Gene', (28, 34))	('myocardial infarction', 'Phenotype', 'HP:0001658', (58, 79))	('decreased', 'NegReg', (44, 53))
26343	32010261	These findings suggested that MALAT1 knockdown ameliorated AMI-induced heart damage.	('knockdown', 'Var', (37, 46))	('heart damage', 'Disease', (71, 83))	('ameliorated', 'PosReg', (47, 58))	('rat', 'Species', '10116', (53, 56))	('heart damage', 'Disease', 'MESH:D006331', (71, 83))	('MALAT1', 'Gene', (30, 36))
26346	32010261	Additionally, both mRNA and protein levels of NLRC5 in HL-1 cells were significantly decreased by miR-125b-5p overexpression (Fig.	('decreased', 'NegReg', (85, 94))	('HL-1', 'CellLine', 'CVCL:0303', (55, 59))	('miR-125b-5p', 'Var', (98, 109))	('overexpression', 'PosReg', (110, 124))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
26349	32010261	4B, the concentration of lactate dehydrogenase (LDH), a marker of cell pyroptosis, was decreased by a miR-125b-5p mimic in H/R-treated HL-1 cells compared with control vector/mimic transfected cells.	('rat', 'Species', '10116', (15, 18))	('decreased', 'NegReg', (87, 96))	('pyroptosis', 'biological_process', 'GO:0070269', ('71', '81'))	('miR-125b-5p mimic', 'Var', (102, 119))	('concentration', 'MPA', (8, 21))	('HL-1', 'CellLine', 'CVCL:0303', (135, 139))	('lactate', 'Chemical', 'MESH:D019344', (25, 32))
26351	32010261	Similarly, the decreased MDA level in miR-125b-5p-overexpressing H/R-treated HL-1 cells was blocked by co-transfection with miR-125b-5p mimics and NLRC5 overexpression plasmid (Fig.	('MDA level', 'MPA', (25, 34))	('miR-125b-5p-overexpressing', 'Var', (38, 64))	('decreased', 'NegReg', (15, 24))	('HL-1', 'CellLine', 'CVCL:0303', (77, 81))	('MDA', 'Chemical', 'MESH:D008315', (25, 28))
26353	32010261	Meanwhile, overexpression of NLRC5 in raised miR-125b-5p expressing HL-1 cells suppressed the cytoprotective effect of miR-125b-5p, as observed by the increased apoptotic cell number (Fig.	('HL-1', 'CellLine', 'CVCL:0303', (68, 72))	('increased', 'PosReg', (151, 160))	('miR-125b-5p', 'Gene', (45, 56))	('miR-125b-5p', 'Var', (119, 130))	('apoptotic cell number', 'CPA', (161, 182))	('suppressed', 'NegReg', (79, 89))	('cytoprotective effect', 'CPA', (94, 115))
26356	32010261	In H/R-treated HL-1 cells, the expression of NLRC5 was increased by MALAT1 overexpression and suppressed by transfection of miR-125b-5p and MALAT1 (Fig.	('MALAT1', 'Gene', (68, 74))	('overexpression', 'PosReg', (75, 89))	('increased', 'PosReg', (55, 64))	('miR-125b-5p', 'Var', (124, 135))	('expression', 'MPA', (31, 41))	('suppressed', 'NegReg', (94, 104))	('HL-1', 'CellLine', 'CVCL:0303', (15, 19))	('NLRC5', 'Gene', (45, 50))
26358	32010261	This increased LDH release and MDA production induced by MALAT1 overexpression was reduced after overexpression of miR-125b-5p in H/R-treated HL-1 cells (Fig.	('LDH release', 'MPA', (15, 26))	('MDA production', 'MPA', (31, 45))	('MDA', 'Chemical', 'MESH:D008315', (31, 34))	('reduced', 'NegReg', (83, 90))	('HL-1', 'CellLine', 'CVCL:0303', (142, 146))	('overexpression', 'PosReg', (64, 78))	('increased', 'PosReg', (5, 14))	('miR-125b-5p', 'Var', (115, 126))	('MALAT1', 'Gene', (57, 63))
26359	32010261	MALAT1 overexpression also induced apoptosis in H/R-treated HL-1 cells, which was inhibited by upregulation of miR-125b-5p (Fig.	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('MALAT1', 'Gene', (0, 6))	('miR-125b-5p', 'Var', (111, 122))	('overexpression', 'PosReg', (7, 21))	('upregulation', 'PosReg', (95, 107))	('apoptosis', 'CPA', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))	('HL-1', 'CellLine', 'CVCL:0303', (60, 64))
26360	32010261	Taken together, these data suggest that MALAT1 may induce HL-1 apoptosis through downregulation of miR-125b-5p, which leads to upregulation of NLRC5.	('MALAT1', 'Var', (40, 46))	('HL-1 apoptosis', 'CPA', (58, 72))	('HL-1', 'CellLine', 'CVCL:0303', (58, 62))	('downregulation', 'NegReg', (81, 95))	('induce', 'PosReg', (51, 57))	('upregulation', 'PosReg', (127, 139))	('NLRC5', 'Gene', (143, 148))	('miR-125b-5p', 'Gene', (99, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
26370	32010261	Han et al reported that miR-125b suppressed bladder cancer development via inhibition of MALAT1.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('MALAT1', 'Protein', (89, 95))	('inhibition', 'NegReg', (75, 85))	('miR-125b', 'Var', (24, 32))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('suppressed', 'NegReg', (33, 43))
26371	32010261	In the present study the expression of miR-125b-5p was negatively regulated by MALAT1 in cardiomyocyte cell line HL-1.	('negatively', 'NegReg', (55, 65))	('expression', 'MPA', (25, 35))	('MALAT1', 'Gene', (79, 85))	('HL-1', 'CellLine', 'CVCL:0303', (113, 117))	('miR-125b-5p', 'Var', (39, 50))
26372	32010261	In H/R-treated HL-1 cells, cell apoptosis was significantly reduced by miR-125b-5p overexpression, as were LDH release and MDA production compared with controls.	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('overexpression', 'Var', (83, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('miR-125b-5p overexpression', 'Var', (71, 97))	('reduced', 'NegReg', (60, 67))	('cell apoptosis', 'CPA', (27, 41))	('MDA', 'Chemical', 'MESH:D008315', (123, 126))	('HL-1', 'CellLine', 'CVCL:0303', (15, 19))	('LDH release', 'MPA', (107, 118))	('MDA production', 'MPA', (123, 137))
26378	32010261	In 2017, Zhou et al reported that silencing of NLRC5 ameliorates cardiac fibrosis.	('ameliorates', 'PosReg', (53, 64))	('NLRC5', 'Gene', (47, 52))	('fibrosis', 'Disease', 'MESH:D005355', (73, 81))	('fibrosis', 'Disease', (73, 81))	('rat', 'Species', '10116', (59, 62))	('silencing', 'Var', (34, 43))
26379	32010261	Consistent with these data, the present study showed that downregulation of NLRC5 by miR-125b-5p mimic transfection decreased apoptosis and intracellular oxidative stress, evidenced by measurement of LDH and MDA levels as well as FACs analysis.	('intracellular oxidative stress', 'MPA', (140, 170))	('NLRC5', 'Gene', (76, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('apoptosis', 'CPA', (126, 135))	('MDA', 'Chemical', 'MESH:D008315', (208, 211))	('downregulation', 'NegReg', (58, 72))	('LDH', 'MPA', (200, 203))	('MDA levels', 'MPA', (208, 218))	('miR-125b-5p mimic', 'Var', (85, 102))	('intracellular', 'cellular_component', 'GO:0005622', ('140', '153'))	('decreased', 'NegReg', (116, 125))
26382	32010261	Ma et al found that knockout of NLRC5 led to myocardial damage in mice on a high fat diet.	('myocardial damage', 'Disease', 'MESH:D009202', (45, 62))	('myocardial damage', 'Disease', (45, 62))	('NLRC5', 'Gene', (32, 37))	('mice', 'Species', '10090', (66, 70))	('knockout', 'Var', (20, 28))	('led to', 'Reg', (38, 44))
26383	32010261	It was demonstrated that MALAT1 may function as a negative regulator of miR-125b-5p to abrogate the protective effects of miR-125b-5p on myocardial cells in AMI through modulating NLRC5 expression.	('miR-125b-5p', 'Var', (122, 133))	('protective effects', 'CPA', (100, 118))	('rat', 'Species', '10116', (14, 17))	('expression', 'MPA', (186, 196))	('modulating', 'Reg', (169, 179))	('abrogate', 'NegReg', (87, 95))	('NLRC5', 'Gene', (180, 185))
26415	31294801	The scRNA-seq datasets of 19k cells from 20 tumors and 4 matched normal adjacent biopsies from 6 lung cancer patients were downloaded from Array Express E-MTAB-6149 and E-MTAB-6653, processed, integrated, sctransform-normalized and the resulting t-SNE was plotted.	('tumors', 'Disease', (44, 50))	('E-MTAB-6149', 'Chemical', 'MESH:C057625', (153, 164))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('patients', 'Species', '9606', (109, 117))	('MTAB', 'molecular_function', 'GO:0047152', ('155', '159'))	('E-MTAB-6653', 'Var', (169, 180))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('MTAB', 'molecular_function', 'GO:0047152', ('171', '175'))	('E-MTAB-6653', 'Chemical', 'MESH:D017962', (169, 180))	('rat', 'Species', '10116', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('E-MTAB-6149', 'Var', (153, 164))
26446	29692417	Frequent genome alterations affecting the function of RB, cyclins, CDKs and CDK inhibitors have underscored the central importance of this regulatory mechanism in cancer, a circuit that has become known as the RB pathway (BOX 1).	('RB', 'Chemical', 'MESH:D012413', (54, 56))	('RB', 'Chemical', 'MESH:D012413', (210, 212))	('CDKs', 'Gene', '1017;1019;1021', (67, 71))	('alterations', 'Var', (16, 27))	('function', 'MPA', (42, 50))	('cyclin', 'Gene', '5111', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('affecting', 'Reg', (28, 37))	('CDK', 'molecular_function', 'GO:0004693', ('76', '79'))	('cyclin', 'Gene', (58, 64))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CDKs', 'Gene', (67, 71))
26447	29692417	The abundance of mutations affecting members of this pathway, and the resulting lack of proliferative control, has led to the idea that RB pathway disruption is a hallmark of cancer.	('RB pathway', 'Pathway', (136, 146))	('RB', 'Chemical', 'MESH:D012413', (136, 138))	('hallmark of cancer', 'Disease', (163, 181))	('hallmark of cancer', 'Disease', 'MESH:D009369', (163, 181))	('disruption', 'NegReg', (147, 157))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
26453	29692417	Further, different cancer types often show mutations of unique RB pathway components, suggesting that the effects of mutations in different RB pathway components are not functionally equivalent.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('RB', 'Chemical', 'MESH:D012413', (140, 142))	('cancer', 'Disease', (19, 25))	('RB pathway', 'Pathway', (63, 73))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('RB', 'Chemical', 'MESH:D012413', (63, 65))
26455	29692417	Although RB-like protein 1 (RBL1, also known as p107) and RBL2 (also known as p130) also regulate E2F and the cell cycle, mutations inactivating the encoding genes are less common in tumours than mutations inactivating RB1 (REFS).	('E2F', 'MPA', (98, 101))	('RBL1', 'Gene', '5933', (28, 32))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('p130', 'Gene', (78, 82))	('tumours', 'Disease', (183, 190))	('p107', 'Gene', (48, 52))	('RBL1', 'Gene', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('RB-like protein 1', 'Gene', (9, 26))	('p107', 'Gene', '5933', (48, 52))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('tumours', 'Disease', 'MESH:D009369', (183, 190))	('RB1', 'Gene', (219, 222))	('cell cycle', 'CPA', (110, 120))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('RB-like protein 1', 'Gene', '5933', (9, 26))	('p130', 'Gene', '5934', (78, 82))	('RBL2', 'Gene', (58, 62))	('RB1', 'Gene', '5925', (219, 222))	('regulate', 'Reg', (89, 97))	('RBL2', 'Gene', '5934', (58, 62))	('mutations inactivating', 'Var', (122, 144))
26456	29692417	Similarly, engineered mutations in the murine Rbl1 and Rbl2 genes give weaker tumour phenotypes than mutations in Rbl (REF).	('weaker', 'NegReg', (71, 77))	('murine', 'Species', '10090', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('Rbl2', 'Gene', '19651', (55, 59))	('tumour', 'Disease', (78, 84))	('mutations', 'Var', (22, 31))	('Rbl1', 'Gene', '19650', (46, 50))	('Rbl2', 'Gene', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('Rbl1', 'Gene', (46, 50))
26471	29692417	The current understanding of RB has long been shaped by the concept that phosphorylation on multiple sites by cyclin D-associated and cyclin E-associated CDKs, so-called hyperphosphorylation, leads to dissociation of RB from chromatin at the beginning of S phase and supposedly renders it functionless for the remainder of the cell cycle.	('phosphorylation', 'Var', (73, 88))	('leads to', 'Reg', (192, 200))	('cyclin', 'Gene', (110, 116))	('cell cycle', 'biological_process', 'GO:0007049', ('327', '337'))	('S phase', 'biological_process', 'GO:0051320', ('255', '262'))	('CDKs', 'Gene', (154, 158))	('dissociation', 'MPA', (201, 213))	('cyclin', 'Gene', '5111', (134, 140))	('cyclin', 'Gene', (134, 140))	('RB', 'Chemical', 'MESH:D012413', (217, 219))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('170', '190'))	('CDKs', 'Gene', '1017;1019;1021', (154, 158))	('cyclin', 'molecular_function', 'GO:0016538', ('134', '140'))	('cyclin', 'molecular_function', 'GO:0016538', ('110', '116'))	('cyclin', 'Gene', '5111', (110, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('chromatin', 'cellular_component', 'GO:0000785', ('225', '234'))	('RB', 'Chemical', 'MESH:D012413', (29, 31))
26474	29692417	Most cyclin-CDK complexes require a basic amino acid patch near the carboxyl terminus of RB to dock and recognize it as a substrate.	('CDK', 'molecular_function', 'GO:0004693', ('12', '15'))	('complexes', 'Interaction', (16, 25))	('cyclin', 'Gene', '5111', (5, 11))	('RB', 'Chemical', 'MESH:D012413', (89, 91))	('cyclin', 'molecular_function', 'GO:0016538', ('5', '11'))	('cyclin', 'Gene', (5, 11))	('basic amino acid', 'Chemical', 'MESH:D024361', (36, 52))	('basic amino acid patch', 'Var', (36, 58))	('dock', 'Interaction', (95, 99))
26475	29692417	A number of studies have described acetylation or methylation of lysine residues in this patch that may inhibit CDK recognition and RB phosphorylation.	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('acetylation', 'Var', (35, 46))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('CDK', 'Protein', (112, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('lysine residues', 'Var', (65, 80))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('inhibit', 'NegReg', (104, 111))	('RB', 'Chemical', 'MESH:D012413', (132, 134))	('methylation', 'Var', (50, 61))
26488	29692417	Importantly, a mutant mouse line bearing an F832A substitution in its RB protein is unable to form this unique RB-E2F1 interaction.	('interaction', 'Interaction', (119, 130))	('RB', 'Chemical', 'MESH:D012413', (111, 113))	('F832A', 'Var', (44, 49))	('unable', 'NegReg', (84, 90))	('RB', 'Chemical', 'MESH:D012413', (70, 72))	('mouse', 'Species', '10090', (22, 27))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('F832A', 'Mutation', 'p.F832A', (44, 49))
26491	29692417	It has also recently been demonstrated that phosphorylation of RB by p38 MAPK on a site distinct from the E2F1 interaction site can actually stimulate E2F1 binding to RB at yet another location in the RB polypeptide and lead to complex formation at promoter regions of E2F target genes.	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('RB', 'Chemical', 'MESH:D012413', (63, 65))	('formation', 'biological_process', 'GO:0009058', ('236', '245'))	('RB', 'Chemical', 'MESH:D012413', (167, 169))	('phosphorylation', 'Var', (44, 59))	('complex formation', 'MPA', (228, 245))	('promoter', 'MPA', (249, 257))	('p38', 'Gene', '1432', (69, 72))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('E2F1', 'Protein', (151, 155))	('lead to', 'Reg', (220, 227))	('MAPK', 'molecular_function', 'GO:0004707', ('73', '77'))	('stimulate', 'PosReg', (141, 150))	('binding', 'Interaction', (156, 163))	('RB', 'Chemical', 'MESH:D012413', (201, 203))	('p38', 'Gene', (69, 72))
26508	29692417	A mutation in RB that cripples its marked box domain interaction with E2F1 has been shown to disrupt binding of both RB and E2F1 to diverse categories of repetitive sequences.	('E2F1', 'Gene', (124, 128))	('mutation', 'Var', (2, 10))	('disrupt', 'NegReg', (93, 100))	('box domain interaction', 'MPA', (42, 64))	('RB', 'Chemical', 'MESH:D012413', (117, 119))	('binding', 'Interaction', (101, 108))	('RB', 'Chemical', 'MESH:D012413', (14, 16))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))
26509	29692417	The cooperative relationship between RB and E2F1 in localizing to repetitive sequences or to DNA breaks, in which neither can localize without the other, might be mechanistically enabled by formation of the CDK phosphorylation-resistant RB-E2F1 complex (FIG.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('formation', 'biological_process', 'GO:0009058', ('190', '199'))	('RB', 'Chemical', 'MESH:D012413', (37, 39))	('localizing', 'MPA', (52, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('211', '226'))	('CDK', 'molecular_function', 'GO:0004693', ('207', '210'))	('RB', 'Chemical', 'MESH:D012413', (237, 239))	('E2F1', 'Gene', (44, 48))	('repetitive sequences', 'Var', (66, 86))
26510	29692417	RB acetylation and methylation are induced by DNA damage, and these modifications reduce CDK phosphorylation of RB, further indicating that RB-E2F1 complexes may be sheltered from CDK activity when engaged in NHEJ and HR functions.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('RB', 'Chemical', 'MESH:D012413', (112, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('RB', 'Chemical', 'MESH:D012413', (140, 142))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('acetylation', 'MPA', (3, 14))	('RB', 'Chemical', 'MESH:D012413', (0, 2))	('reduce', 'NegReg', (82, 88))	('CDK phosphorylation', 'MPA', (89, 108))	('CDK activity', 'molecular_function', 'GO:0004693', ('180', '192'))	('induced', 'Reg', (35, 42))	('methylation', 'MPA', (19, 30))	('CDK', 'molecular_function', 'GO:0004693', ('89', '92'))	('modifications', 'Var', (68, 81))	('NHEJ', 'biological_process', 'GO:0006303', ('209', '213'))
26516	29692417	At double-stranded DNA breaks, RB interacts with DNA end-binding proteins X-ray repair cross-complementing protein 5 (XRCC5) and XRCC6 to facilitate repair of DNA breaks through end joining.	('XRCC6', 'Gene', '2547', (129, 134))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('XRCC5', 'Gene', (118, 123))	('double-stranded DNA', 'Var', (3, 22))	('repair', 'MPA', (149, 155))	('X-ray repair cross-complementing protein 5', 'Gene', (74, 116))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('XRCC6', 'Gene', (129, 134))	('facilitate', 'PosReg', (138, 148))	('interacts', 'Interaction', (34, 43))	('end joining', 'MPA', (178, 189))	('X-ray repair cross-complementing protein 5', 'Gene', '7520', (74, 116))	('RB', 'Chemical', 'MESH:D012413', (31, 33))	('XRCC5', 'Gene', '7520', (118, 123))	('DNA end-binding', 'molecular_function', 'GO:0045027', ('49', '64'))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
26523	29692417	It has also been shown that failure to recruit these factors negatively affects DNA replication patterns earlier in the cell cycle during S phase and that insufficiently condensed chromosomes and mitotic errors may in part be due to DNA lesions that originate in defective replication.	('DNA', 'cellular_component', 'GO:0005574', ('233', '236'))	('cell cycle', 'biological_process', 'GO:0007049', ('120', '130'))	('S phase', 'biological_process', 'GO:0051320', ('138', '145'))	('lesions', 'Var', (237, 244))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNA replication', 'biological_process', 'GO:0006260', ('80', '95'))	('affects', 'Reg', (72, 79))	('negatively', 'NegReg', (61, 71))	('insufficiently', 'Disease', 'MESH:D000309', (155, 169))	('insufficiently', 'Disease', (155, 169))	('DNA replication patterns', 'MPA', (80, 104))	('mitotic errors', 'CPA', (196, 210))
26529	29692417	Because these repair and epigenetic functions adopt CDK-resistance mechanisms and involve somewhat direct RB participation (FIG.	('CDK-resistance', 'MPA', (52, 66))	('CDK', 'molecular_function', 'GO:0004693', ('52', '55'))	('epigenetic', 'Var', (25, 35))	('RB', 'Chemical', 'MESH:D012413', (106, 108))
26534	29692417	Defective RB function can influence cellular responses to a variety of cancer treatment approaches.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('influence', 'Reg', (26, 35))	('cancer', 'Disease', (71, 77))	('Defective', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RB', 'Chemical', 'MESH:D012413', (10, 12))
26538	29692417	Deregulated proliferation is likely influenced by mutations or copy number changes in genes encoding CDK inhibitor 2A (CDKN2A, also known as p16-INK4A), cyclin D, CDK4, CDK6 and RB that are commonplace in this cancer (BOX 1), and rapid proliferation creates sensitivity to DNA damage.	('CDK6', 'Gene', '1021', (169, 173))	('cyclin', 'Gene', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('CDK', 'molecular_function', 'GO:0004693', ('169', '172'))	('CDK', 'molecular_function', 'GO:0004693', ('163', '166'))	('INK4A', 'Gene', '1029', (145, 150))	('CDK6', 'Gene', (169, 173))	('CDK4', 'Gene', (163, 167))	('RB', 'Chemical', 'MESH:D012413', (178, 180))	('cyclin', 'molecular_function', 'GO:0016538', ('153', '159'))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('101', '114'))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('DNA', 'cellular_component', 'GO:0005574', ('273', '276'))	('copy number changes', 'Var', (63, 82))	('INK4A', 'Gene', (145, 150))	('CDK4', 'Gene', '1019', (163, 167))	('CDKN2A', 'Gene', (119, 125))	('CDK inhibitor 2A', 'Gene', (101, 117))	('p16', 'Gene', (141, 144))	('CDK inhibitor 2A', 'Gene', '1029', (101, 117))	('cyclin', 'Gene', '5111', (153, 159))	('Deregulated', 'MPA', (0, 11))	('p16', 'Gene', '1029', (141, 144))	('mutations', 'Var', (50, 59))	('influenced', 'Reg', (36, 46))	('CDKN2A', 'Gene', '1029', (119, 125))	('cancer', 'Disease', (210, 216))
26539	29692417	Loss of RB, but not other canonical pathway components, however, correlates with improved response to DNA damage agents and longer patient survival.	('improved', 'PosReg', (81, 89))	('RB', 'Chemical', 'MESH:D012413', (8, 10))	('response to DNA damage agents', 'MPA', (90, 119))	('patient', 'Species', '9606', (131, 138))	('Loss', 'Var', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
26544	29692417	However, p53 is upstream of RB in the same DNA damage response cell cycle arrest checkpoint, suggesting that failure of the p53-dependent DNA damage response should similarly increase treatment sensitivity to levels similar to those observed with RB loss.	('p53', 'Gene', (124, 127))	('RB loss', 'Disease', (247, 254))	('failure', 'Var', (109, 116))	('RB loss', 'Disease', 'MESH:D012175', (247, 254))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('DNA damage response', 'biological_process', 'GO:0006974', ('138', '157'))	('p53', 'Gene', '7157', (124, 127))	('RB', 'Chemical', 'MESH:D012413', (247, 249))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('63', '80'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('RB', 'Chemical', 'MESH:D012413', (28, 30))	('increase', 'PosReg', (175, 183))	('DNA damage response', 'biological_process', 'GO:0006974', ('43', '62'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('treatment sensitivity', 'MPA', (184, 205))
26556	29692417	Blockade of D-type cyclin-CDK4 or CDK6 kinase activity is known to require RB for growth arrest, and these agents were designed to re-activate the canonical RB pathway.	('RB', 'Chemical', 'MESH:D012413', (75, 77))	('cyclin', 'Gene', '5111', (19, 25))	('CDK', 'molecular_function', 'GO:0004693', ('26', '29'))	('growth arrest', 'Disease', 'MESH:D006323', (82, 95))	('Blockade', 'Var', (0, 8))	('growth arrest', 'Disease', (82, 95))	('cyclin', 'Gene', (19, 25))	('RB', 'Chemical', 'MESH:D012413', (157, 159))	('CDK6', 'Gene', (34, 38))	('activity', 'MPA', (46, 54))	('CDK4', 'Gene', '1019', (26, 30))	('CDK4', 'Gene', (26, 30))	('CDK6', 'Gene', '1021', (34, 38))	('CDK', 'molecular_function', 'GO:0004693', ('34', '37'))	('growth arrest', 'Phenotype', 'HP:0001510', (82, 95))	('kinase activity', 'molecular_function', 'GO:0016301', ('39', '54'))	('canonical RB pathway', 'Pathway', (147, 167))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))
26560	29692417	A common mechanism of acquired anti-androgen resistance is genetic alteration of AR itself, leading to persistent and sometimes ligand-independent AR signalling.	('signalling', 'biological_process', 'GO:0023052', ('150', '160'))	('AR', 'Gene', '367', (81, 83))	('anti-androgen resistance', 'Disease', (31, 55))	('androgen resistance', 'Phenotype', 'HP:0008226', (36, 55))	('-androgen resistance', 'Phenotype', 'HP:0008226', (35, 55))	('genetic alteration', 'Var', (59, 77))	('AR', 'Gene', '367', (147, 149))	('ligand', 'molecular_function', 'GO:0005488', ('128', '134'))
26563	29692417	One type of the AR-deficient variant undergoes histological transdifferentiation from the luminal epithelial phenotype of the original adenocarcinoma to a neuroendocrine phenotype (FIG.	('original adenocarcinoma', 'Disease', 'MESH:D000230', (126, 149))	('original adenocarcinoma', 'Disease', (126, 149))	('transdifferentiation', 'biological_process', 'GO:0060290', ('60', '80'))	('variant', 'Var', (29, 36))	('AR', 'Gene', '367', (16, 18))	('undergoes', 'Reg', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
26564	29692417	These treatment-acquired neuroendocrine prostate cancer variants share clonal origin with the pre-existing adenocarcinoma, as they contain the same mutations.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))	('variants', 'Var', (56, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('pre', 'molecular_function', 'GO:0003904', ('94', '97'))	('adenocarcinoma', 'Disease', (107, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('neuroendocrine prostate cancer', 'Disease', (25, 55))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (25, 55))
26567	29692417	Pten mutation in mouse prostate epithelium generates a weakly metastatic adenocarcinoma that does not transdifferentiate, and Rb1 mutation in the same cells does not cause cancer.	('adenocarcinoma', 'Disease', 'MESH:D000230', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mouse', 'Species', '10090', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('adenocarcinoma', 'Disease', (73, 87))	('Pten', 'Gene', (0, 4))	('weakly metastatic', 'CPA', (55, 72))	('cancer', 'Disease', (172, 178))	('mutation', 'Var', (5, 13))
26568	29692417	Prostate cancer cells deficient in both Pten and Rb1 develop as adenocarcinoma then transition into a mixed tumour containing both luminal-like and neuroendocrine-like prostate cancer cells, demonstrating lineage plasticity.	('tumour', 'Disease', (108, 114))	('transition', 'Reg', (84, 94))	('neuroendocrine-like prostate cancer', 'Disease', 'MESH:D011471', (148, 183))	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('Pten', 'Gene', (40, 44))	('deficient', 'Var', (22, 31))	('adenocarcinoma', 'Disease', (64, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Prostate cancer', 'Disease', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('neuroendocrine-like prostate cancer', 'Disease', (148, 183))	('Rb1', 'Gene', (49, 52))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))
26569	29692417	Tumours are highly metastatic and remain sensitive to anti-androgen therapy but inevitably relapse in a form lacking AR expression, possessing neuroendocrine markers and often having acquired spontaneous Trp53 mutations.	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('mutations', 'Var', (210, 219))	('Trp53', 'Gene', (204, 209))	('AR', 'Gene', '367', (117, 119))	('Trp53', 'Gene', '7157', (204, 209))
26571	29692417	The second study used a combination of RNAi and Cas9-mediated gene deletions to inactivate RB1 and TP53 in human anti-androgen-sensitive prostate cancer cell lines.	('TP53', 'Gene', (99, 103))	('Cas', 'cellular_component', 'GO:0005650', ('48', '51'))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('deletions', 'Var', (67, 76))	('human', 'Species', '9606', (107, 112))	('RB1', 'Gene', (91, 94))	('prostate cancer', 'Disease', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('RB1', 'Gene', '5925', (91, 94))	('TP53', 'Gene', '7157', (99, 103))	('RNAi', 'biological_process', 'GO:0016246', ('39', '43'))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))	('inactivate', 'NegReg', (80, 90))
26576	29692417	Silencing of SOX2 or EZH2 reversed NEPC transformation and restored sensitivity to anti-androgen therapy.	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (21, 25))	('restored', 'PosReg', (59, 67))	('sensitivity to anti-androgen therapy', 'MPA', (68, 104))	('SOX2', 'Gene', '6657', (13, 17))	('Silencing', 'Var', (0, 9))	('SOX2', 'Gene', (13, 17))	('NEPC', 'Disease', (35, 39))
26577	29692417	Small molecule EZH2 inhibitors can also reverse NEPC transformation and anti-androgen resistance.	('anti-androgen resistance', 'CPA', (72, 96))	('reverse', 'Reg', (40, 47))	('inhibitors', 'Var', (20, 30))	('androgen resistance', 'Phenotype', 'HP:0008226', (77, 96))	('-androgen resistance', 'Phenotype', 'HP:0008226', (76, 96))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))	('NEPC', 'Disease', (48, 52))
26578	29692417	These exciting data support a model of epigenetic instability fuelled by RB loss and lineage plasticity, which is detailed in FIG.	('RB loss', 'Disease', 'MESH:D012175', (73, 80))	('epigenetic instability', 'Var', (39, 61))	('lineage plasticity', 'CPA', (85, 103))	('RB loss', 'Disease', (73, 80))
26579	29692417	Collectively, these studies offer a mechanistic link between RB loss, de-repression of epigenetic reprogramming factors, prostate cancer lineage plasticity and acquired anti-androgen resistance.	('prostate cancer', 'Disease', 'MESH:D011471', (121, 136))	('RB loss', 'Disease', (61, 68))	('RB loss', 'Disease', 'MESH:D012175', (61, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('prostate cancer', 'Disease', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('de-repression', 'Var', (70, 83))	('androgen resistance', 'Phenotype', 'HP:0008226', (174, 193))	('-androgen resistance', 'Phenotype', 'HP:0008226', (173, 193))
26583	29692417	For example, acquisition of a second site T790M substitution reduces erlotinib binding and reactivates EGFR signalling.	('EGFR', 'Gene', '1956', (103, 107))	('erlotinib', 'Protein', (69, 78))	('reactivates', 'NegReg', (91, 102))	('EGFR', 'Gene', (103, 107))	('T790M substitution', 'Var', (42, 60))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('binding', 'Interaction', (79, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('T790M', 'Mutation', 'rs121434569', (42, 47))	('signalling', 'biological_process', 'GO:0023052', ('108', '118'))	('reduces', 'NegReg', (61, 68))	('erlotinib', 'Chemical', 'MESH:D000069347', (69, 78))
26588	29692417	In one particularly informative patient, three distinct metastatic tumours were sampled after relapse, and all shared the EGFR driver mutation of the original adenocarcinoma.	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('tumours', 'Disease', (67, 74))	('mutation', 'Var', (134, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('original adenocarcinoma', 'Disease', 'MESH:D000230', (150, 173))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('patient', 'Species', '9606', (32, 39))	('EGFR', 'Gene', '1956', (122, 126))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('EGFR', 'Gene', (122, 126))	('original adenocarcinoma', 'Disease', (150, 173))
26595	29692417	This is often caused by secondary mutations to the original therapeutic target, such as the T790M substitution in EGFR.	('caused', 'Reg', (14, 20))	('T790M', 'Mutation', 'rs121434569', (92, 97))	('T790M', 'Var', (92, 97))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))
26613	29692417	Inputs such as p38 MAPK phosphorylation, as well as methylation or acetylation of RB, can serve to activate or preserve non-canonical aspects of RB function in proliferating cells (FIG.	('acetylation', 'MPA', (67, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('19', '23'))	('activate', 'PosReg', (99, 107))	('RB', 'Chemical', 'MESH:D012413', (82, 84))	('p38', 'Gene', (15, 18))	('RB', 'Chemical', 'MESH:D012413', (145, 147))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('p38', 'Gene', '1432', (15, 18))	('phosphorylation', 'Var', (24, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
26620	29692417	We expect that upstream mutations affecting CDK regulation do not necessarily inactivate non-canonical RB functions.	('non-canonical RB functions', 'MPA', (89, 115))	('inactivate', 'NegReg', (78, 88))	('CDK', 'Gene', (44, 47))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('RB', 'Chemical', 'MESH:D012413', (103, 105))	('mutations', 'Var', (24, 33))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))
26622	29692417	The best evidence for a non-canonical tumour suppressor pathway is a mutant mouse in which RB does not contact E2F1 through its marked box and yet the mouse is prone to develop spontaneous cancers without apparent cell cycle disruption.	('cell cycle', 'biological_process', 'GO:0007049', ('214', '224'))	('mouse', 'Species', '10090', (151, 156))	('mutant', 'Var', (69, 75))	('RB', 'Chemical', 'MESH:D012413', (91, 93))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('develop', 'PosReg', (169, 176))	('mouse', 'Species', '10090', (76, 81))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('tumour', 'Disease', (38, 44))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (189, 196))
26624	29692417	However, it is difficult to connect alterations in condensin II or Ezh2 that are contributing to cancer development directly to their impact on a non-canonical RB pathway owing to their multiple RB-independent functions.	('Ezh2', 'Gene', (67, 71))	('cancer', 'Disease', (97, 103))	('RB', 'Chemical', 'MESH:D012413', (160, 162))	('RB', 'Chemical', 'MESH:D012413', (195, 197))	('alterations', 'Var', (36, 47))	('impact', 'Reg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('non-canonical RB pathway', 'Pathway', (146, 170))	('contributing', 'Reg', (81, 93))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
26625	29692417	Our present understanding of non-canonical functions suggests that complete loss-of-function mutations in RB1 itself are the most reliable indicators of the lack of non-canonical RB pathway activity.	('mutations', 'Var', (93, 102))	('RB1', 'Gene', '5925', (106, 109))	('non-canonical RB pathway', 'Pathway', (165, 189))	('activity', 'MPA', (190, 198))	('RB', 'Chemical', 'MESH:D012413', (106, 108))	('RB', 'Chemical', 'MESH:D012413', (179, 181))	('loss-of-function', 'NegReg', (76, 92))	('RB1', 'Gene', (106, 109))	('lack', 'NegReg', (157, 161))
26626	29692417	Indeed, most RB1 mutations catalogued from comprehensive cancer genomic efforts are deletions or nonsense changes that are predicted to create null alleles (cBioPortal database).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('RB1', 'Gene', '5925', (13, 16))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('RB1', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('deletions', 'Var', (84, 93))
26629	29692417	On the basis of the prostate and lung cancer studies highlighted in this article, we suggest that genes encoding components of the canonical RB pathway are mutated early to contribute to proliferation (for example, activation of CDK4), while later mutation of RB1 proves advantageous for transdifferentiation or other epigenetic alterations that contribute to cancer progression or treatment resistance.	('contribute', 'Reg', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('CDK4', 'Gene', '1019', (229, 233))	('RB', 'Chemical', 'MESH:D012413', (260, 262))	('RB1', 'Gene', (260, 263))	('CDK', 'molecular_function', 'GO:0004693', ('229', '232'))	('prostate and lung cancer', 'Disease', 'MESH:D011471', (20, 44))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('mutated', 'Var', (156, 163))	('mutation', 'Var', (248, 256))	('transdifferentiation', 'biological_process', 'GO:0060290', ('288', '308'))	('cancer', 'Disease', (38, 44))	('RB1', 'Gene', '5925', (260, 263))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('activation', 'PosReg', (215, 225))	('proliferation', 'CPA', (187, 200))	('CDK4', 'Gene', (229, 233))	('cancer', 'Disease', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('RB', 'Chemical', 'MESH:D012413', (141, 143))
26636	29692417	Mutations in the canonical RB pathway can trigger inappropriate cell proliferation while leaving the RB1 gene intact and preserving the non-canonical pathway at relatively early stages in tumorigenesis.	('cell proliferation', 'CPA', (64, 82))	('RB1', 'Gene', (101, 104))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('Mutations', 'Var', (0, 9))	('RB', 'Chemical', 'MESH:D012413', (27, 29))	('RB1', 'Gene', '5925', (101, 104))	('non-canonical pathway', 'Pathway', (136, 157))	('trigger', 'Reg', (42, 49))	('RB', 'Chemical', 'MESH:D012413', (101, 103))
26637	29692417	Later in disease progression, loss of RB may fuel metastatic dissemination through lineage alterations and genome instability, or loss of RB may allow escape from targeted therapies.	('fuel', 'PosReg', (45, 49))	('lineage alterations', 'CPA', (83, 102))	('escape', 'CPA', (151, 157))	('RB', 'Chemical', 'MESH:D012413', (38, 40))	('genome instability', 'CPA', (107, 125))	('metastatic dissemination', 'CPA', (50, 74))	('RB', 'Chemical', 'MESH:D012413', (138, 140))	('loss', 'Var', (130, 134))	('loss', 'Var', (30, 34))
26642	29692417	In all cases, alterations to RB regulators lead to its hyperphosphorylation and cell cycle progression.	('alterations', 'Var', (14, 25))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('55', '75'))	('hyperphosphorylation', 'MPA', (55, 75))	('cell cycle progression', 'CPA', (80, 102))	('lead to', 'Reg', (43, 50))	('cell cycle', 'biological_process', 'GO:0007049', ('80', '90'))	('RB', 'Chemical', 'MESH:D012413', (29, 31))
26643	29692417	The basic concept of this pathway is that cell cycle control is disrupted through loss-of-function mutations in either RB1 or CDKN2A.	('loss-of-function', 'NegReg', (82, 98))	('CDKN2A', 'Gene', (126, 132))	('cell cycle control', 'biological_process', 'GO:1901987', ('42', '60'))	('cell cycle control', 'CPA', (42, 60))	('disrupted', 'NegReg', (64, 73))	('mutations', 'Var', (99, 108))	('CDKN2A', 'Gene', '1029', (126, 132))	('RB1', 'Gene', (119, 122))	('RB1', 'Gene', '5925', (119, 122))
26644	29692417	Alternatively, gain-of-function mutations in genes encoding D-type cyclins (CCND1, CCND2 and CCND3) or CDK4 or CDK6 constitutively phosphorylate and inactivate RB.	('CDK4', 'Gene', '1019', (103, 107))	('gain-of-function', 'PosReg', (15, 31))	('CCND1', 'Gene', (76, 81))	('CCND2', 'Gene', '894', (83, 88))	('CCND3', 'Gene', '896', (93, 98))	('CDK6', 'Gene', '1021', (111, 115))	('CDK', 'molecular_function', 'GO:0004693', ('111', '114'))	('mutations', 'Var', (32, 41))	('CDK6', 'Gene', (111, 115))	('cyclin', 'Gene', '5111', (67, 73))	('CDK', 'molecular_function', 'GO:0004693', ('103', '106'))	('CDK4', 'Gene', (103, 107))	('CCND3', 'Gene', (93, 98))	('RB', 'Chemical', 'MESH:D012413', (160, 162))	('cyclin', 'Gene', (67, 73))	('CCND1', 'Gene', '595', (76, 81))	('CCND2', 'Gene', (83, 88))	('phosphorylate', 'MPA', (131, 144))	('inactivate', 'NegReg', (149, 159))
26645	29692417	Tabulation of genetic alterations to this pathway have indicated that RB pathway disruption is widespread in cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('genetic', 'Var', (14, 21))	('RB pathway', 'Pathway', (70, 80))	('disruption', 'NegReg', (81, 91))	('RB', 'Chemical', 'MESH:D012413', (70, 72))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
26646	29692417	Cancer genomic studies indicate that near-ubiquitous RB pathway mutations can be found in some cancer types.	('RB', 'Chemical', 'MESH:D012413', (53, 55))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (64, 73))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('RB pathway', 'Pathway', (53, 63))
26647	29692417	The Cancer Genome Atlas data illustrating RB pathway mutations for lung adenocarcinoma, prostate carcinoma, colorectal adenocarcinoma and invasive breast carcinomas are shown (see the figure, part b).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('breast carcinomas', 'Phenotype', 'HP:0003002', (147, 164))	('lung adenocarcinoma', 'Disease', (67, 86))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('invasive breast carcinomas', 'Disease', (138, 164))	('RB', 'Chemical', 'MESH:D012413', (42, 44))	('Cancer', 'Disease', (4, 10))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('prostate carcinoma', 'Disease', 'MESH:D011472', (88, 106))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (138, 164))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mutations', 'Var', (53, 62))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (88, 106))	('RB pathway', 'Gene', (42, 52))	('colorectal adenocarcinoma', 'Disease', (108, 133))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('prostate carcinoma', 'Disease', (88, 106))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (108, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
26648	29692417	The left-most graphs depict mutation frequency in these cancer types for the best-known RB pathway components, whereas the right-most graphs show an expanded view of RB regulation in which genetic alterations of all CDK inhibitors and G1 CDKs are included.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('CDKs', 'Gene', '1017;1019;1021', (238, 242))	('RB', 'Chemical', 'MESH:D012413', (88, 90))	('regulation', 'biological_process', 'GO:0065007', ('169', '179'))	('CDK', 'molecular_function', 'GO:0004693', ('216', '219'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (28, 36))	('RB pathway', 'Pathway', (88, 98))	('cancer', 'Disease', (56, 62))	('CDKs', 'Gene', (238, 242))	('RB', 'Chemical', 'MESH:D012413', (166, 168))
26649	29692417	These data illustrate that the majority of lung and breast cancers possess recognizable loss-of-function changes in RB1 and CDKN2A or gain-of-function alterations in genes encoding D-type cyclins and associated CDKs.	('CDKN2A', 'Gene', (124, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (52, 66))	('RB1', 'Gene', '5925', (116, 119))	('changes', 'Var', (105, 112))	('CDKs', 'Gene', '1017;1019;1021', (211, 215))	('CDKN2A', 'Gene', '1029', (124, 130))	('cyclin', 'Gene', '5111', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gain-of-function', 'PosReg', (134, 150))	('breast cancers', 'Disease', 'MESH:D001943', (52, 66))	('breast cancers', 'Disease', (52, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cyclin', 'Gene', (188, 194))	('RB1', 'Gene', (116, 119))	('lung', 'Disease', (43, 47))	('alterations', 'Var', (151, 162))	('loss-of-function', 'NegReg', (88, 104))	('CDKs', 'Gene', (211, 215))
26651	29692417	This finding illustrates the challenges in accounting for loss of proliferative control in some cancer types using RB pathway mutations.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('RB pathway', 'Pathway', (115, 125))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (96, 102))	('RB', 'Chemical', 'MESH:D012413', (115, 117))
26711	31410344	Kato and colleagues meanwhile, in their paper suggested MDM2/MDM4 amplification and EGFR aberrations as a possible predisposing factor to hyperprogression .	('MDM4', 'Gene', (61, 65))	('MDM4', 'Gene', '4194', (61, 65))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('hyperprogression', 'Disease', (138, 154))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('aberrations', 'Var', (89, 100))	('MDM2', 'Gene', (56, 60))	('MDM2', 'Gene', '4193', (56, 60))
26718	31410344	Further, in animal models, they demonstrated hyperprogression in mice treated with anti PD1 but not with anti PD1 F(ab)2 fragments which lacked the Fc component, thereby implicating the Fc component of anti PD1 agent as the crucial factor for hyperprogression.	('mice', 'Species', '10090', (65, 69))	('anti PD1', 'Var', (83, 91))	('hyperprogression', 'CPA', (45, 61))
26720	31410344	The most recently proposed hypothesis is put forth by Kamada and colleagues, who examined hyperprogression in gastric cancer patients, and on analyzing tumor samples before and after therapy noted markedly increased Ki67+ effector T regulatory cells (FoxP3CD45RA-CD4+) in majority of hyperprogressive patients after ICI therapy .	('gastric cancer', 'Disease', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('increased', 'PosReg', (206, 215))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('patients', 'Species', '9606', (301, 309))	('tumor', 'Disease', (152, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('Ki67+', 'Var', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FoxP3CD45RA-CD4+', 'Var', (251, 267))	('patients', 'Species', '9606', (125, 133))
26721	31410344	In vitro studies also showed that either genetic ablation or antibody mediated blockade of PD1 in T regulatory cells increased the proliferation of these cells with a noted suppression of antitumor immune response.	('tumor', 'Disease', (192, 197))	('increased', 'PosReg', (117, 126))	('antibody', 'cellular_component', 'GO:0042571', ('61', '69'))	('proliferation', 'CPA', (131, 144))	('suppression', 'NegReg', (173, 184))	('PD1', 'Gene', (91, 94))	('blockade', 'Var', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('antibody', 'cellular_component', 'GO:0019815', ('61', '69'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('antibody', 'cellular_component', 'GO:0019814', ('61', '69'))	('antibody', 'molecular_function', 'GO:0003823', ('61', '69'))	('immune response', 'biological_process', 'GO:0006955', ('198', '213'))
26790	30968597	The reason why no mucinous adenocarcinoma cases were observed may have been because the patients in our study were all Japanese and therefore included many cases of adenocarcinoma with EGFR mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('EGFR', 'Gene', (185, 189))	('mutations', 'Var', (190, 199))	('patients', 'Species', '9606', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('adenocarcinoma', 'Disease', (165, 179))	('adenocarcinoma', 'Disease', (27, 41))	('adenocarcinoma', 'Disease', 'MESH:D000230', (165, 179))	('adenocarcinoma', 'Disease', 'MESH:D000230', (27, 41))	('mucinous adenocarcinoma', 'Disease', (18, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('185', '189'))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (18, 41))	('EGFR', 'Gene', '1956', (185, 189))
26816	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))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('patients', 'Species', '9606', (77, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('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))
26817	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))
26823	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))
26854	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))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (147, 155))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))
26870	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))	('EGFR', 'molecular_function', 'GO:0005006', ('165', '169'))	('LUAD', 'Disease', (12, 16))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('patients', 'Species', '9606', (141, 149))	('EGFR', 'Gene', '1956', (165, 169))
26876	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))
26878	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))
26879	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))
26908	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))
26962	30999966	Fas/Fas ligand (Fas/FasL) pathway disorder has been reported to induce malignant lung cells to evade the killing effect of cytotoxic T cells and thus resist the immune system.	('Fas ligand', 'Gene', (4, 14))	('induce', 'PosReg', (64, 70))	('FasL', 'Gene', (20, 24))	('FasL', 'Gene', '356', (20, 24))	('Fas ligand', 'Gene', '356', (4, 14))	('disorder', 'Var', (34, 42))	('ligand', 'molecular_function', 'GO:0005488', ('8', '14'))	('evade', 'NegReg', (95, 100))
26963	30999966	Recent studies have shown that NSCLC patients with low ratio of CD4+/CD8+ in peripheral blood T cells may have better prognosis.	('patients', 'Species', '9606', (37, 45))	('NSCLC', 'Disease', (31, 36))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('low ratio of CD4+', 'Phenotype', 'HP:0005407', (51, 68))	('CD8', 'Gene', (69, 72))	('CD8', 'Gene', '925', (69, 72))	('low ratio', 'Var', (51, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))
26974	30999966	Clinical trials of anti-PD-1 or anti-PD-L1 combined with anti-CTLA-4 drugs for NSCLC have been carried out, and positive results have been preliminarily obtained which mainly reflected in a higher OS rate and durable responses.	('OS rate', 'MPA', (197, 204))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('Clinical', 'Species', '191496', (0, 8))	('anti-PD-L1', 'Var', (32, 42))	('OS', 'Chemical', '-', (197, 199))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('NSCLC', 'Disease', (79, 84))	('higher', 'PosReg', (190, 196))
26977	30999966	The proportion of CD4+ CD25high T cells in tumors is higher than that in normal tissues or peripheral blood, which can confirm that Tregs are enriched in the TME.	('CD4+ CD25high', 'Var', (18, 31))	('CD', 'Chemical', 'MESH:D002104', (23, 25))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('CD', 'Chemical', 'MESH:D002104', (18, 20))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
27006	30999966	Some studies have shown that patients with high levels of FOXP3+ TILs have poor chemosensitivity and worse prognosis, while others reported that breast cancer patients with high levels of FOXP3+ T cells had better outcomes.	('FOXP3', 'Gene', (188, 193))	('high levels', 'Var', (43, 54))	('FOXP3', 'Gene', (58, 63))	('patients', 'Species', '9606', (29, 37))	('FOXP3', 'Gene', '50943', (188, 193))	('chemosensitivity', 'CPA', (80, 96))	('FOXP3', 'Gene', '50943', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('patients', 'Species', '9606', (159, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
27040	30197670	Previously, it was reported that JFK-induced epigenetic alteration is involved in anti-lung cancer activity.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('JFK-induced', 'Gene', (33, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('lung cancer', 'Disease', (87, 98))	('involved', 'Reg', (70, 78))	('epigenetic alteration', 'Var', (45, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
27042	30197670	JFK was observed to decrease lung cancer cell viability and simultaneously induce cellular morphology alteration.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cellular morphology alteration', 'CPA', (82, 112))	('decrease', 'NegReg', (20, 28))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('decrease lung', 'Phenotype', 'HP:0002089', (20, 33))	('induce', 'Reg', (75, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('lung cancer', 'Disease', (29, 40))	('JFK', 'Var', (0, 3))
27045	30197670	Particularly, the present results indicate knockdown of Fas and DR4 attenuates JFK-induced apoptosis in A549 cells.	('attenuates', 'NegReg', (68, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('Fas', 'Gene', (56, 59))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('DR4', 'Gene', '8797', (64, 67))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('DR4', 'Gene', (64, 67))	('knockdown', 'Var', (43, 52))	('JFK-induced', 'Disease', (79, 90))
27046	30197670	Overall, the present study suggests JFK induces cellular apoptosis through activation of Fas and DR4 in A549 cells and provides an insight for understanding the antitumor mechanisms of this Chinese traditional medicine.	('DR4', 'Gene', (97, 100))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('JFK', 'Var', (36, 39))	('activation', 'PosReg', (75, 85))	('Fas', 'Protein', (89, 92))	('cellular apoptosis', 'CPA', (48, 66))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('DR4', 'Gene', '8797', (97, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('tumor', 'Disease', (165, 170))
27055	30197670	Although a previous study reported that JFK could inhibit proliferation and promote apoptosis of cancer cells in rats, the underlying mechanisms remain elusive.	('promote', 'PosReg', (76, 83))	('proliferation', 'CPA', (58, 71))	('cancer', 'Disease', (97, 103))	('apoptosis', 'CPA', (84, 93))	('inhibit', 'NegReg', (50, 57))	('JFK', 'Var', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('rats', 'Species', '10116', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
27057	30197670	A previous study indicated that JFK-induced epigenetic alteration is involved in anti-lung cancer activity.	('JFK-induced', 'Gene', (32, 43))	('involved', 'Reg', (69, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('epigenetic alteration', 'Var', (44, 65))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
27088	30197670	To examine the effects of JFK on lung cancer cell growth, A549, NCI-H1975, NCI-H1650 and NCI-H2228 cells were treated with JFK at various concentrations (0, 0.041, 0.054, 0.081, 0.108, 0.162 and 0.216 mg/ml) for 48 h and cell viability was assessed.	('0.054', 'Var', (164, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('0.081', 'Var', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('0.162', 'Var', (185, 190))	('NCI-H1975', 'CellLine', 'CVCL:1511', (64, 73))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('NCI-H1650', 'CellLine', 'CVCL:1483', (75, 84))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))	('NCI-H2228', 'CellLine', 'CVCL:1543', (89, 98))	('0.108', 'Var', (178, 183))	('lung cancer', 'Disease', (33, 44))
27089	30197670	The cell viability of these human lung cancer cell lines decreases significantly in a concentration-dependent manner following JFK treatment (Fig.	('cell viability', 'CPA', (4, 18))	('lung cancer', 'Disease', (34, 45))	('human', 'Species', '9606', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('JFK', 'Var', (127, 130))	('decreases', 'NegReg', (57, 66))
27090	30197670	Additionally, JFK was observed to exert an increased inhibition effect on A549 cells compared with other three human lung cancer cell lines, with a IC50 of ~0.054 mg/ml.	('inhibition', 'NegReg', (53, 63))	('lung cancer', 'Disease', (117, 128))	('human', 'Species', '9606', (111, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('JFK', 'Var', (14, 17))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
27095	30197670	1D, cell cycle analysis indicates that a significant portion of A549 cells accumulates in G1 and G2 phase upon JFK (0.054 mg/ml) treatment, suggesting that JFK could induce G1/S and G2/M transition arrest.	('accumulates', 'PosReg', (75, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('JFK', 'Var', (156, 159))	('arrest', 'Disease', 'MESH:D006323', (198, 204))	('G2 phase', 'biological_process', 'GO:0051319', ('97', '105'))	('arrest', 'Disease', (198, 204))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('induce', 'PosReg', (166, 172))
27101	30197670	3D and E, protein levels of CDK4 and CCNB1 decrease and those of Fas and DR4 increase after JFK (0.054 mg/ml) treatment.	('DR4', 'Gene', (73, 76))	('decrease', 'NegReg', (43, 51))	('protein levels', 'MPA', (10, 24))	('0.054 mg/ml', 'Var', (97, 108))	('CDK4', 'Gene', '1019', (28, 32))	('CCNB1', 'Gene', (37, 42))	('CDK', 'molecular_function', 'GO:0004693', ('28', '31'))	('CCNB1', 'Gene', '891', (37, 42))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('increase', 'PosReg', (77, 85))	('DR4', 'Gene', '8797', (73, 76))	('CDK4', 'Gene', (28, 32))
27104	30197670	The protein expression levels of Fas and DR4 also drop when Fas and DR4 were knocked down (Fig.	('knocked down', 'Var', (77, 89))	('DR4', 'Gene', '8797', (68, 71))	('DR4', 'Gene', '8797', (41, 44))	('DR4', 'Gene', (68, 71))	('drop', 'NegReg', (50, 54))	('protein expression levels', 'MPA', (4, 29))	('Fas', 'Gene', (60, 63))	('DR4', 'Gene', (41, 44))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
27109	30197670	The cellular behavior of lung cancer cell lines treated with JFK were examined, and it was found that JFK could induce cellular growth arrest and the cell cycle is regulated by a complex cascade of events and mediated by cell cycle regulatory proteins, including cyclins and CDKs.	('growth arrest', 'Disease', (128, 141))	('cell cycle', 'biological_process', 'GO:0007049', ('150', '160'))	('cellular growth', 'biological_process', 'GO:0016049', ('119', '134'))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('CDKs', 'Gene', (275, 279))	('growth arrest', 'Phenotype', 'HP:0001510', (128, 141))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('cell cycle', 'biological_process', 'GO:0007049', ('221', '231'))	('growth arrest', 'Disease', 'MESH:D006323', (128, 141))	('JFK', 'Var', (102, 105))	('CDKs', 'Gene', '1017;1019', (275, 279))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))	('cell cycle', 'CPA', (150, 160))	('cyclins', 'Protein', (263, 270))
27115	30197670	These results suggest that JFK leads to A549 cell cycle arrest through the suppression of the cell cycle pathway.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('45', '62'))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('arrest', 'Disease', (56, 62))	('suppression', 'NegReg', (75, 86))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (45, 62))	('cell cycle pathway', 'Pathway', (94, 112))	('JFK', 'Var', (27, 30))	('arrest', 'Disease', 'MESH:D006323', (56, 62))
27122	30197670	TP53BP2 and BNIP3L are also activated by JFK (Fig.	('TP53BP2', 'Gene', '7159', (0, 7))	('BNIP3L', 'Gene', '665', (12, 18))	('activated', 'PosReg', (28, 37))	('JFK', 'Var', (41, 44))	('BNIP3L', 'Gene', (12, 18))	('TP53BP2', 'Gene', (0, 7))
27124	30197670	However, this phenomenon was not observed to occur in the human lung cancer NCI-H1650 and NCI-H228 cell lines, although JFK also exerts an inhibitory viability effect on these two cell lines (Fig.	('lung cancer NCI-H1650', 'Disease', 'MESH:D008175', (64, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('human', 'Species', '9606', (58, 63))	('inhibitory viability', 'MPA', (139, 159))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancer NCI-H1650', 'Disease', (64, 85))	('JFK', 'Var', (120, 123))	('NCI-H228', 'CellLine', 'CVCL:0B43', (90, 98))
27125	30197670	JFK enhances the transcription of DR4 and Fas in NCI-H2228 cells, but induces marginal apoptosis in siRNA knockdown assays (Fig.	('Fas', 'Gene', (42, 45))	('NCI-H2228', 'CellLine', 'CVCL:1543', (49, 58))	('transcription', 'MPA', (17, 30))	('induces', 'Reg', (70, 77))	('transcription', 'biological_process', 'GO:0006351', ('17', '30'))	('DR4', 'Gene', '8797', (34, 37))	('enhances', 'PosReg', (4, 12))	('DR4', 'Gene', (34, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('JFK', 'Var', (0, 3))
27126	30197670	Overall, the present study reported that JFK induces cellular growth arrest and apoptosis in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (62, 75))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('JFK', 'Var', (41, 44))	('cellular growth', 'biological_process', 'GO:0016049', ('53', '68'))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('growth arrest', 'Disease', 'MESH:D006323', (62, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('growth arrest', 'Disease', (62, 75))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('apoptosis', 'CPA', (80, 89))
27127	30197670	The transcriptome profiling analysis identified 5,281 genes whose expression was modulated by JFK and it was demonstrated that JFK contributes to A549 cellular apoptosis partially through activation of DR4 and Fas.	('DR4', 'Gene', (202, 205))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('DR4', 'Gene', '8797', (202, 205))	('JFK', 'Var', (127, 130))	('activation', 'PosReg', (188, 198))	('Fas', 'Gene', (210, 213))
27130	30019008	Identification of a Novel BRAF Thr599dup Mutation in Lung Adenocarcinoma BRAF mutations are known as oncogenic drivers of non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('Thr599dup', 'Chemical', '-', (31, 40))	('BRAF', 'Gene', '673', (26, 30))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('BRAF', 'Gene', (26, 30))	('non-small cell lung cancer', 'Disease', (122, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('NSCLC', 'Disease', (150, 155))	('BRAF', 'Gene', (73, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('Thr599dup Mutation', 'Var', (31, 49))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))	('Adenocarcinoma', 'Disease', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('BRAF', 'Gene', '673', (73, 77))
27131	30019008	BRAF inhibition has demonstrated anti-tumor activity in patients with BRAF V600E mutant NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('patients', 'Species', '9606', (56, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', '673', (0, 4))	('NSCLC', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('V600E', 'Var', (75, 80))	('BRAF', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('BRAF', 'Gene', (70, 74))
27132	30019008	Further molecular screening for novel BRAF thr599dup mutation is warranted.	('thr599dup', 'Chemical', '-', (43, 52))	('thr599dup mutation', 'Var', (43, 61))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (38, 42))
27133	30019008	The novel BRAF Thr599dup gene mutation, for which the repeat amino acid-tyrosine is inserted between the 599th amino acid and the 600th amino acid in exon 15 of BRAF, was identified by next-generation sequencing (NGS) during routine clinical care in a lung carcinoma sample from an Asian never-smoker.	('lung carcinoma', 'Disease', 'MESH:D008175', (252, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('Thr599dup', 'Chemical', '-', (15, 24))	('lung carcinoma', 'Disease', (252, 266))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('Thr599dup', 'Var', (15, 24))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('amino acid-tyrosine', 'Chemical', '-', (61, 80))
27135	30019008	BRAF Thr599dup gene mutation analysis was consistent with BRAF v600E gene mutation.	('v600E', 'Var', (63, 68))	('Thr599dup', 'Chemical', '-', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (58, 62))
27136	30019008	Here we report a novel BRAF gene mutation with molecular characteristics consistent with those in BRAF-driven NSCLC.	('mutation', 'Var', (33, 41))	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (98, 102))	('NSCLC', 'Disease', (110, 115))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (98, 102))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
27137	30019008	Our case expands the scope of BRAF gene mutations and provides broader molecular profiling for optimizing therapeutic options for patients with NSCLC.	('NSCLC', 'Disease', (144, 149))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (40, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))
27138	30019008	The new BRAF gene mutation has important clinical meaning for cancer patients.	('BRAF', 'Gene', '673', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BRAF', 'Gene', (8, 12))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (69, 77))
27142	30019008	The classification is constructed depending on mutations of genes, including EGFR, HER2, KRAS, PIK3CA, BRAF, and others in frequencies of more than 1%.	('HER2', 'Gene', '2064', (83, 87))	('PIK3CA', 'Gene', (95, 101))	('PIK3CA', 'Gene', '5290', (95, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('mutations', 'Var', (47, 56))	('EGFR', 'Gene', '1956', (77, 81))	('BRAF', 'Gene', '673', (103, 107))	('HER2', 'Gene', (83, 87))	('KRAS', 'Gene', (89, 93))	('EGFR', 'Gene', (77, 81))	('BRAF', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (89, 93))
27145	30019008	BRAF variations have been investigated in multiple cancers, such as colorectal, papillary thyroid, and ovarian cancers, as well as melanoma.	('variations', 'Var', (5, 15))	('multiple cancers', 'Disease', 'MESH:D009369', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('ovarian cancers', 'Disease', (103, 118))	('papillary thyroid', 'Disease', 'MESH:D000077273', (80, 97))	('ovarian cancers', 'Disease', 'MESH:D010051', (103, 118))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colorectal', 'Disease', 'MESH:D015179', (68, 78))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('multiple cancers', 'Disease', (42, 58))	('papillary thyroid', 'Disease', (80, 97))	('ovarian cancers', 'Phenotype', 'HP:0100615', (103, 118))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('colorectal', 'Disease', (68, 78))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('investigated', 'Reg', (26, 38))
27146	30019008	Moreover, BRAF variations have also been observed in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('variations', 'Var', (15, 25))	('observed', 'Reg', (41, 49))	('BRAF', 'Gene', (10, 14))	('NSCLC', 'Disease', (53, 58))	('BRAF', 'Gene', '673', (10, 14))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
27147	30019008	According to Davies et al, the incidence of BRAF mutation is 8% across all cancers and 3% in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('BRAF', 'Gene', '673', (44, 48))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('BRAF', 'Gene', (44, 48))	('cancers', 'Disease', (75, 82))	('mutation', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
27148	30019008	Worldwide, this means that about 35,000 patients might benefit from BRAF inhibitors, which is similar to the number of patients who might benefit from ALK inhibitors.	('BRAF', 'Gene', '673', (68, 72))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (119, 127))	('benefit', 'PosReg', (55, 62))	('ALK', 'Gene', (151, 154))	('BRAF', 'Gene', (68, 72))	('ALK', 'Gene', '238', (151, 154))	('inhibitors', 'Var', (73, 83))
27149	30019008	The BRAF mutations constitutively activate the MAPK (mitogen activated protein kinase) pathway, resulting in a constant stimulation to cell growth and proliferation.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('MAPK', 'Gene', (47, 51))	('activate', 'PosReg', (34, 42))	('cell growth', 'CPA', (135, 146))	('stimulation', 'PosReg', (120, 131))	('mutations', 'Var', (9, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('cell growth', 'biological_process', 'GO:0016049', ('135', '146'))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('MAPK', 'Gene', '5594', (47, 51))
27150	30019008	Also, BRAF activating mutations are associated with MEK and ERK activation.	('ERK', 'Gene', '5594', (60, 63))	('activating', 'PosReg', (11, 21))	('ERK', 'molecular_function', 'GO:0004707', ('60', '63'))	('ERK', 'Gene', (60, 63))	('BRAF', 'Gene', '673', (6, 10))	('MEK', 'Gene', (52, 55))	('mutations', 'Var', (22, 31))	('MEK', 'Gene', '5609', (52, 55))	('BRAF', 'Gene', (6, 10))	('associated', 'Reg', (36, 46))
27151	30019008	In addition, some studies report that BRAF Thr599dup gene mutation analysis is consistent with that of BRAF v600E gene mutation, which activates MEK/ERK signaling pathways.	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('ERK', 'Gene', (149, 152))	('ERK', 'molecular_function', 'GO:0004707', ('149', '152'))	('activates', 'PosReg', (135, 144))	('BRAF', 'Gene', '673', (38, 42))	('MEK', 'Gene', (145, 148))	('MEK', 'Gene', '5609', (145, 148))	('Thr599dup', 'Chemical', '-', (43, 52))	('v600E', 'Var', (108, 113))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (103, 107))	('ERK', 'Gene', '5594', (149, 152))	('BRAF', 'Gene', (103, 107))
27152	30019008	Here we describe a novel BRAF Thr599dup gene mutation.	('Thr599dup gene mutation', 'Var', (30, 53))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('Thr599dup', 'Chemical', '-', (30, 39))
27156	30019008	The novel BRAF Thr599dup gene mutation was found in exon 15 of BRAF, where the repeat amino acid-tyrosine was inserted between the 599th and 600th amino acid (Fig.	('amino acid-tyrosine', 'Chemical', '-', (86, 105))	('Thr599dup', 'Chemical', '-', (15, 24))	('Thr599dup', 'Var', (15, 24))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))
27159	30019008	Targeted therapy has been proven to be a successful strategy in patients with NSCLC harboring oncogenic driver mutations.	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
27160	30019008	For example, EGFR tyrosine kinase inhibitors induce both a high overall response ( 70%) and a durable response (9.7- to 11.0-month median PFS) in treatment-naive patients with activating EGFR mutations.	('patients', 'Species', '9606', (162, 170))	('EGFR', 'Gene', '1956', (187, 191))	('activating', 'PosReg', (176, 186))	('EGFR', 'Gene', (187, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('EGFR', 'Gene', '1956', (13, 17))	('mutations', 'Var', (192, 201))	('EGFR', 'Gene', (13, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))
27161	30019008	Similarly, Met/ALK/ROS inhibitor crizotinib (Xalkori ) has shown outstanding clinical effects in patients with corresponding mutations.	('crizotinib', 'Chemical', 'MESH:D000077547', (33, 43))	('ALK', 'Gene', (15, 18))	('mutations', 'Var', (125, 134))	('ALK', 'Gene', '238', (15, 18))	('patients', 'Species', '9606', (97, 105))
27162	30019008	BRAF mutations are primarily and most frequently identified in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('identified', 'Reg', (49, 59))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
27163	30019008	The most common type is V600E, where a glutamate is substituted with a valine at codon 600.	('glutamate', 'Protein', (39, 48))	('V600E', 'Var', (24, 29))	('glutamate is substituted with a valine at codon 600', 'Mutation', 'rs113488022', (39, 90))	('V600E', 'Mutation', 'rs113488022', (24, 29))
27165	30019008	However, there is a possibility that the incidence of V600E mutation in lung cancer might be underestimated, and, besides sequencing, sensitive methods should be used to evaluate V600E mutation status.	('V600E', 'Mutation', 'rs113488022', (54, 59))	('lung cancer', 'Disease', (72, 83))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('V600E', 'Var', (54, 59))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
27166	30019008	Although the prognostic implications of BRAF V600E mutations in NSCLC remain unclear, the V600E inhibitor vemurafenib has been reported to be effective in V600E-harboring lung cancers in some cases.	('BRAF', 'Gene', '673', (40, 44))	('V600E-harboring', 'Var', (155, 170))	('V600E', 'Mutation', 'rs113488022', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('BRAF', 'Gene', (40, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('V600E', 'Var', (90, 95))	('lung cancers', 'Disease', 'MESH:D008175', (171, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('lung cancers', 'Phenotype', 'HP:0100526', (171, 183))	('V600E', 'Mutation', 'rs113488022', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('NSCLC', 'Disease', (64, 69))	('V600E', 'Mutation', 'rs113488022', (155, 160))	('lung cancers', 'Disease', (171, 183))	('vemurafenib', 'Chemical', 'MESH:D000077484', (106, 117))
27167	30019008	Recruitment of NSCLC patients with BRAF mutations for targeted therapies should be encouraged in clinical trials, because that would contribute to improved knowledge about those rare mutations, resulting in targeted therapies with enhanced effectivity and reduced toxicity.	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('BRAF', 'Gene', (35, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('effectivity', 'MPA', (240, 251))	('toxicity', 'Disease', 'MESH:D064420', (264, 272))	('toxicity', 'Disease', (264, 272))	('mutations', 'Var', (40, 49))	('NSCLC', 'Disease', (15, 20))	('patients', 'Species', '9606', (21, 29))	('enhanced', 'PosReg', (231, 239))	('BRAF', 'Gene', '673', (35, 39))
27169	30019008	In this study we identified a novel BRAF gene mutation in an Asian never-smoker patient with NSCLC.	('BRAF', 'Gene', (36, 40))	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('mutation', 'Var', (46, 54))	('patient', 'Species', '9606', (80, 87))	('BRAF', 'Gene', '673', (36, 40))
27170	30019008	The newly discovered BRAF mutation provides immediate clinical significance.	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (21, 25))	('mutation', 'Var', (26, 34))
27182	29673312	Breast cancer mortalities are usually associated with spread and metastasis.	('metastasis', 'CPA', (65, 75))	('mortalities', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('associated', 'Reg', (38, 48))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Breast cancer', 'Disease', (0, 13))	('spread', 'CPA', (54, 60))
27251	29673312	Twelve days after tumor implantation, the volumes of CNTN1 transfected xenograft tumors were significantly higher than either untrasfected or empty-vector transfected tumors.	('transfected', 'Var', (59, 70))	('CNTN1', 'Gene', (53, 58))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('higher', 'PosReg', (107, 113))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (81, 86))	('transfected tumors', 'Disease', (155, 173))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('xenograft tumors', 'Disease', (71, 87))	('transfected tumors', 'Disease', 'MESH:D009369', (155, 173))	('volumes', 'CPA', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('xenograft tumors', 'Disease', 'MESH:D009369', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
27252	29673312	By day 20, this difference was increased, and pEGFP-N1 and pEGFP-N1-CNTN1 tumors reached an average volume of 1.27 +- 0.27, 1.32 +- 0.30 and 2.25 +- 0.30 cm3, respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('N1-CNTN1 tumors', 'Disease', 'MESH:D009369', (65, 80))	('N1-CNTN1 tumors', 'Disease', (65, 80))	('pEGFP-N1', 'Var', (46, 54))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
27256	29673312	Additionally, the increased rate of promotion of tumor weight was significantly higher in the pEGFP-N1-CNTN1 group (3.91/4.28) compared to the pEGFP-N1 group (0.28/2.61).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('pEGFP-N1-CNTN1', 'Var', (94, 108))	('tumor', 'Disease', (49, 54))	('promotion', 'PosReg', (36, 45))	('higher', 'PosReg', (80, 86))
27262	29673312	Thus, aberrant expression of CNTN1 promote survival and growth of malignancies including lung cancer, gastric cancer and/or squamous carcinoma.	('gastric cancer', 'Disease', (102, 116))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (124, 142))	('CNTN1', 'Gene', (29, 34))	('growth', 'CPA', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous carcinoma', 'Disease', 'MESH:D002294', (124, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('aberrant expression', 'Var', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('survival', 'CPA', (43, 51))	('lung cancer', 'Disease', (89, 100))	('expression', 'Species', '29278', (15, 25))	('squamous carcinoma', 'Disease', (124, 142))	('promote', 'PosReg', (35, 42))
27263	29673312	Furthermore, modulation of certain genes has been implicated in tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (64, 80))	('tumor metastasis', 'Disease', (64, 80))	('implicated', 'Reg', (50, 60))	('genes', 'Gene', (35, 40))	('modulation', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
27266	29673312	Moreover, silencing of CNTN1 inhibits tumor metastasis and increased tumor survival in a metastatic murine tumor model.	('CNTN1', 'Gene', (23, 28))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (69, 74))	('tumor metastasis', 'Disease', 'MESH:D009362', (38, 54))	('tumor metastasis', 'Disease', (38, 54))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('inhibits', 'NegReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('murine', 'Species', '10090', (100, 106))	('increased', 'PosReg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('silencing', 'Var', (10, 19))
27267	29673312	This finding was consistent with clinical report that tumors that express high levels of CNTN1 are most often found in patients at an advanced stage of disease, and are associated with worse survival than patients with tumors expressing low levels of CNTN1.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('patients', 'Species', '9606', (205, 213))	('worse', 'NegReg', (185, 190))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('CNTN1', 'Gene', (89, 94))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('high levels', 'Var', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
27273	29673312	Moreover, CNTN1 expression also enhanced tumor growth in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('expression', 'Var', (16, 26))	('tumor', 'Disease', (41, 46))	('nude mice', 'Species', '10090', (57, 66))	('CNTN1', 'Gene', (10, 15))	('enhanced', 'PosReg', (32, 40))	('expression', 'Species', '29278', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
27284	29170613	Thus, 1 was evaluated for the in vivo anticancer activity against 4T1 mammary gland carcinoma and KLN205 murine lung carcinoma in mouse models.	('carcinoma', 'Disease', 'MESH:D002277', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung carcinoma', 'Disease', 'MESH:D008175', (112, 126))	('KLN205 murine', 'Var', (98, 111))	('carcinoma', 'Disease', 'MESH:D002277', (84, 93))	('murine', 'Species', '10090', (105, 111))	('carcinoma', 'Disease', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('lung carcinoma', 'Disease', (112, 126))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('mammary gland carcinoma', 'Phenotype', 'HP:0003002', (70, 93))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('carcinoma', 'Disease', (84, 93))	('mouse', 'Species', '10090', (130, 135))
27285	29170613	The anticancer effect was observed in the KLN205 model with a 37% tumor growth inhibition at the 20 mg/kg dose.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Disease', (8, 14))	('tumor', 'Disease', (66, 71))	('KLN205', 'Var', (42, 48))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
27448	29170613	Therefore, compound 1 was selected for further investigations in the in vivo mouse models of 4T1 mammary gland carcinoma and KLN205 murine lung carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (111, 120))	('murine', 'Species', '10090', (132, 138))	('carcinoma', 'Disease', (144, 153))	('mammary gland carcinoma', 'Phenotype', 'HP:0003002', (97, 120))	('lung carcinoma', 'Disease', (139, 153))	('lung carcinoma', 'Disease', 'MESH:D008175', (139, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinoma', 'Disease', (111, 120))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('carcinoma', 'Disease', 'MESH:D002277', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('KLN205 murine', 'Var', (125, 138))	('mouse', 'Species', '10090', (77, 82))
27450	29170613	doses, whereas the anticancer effect was observed in the KLN205 model.	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('KLN205', 'Var', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
27457	29170613	Thus, we verified the results of our enhanced in vivo studies in two mouse models, which led us to the conclusion that compound 1 displayed an anticancer activity in the KLN205 mouse model.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mouse', 'Species', '10090', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('N', 'Chemical', 'MESH:D009584', (172, 173))	('mouse', 'Species', '10090', (177, 182))	('KLN205', 'Var', (170, 176))	('cancer', 'Disease', (147, 153))
27461	29170613	Therefore, for the conjugates containing the guanidine group, a study of biological interactions with the tumor models in order to find the selectivity factors related to specific signaling pathways responsible for the cancer growth is intended.	('guanidine', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('guanidine', 'Chemical', 'MESH:D019791', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', (219, 225))	('signaling', 'biological_process', 'GO:0023052', ('180', '189'))	('tumor', 'Disease', (106, 111))
27464	29170613	The biological studies proved that 1 has a high anticancer activity against KLN205 murine lung carcinoma with a 37% tumor growth inhibition at the 20 mg/kg dose.	('lung carcinoma', 'Disease', (90, 104))	('lung carcinoma', 'Disease', 'MESH:D008175', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('KLN205', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (116, 121))	('murine', 'Species', '10090', (83, 89))
27470	27642729	In contrast, selective inactivation of macrophage PI3Kgamma stimulates and prolongs NFkappaB activation and inhibits C/EBPbeta activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer.	('activation', 'PosReg', (93, 103))	('stimulates', 'PosReg', (60, 70))	('tumor', 'Disease', (313, 318))	('restores', 'PosReg', (204, 212))	('CD8', 'Gene', '925', (213, 216))	('NFkappaB', 'Gene', '18033', (84, 92))	('activation', 'MPA', (127, 137))	('cytotoxicity', 'Disease', (240, 252))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('survival', 'CPA', (341, 349))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('NFkappaB', 'Gene', (84, 92))	('cytotoxicity', 'Disease', 'MESH:D064420', (240, 252))	('inhibits', 'NegReg', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('T cell activation', 'biological_process', 'GO:0042110', ('218', '235'))	('CD8', 'Gene', (213, 216))	('extend', 'PosReg', (334, 340))	('C/EBPbeta', 'Gene', (117, 126))	('C/EBPbeta', 'Gene', '12608', (117, 126))	('promoting', 'PosReg', (144, 153))	('promote', 'PosReg', (305, 312))	('cancer', 'Disease', (369, 375))	('mouse', 'Species', '10090', (353, 358))	('immunostimulatory transcriptional program', 'MPA', (157, 198))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('inactivation', 'Var', (23, 35))
27472	27642729	We investigated the association between immune responses and survival in primary tumors from HPV+ (n=97) and HPV- (n=423) head and neck squamous cell carcinoma (HNSCC) cohorts from TCGA.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('neck', 'cellular_component', 'GO:0044326', ('131', '135'))	('investigated', 'Reg', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('neck squamous cell carcinoma', 'Disease', (131, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (122, 159))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (161, 166))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (131, 159))	('HPV-', 'Var', (109, 113))
27480	27642729	1i-k), suggesting that PI3Kgamma inhibits macrophage inflammatory responses and might do so in the tumor microenvironment.	('tumor', 'Disease', (99, 104))	('PI3Kgamma', 'Var', (23, 32))	('macrophage inflammatory responses', 'CPA', (42, 75))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inhibits', 'NegReg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
27481	27642729	Mice lacking PI3Kgamma and mice that were treated with PI3Kgamma antagonists (TG100-115 or IPI-549) exhibited significantly suppressed growth of implanted HPV+ (MEER) and HPV- (SCCVII) HNSCC, lung carcinoma (LLC), and breast carcinoma (PyMT) tumors (Fig.	('IPI-549', 'CellLine', 'CVCL:3825', (91, 98))	('lung carcinoma', 'Disease', 'MESH:D008175', (192, 206))	('LLC', 'cellular_component', 'GO:0038045', ('208', '211'))	('mice', 'Species', '10090', (27, 31))	('IPI-549', 'Var', (91, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('TG100', 'Chemical', '-', (78, 83))	('breast carcinoma', 'Phenotype', 'HP:0003002', (218, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('breast carcinoma (PyMT) tumors', 'Disease', 'MESH:D001943', (218, 248))	('Mice', 'Species', '10090', (0, 4))	('lung carcinoma', 'Disease', (192, 206))	('growth', 'MPA', (135, 141))	('suppressed', 'NegReg', (124, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (185, 190))
27484	27642729	PI3Kgamma inhibition suppressed long-term growth and metastases of spontaneous breast tumors, extended survival of mice with orthotopic breast tumors and enhanced the sensitivity of tumors to the nucleoside analogue gemcitabine (Fig.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('enhanced', 'PosReg', (154, 162))	('PI3Kgamma', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('breast tumors', 'Disease', 'MESH:D001943', (136, 149))	('survival', 'CPA', (103, 111))	('long-term growth', 'CPA', (32, 48))	('breast tumors', 'Disease', 'MESH:D001943', (79, 92))	('breast tumors', 'Disease', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('gemcitabine', 'Chemical', 'MESH:C056507', (216, 227))	('breast tumors', 'Phenotype', 'HP:0100013', (136, 149))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', (143, 149))	('breast tumors', 'Phenotype', 'HP:0100013', (79, 92))	('tumors', 'Disease', (86, 92))	('inhibition', 'Var', (10, 20))	('mice', 'Species', '10090', (115, 119))	('sensitivity', 'MPA', (167, 178))	('orthotopic breast tumors', 'Disease', 'MESH:D001943', (125, 149))	('orthotopic breast tumors', 'Disease', (125, 149))	('extended', 'PosReg', (94, 102))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('suppressed', 'NegReg', (21, 31))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('metastases', 'Disease', (53, 63))	('nucleoside', 'Chemical', 'MESH:D009705', (196, 206))
27491	27642729	PI3Kgamma ablation rapidly and sustainably stimulated RelA DNA binding activity in macrophages (Fig.	('RelA', 'Gene', (54, 58))	('DNA binding', 'molecular_function', 'GO:0003677', ('59', '70'))	('stimulated', 'PosReg', (43, 53))	('PI3Kgamma', 'Var', (0, 9))	('ablation', 'Var', (10, 18))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('RelA', 'Gene', '19697', (54, 58))
27492	27642729	In contrast, PI3Kgamma ablation suppressed DNA binding activity of C/EBPbeta (Fig.	('DNA binding', 'molecular_function', 'GO:0003677', ('43', '54'))	('DNA binding activity', 'MPA', (43, 63))	('PI3Kgamma', 'Var', (13, 22))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('C/EBPbeta', 'Gene', '12608', (67, 76))	('C/EBPbeta', 'Gene', (67, 76))	('suppressed', 'NegReg', (32, 42))
27493	27642729	Consistent with these findings, PI3Kgamma inhibition stimulated and sustained p65 RelA phosphorylation and simultaneously inhibited C/EBPbeta and Akt phosphorylation (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('RelA', 'Gene', '19697', (82, 86))	('p65', 'Gene', (78, 81))	('RelA', 'Gene', (82, 86))	('inhibited', 'NegReg', (122, 131))	('Akt', 'Gene', (146, 149))	('stimulated', 'PosReg', (53, 63))	('p65', 'Gene', '19697', (78, 81))	('inhibition', 'Var', (42, 52))	('C/EBPbeta', 'Gene', '12608', (132, 141))	('C/EBPbeta', 'Gene', (132, 141))	('Akt', 'Gene', '11651', (146, 149))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
27495	27642729	PI3Kgamma deletion enhanced phosphorylation of IKKbeta and TBK1 and degradation of IRAK-1 and IkappaBalpha in LPS-stimulated p110gamma-/- macrophages (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('59', '63'))	('IKKbeta', 'Protein', (47, 54))	('LPS', 'Gene', '21898', (110, 113))	('TBK1', 'Gene', '56480', (59, 63))	('IRAK-1', 'Gene', '16179', (83, 89))	('IRAK-1', 'Gene', (83, 89))	('LPS', 'Gene', (110, 113))	('TBK1', 'Gene', (59, 63))	('phosphorylation', 'MPA', (28, 43))	('IkappaBalpha', 'Gene', (94, 106))	('degradation', 'biological_process', 'GO:0009056', ('68', '79'))	('IkappaBalpha', 'Gene', '18035', (94, 106))	('degradation', 'MPA', (68, 79))	('p110gamma', 'Gene', (125, 134))	('p110gamma', 'Gene', '30955', (125, 134))	('PI3Kgamma deletion', 'Var', (0, 18))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))	('enhanced', 'PosReg', (19, 27))
27498	27642729	2i), these results indicate PI3Kgamma is both a feedback inhibitor of the TLR4-NFkappaB activation pathway and a promoter of IL-4 and C/EBPbeta signaling.	('IL-4', 'Gene', '16189', (125, 129))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('PI3Kgamma', 'Var', (28, 37))	('TLR4', 'Gene', '21898', (74, 78))	('IL-4', 'molecular_function', 'GO:0005136', ('125', '129'))	('NFkappaB', 'Gene', (79, 87))	('NFkappaB', 'Gene', '18033', (79, 87))	('IL-4', 'Gene', (125, 129))	('TLR4', 'Gene', (74, 78))	('C/EBPbeta', 'Gene', (134, 143))	('C/EBPbeta', 'Gene', '12608', (134, 143))
27500	27642729	Expression of constitutively activated PI3Kgamma (p110gammaCAAX) was sufficient to induce Arg-1 expression, in a manner that was inhibited by Cebpb, Mtor, or S6ka knockdown (Extended Data Fig.	('Mtor', 'Gene', '56717', (149, 153))	('PI3Kgamma', 'Var', (39, 48))	('Mtor', 'Gene', (149, 153))	('Cebpb', 'Chemical', '-', (142, 147))	('expression', 'MPA', (96, 106))	('induce', 'PosReg', (83, 89))	('Arg-1', 'Gene', '11846', (90, 95))	('Arg-1', 'Gene', (90, 95))	('p110gamma', 'Gene', (50, 59))	('p110gamma', 'Gene', '30955', (50, 59))
27501	27642729	Cebpb knockdown as well as inhibitors of S6K and mTOR suppressed expression of immune suppressive factors and stimulated expression of pro-inflammatory cytokines (Extended Data Fig.	('mTOR', 'Gene', (49, 53))	('suppressed', 'NegReg', (54, 64))	('Cebpb', 'Gene', (0, 5))	('inhibitors', 'Var', (27, 37))	('expression', 'MPA', (65, 75))	('knockdown', 'Var', (6, 15))	('expression of pro-inflammatory cytokines', 'MPA', (121, 161))	('Cebpb', 'Chemical', '-', (0, 5))	('stimulated', 'PosReg', (110, 120))
27502	27642729	These results show that PI3Kgamma promotes immune suppression by activating mTor-S6Kalpha-C/EBPbeta and inhibiting NFkappaB, thereby controlling a switch that regulates the balance between immune suppression and stimulation.	('mTor', 'Gene', '56717', (76, 80))	('NFkappaB', 'Gene', '18033', (115, 123))	('mTor', 'Gene', (76, 80))	('promotes', 'PosReg', (34, 42))	('activating', 'PosReg', (65, 75))	('PI3Kgamma', 'Var', (24, 33))	('immune suppression', 'CPA', (43, 61))	('inhibiting', 'NegReg', (104, 114))	('C/EBPbeta', 'Gene', (90, 99))	('C/EBPbeta', 'Gene', '12608', (90, 99))	('NFkappaB', 'Gene', (115, 123))
27506	27642729	6h), indicating that PI3Kgamma signaling in TAMs inhibits CD8+ T cell recruitment to tumors.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('6h', 'Chemical', '-', (0, 2))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('CD8', 'Gene', (58, 61))	('inhibits', 'NegReg', (49, 57))	('CD8', 'Gene', '925', (58, 61))	('PI3Kgamma', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
27509	27642729	To determine which macrophage-derived immune factors affect tumor growth in vivo, we treated WT and p110gamma-/- TAMs ex vivo with inhibitors of mTor, Arginase, IKKbeta, IL-12 or NOS2 prior to mixing with tumor cells and implanting in mice (Extended Data Fig.	('mTor', 'Gene', '56717', (145, 149))	('NOS2', 'Gene', '18126', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mTor', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('IL-12', 'molecular_function', 'GO:0005143', ('170', '175'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('p110gamma', 'Gene', (100, 109))	('p110gamma', 'Gene', '30955', (100, 109))	('inhibitors', 'Var', (131, 141))	('tumor', 'Disease', (60, 65))	('NOS2', 'Gene', (179, 183))	('mice', 'Species', '10090', (235, 239))
27510	27642729	Blockade of mTOR or Arginase in WT macrophages suppressed tumor growth, while inhibition of NOS2, IL-12 or IKKbeta in p110gamma-/- macrophages stimulated tumor growth.	('p110gamma', 'Gene', (118, 127))	('suppressed', 'NegReg', (47, 57))	('tumor', 'Disease', (58, 63))	('p110gamma', 'Gene', '30955', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('inhibition', 'Var', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mTOR', 'Gene', (12, 16))	('NOS2', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('IL-12', 'molecular_function', 'GO:0005143', ('98', '103'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('stimulated', 'PosReg', (143, 153))	('NOS2', 'Gene', '18126', (92, 96))	('tumor', 'Disease', (154, 159))
27511	27642729	These results indicate that PI3Kgamma-mTOR mediated immune suppression promotes tumor growth and that PI3Kgamma inhibition reverses these effects by shifting macrophages toward NFkappabeta-dependent pro-inflammatory polarization.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('NFkappabeta', 'Gene', (177, 188))	('PI3Kgamma-mTOR', 'Var', (28, 42))	('promotes', 'PosReg', (71, 79))	('pen', 'Gene', '232670', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pen', 'Gene', (191, 194))	('NFkappabeta', 'Gene', '18033', (177, 188))	('tumor', 'Disease', (80, 85))	('shifting', 'Reg', (149, 157))
27513	27642729	PI3Kgamma inhibitor and clodronate liposome treatment each partially inhibited tumor growth and stimulated T cell recruitment, but the combination had no additive effects, confirming that PI3Kgamma in macrophages, rather than other cell types, promotes tumor growth (Extended Data Fig.	('tumor', 'Disease', (79, 84))	('clodronate', 'Chemical', 'MESH:D004002', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('PI3Kgamma', 'Var', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('rat', 'Species', '10116', (214, 217))	('promotes', 'PosReg', (244, 252))	('tumor', 'Disease', (253, 258))	('inhibited', 'NegReg', (69, 78))	('stimulated', 'PosReg', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
27516	27642729	PI3Kgamma inhibition did not suppress tumor growth in CD8 null or antibody-depleted mice, suggesting PI3Kgamma inhibition blocks tumor growth by recruiting and/or activating CD8+ T cells (Fig.	('CD8', 'Gene', '925', (174, 177))	('tumor', 'Disease', (129, 134))	('antibody', 'cellular_component', 'GO:0019814', ('66', '74'))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('CD8', 'Gene', '925', (54, 57))	('blocks tumor', 'Disease', 'MESH:D006327', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('blocks tumor', 'Disease', (122, 134))	('PI3Kgamma', 'Var', (101, 110))	('antibody', 'molecular_function', 'GO:0003823', ('66', '74'))	('inhibition', 'Var', (111, 121))	('CD8', 'Gene', (174, 177))	('antibody', 'cellular_component', 'GO:0042571', ('66', '74'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('activating', 'PosReg', (163, 173))	('CD8', 'Gene', (54, 57))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('antibody', 'cellular_component', 'GO:0019815', ('66', '74'))
27520	27642729	T cells from p110gamma-/- or PI3Kgamma inhibitor-treated animals expressed significantly more IFNgamma and Granzyme B and significantly less TGFbeta1 and IL10 protein and mRNA than T cells from WT animals (Fig.	('PI3Kgamma', 'Var', (29, 38))	('TGFbeta1', 'Gene', '21803', (141, 149))	('IFNgamma', 'Gene', (94, 102))	('IFNgamma', 'Gene', '15978', (94, 102))	('Granzyme B', 'Gene', '14939', (107, 117))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('p110gamma', 'Gene', (13, 22))	('p110gamma', 'Gene', '30955', (13, 22))	('less', 'NegReg', (136, 140))	('more', 'PosReg', (89, 93))	('mRNA', 'MPA', (171, 175))	('IL10', 'molecular_function', 'GO:0005141', ('154', '158'))	('IL10', 'Gene', '16153', (154, 158))	('IL10', 'Gene', (154, 158))	('Granzyme B', 'Gene', (107, 117))	('TGFbeta1', 'Gene', (141, 149))
27522	27642729	To determine whether PI3Kgamma inhibition interacts with other immune therapies, we combined PI3Kgamma and the checkpoint inhibitor anti-PD-1 in mouse tumor models.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mouse', 'Species', '10090', (145, 150))	('tumor', 'Disease', (151, 156))	('PI3Kgamma', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
27528	27642729	These studies show that PI3Kgamma inhibition can synergize with T cell targeted therapy to promote anti-tumor immune responses that induce sustained tumor regression in murine models of cancer.	('promote', 'PosReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('murine', 'Species', '10090', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PI3Kgamma', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
27529	27642729	PI3Kgamma-regulated immune responses might also affect outcome in cancer patients.	('affect', 'Reg', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PI3Kgamma-regulated', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('outcome', 'CPA', (55, 62))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', (66, 72))
27534	27642729	These results suggest that a PI3Kgamma-regulated immune suppression signature is associated with survival in cancer patients and that PI3Kgamma inhibitors might provide clinical benefit in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PI3Kgamma-regulated', 'Var', (29, 48))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', (109, 115))	('patients', 'Species', '9606', (196, 204))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', (189, 195))
27535	27642729	Here we have shown that PI3Kgamma regulates innate immunity during inflammation and cancer (Extended Data Fig.10b-c).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('PI3Kgamma', 'Var', (24, 33))	('regulates', 'Reg', (34, 43))	('inflammation', 'biological_process', 'GO:0006954', ('67', '79'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('inflammation', 'Disease', (67, 79))	('innate immunity', 'biological_process', 'GO:0045087', ('44', '59'))	('innate immunity', 'MPA', (44, 59))
27536	27642729	Prior studies have implicated PI3Ks in the regulation of pro-inflammatory immune responses in macrophages, as pan-PI3K inhibitors and null mutations in the PI3Kgamma effectors PDK1, Akt1 and TSC enhanced pro-inflammatory NFkappaB dependent transcription in macrophages, while inhibition of PTEN and SHIP, which oppose PI3Kinase function, promotes immune suppression.	('immune suppression', 'CPA', (347, 365))	('PTEN', 'Gene', (290, 294))	('promotes', 'PosReg', (338, 346))	('TSC', 'Gene', '21807', (191, 194))	('PI3K', 'molecular_function', 'GO:0016303', ('114', '118'))	('SHIP', 'Gene', '16331', (299, 303))	('PDK1', 'Gene', '228026', (176, 180))	('PI3Kgamma', 'Gene', (156, 165))	('PDK1', 'molecular_function', 'GO:0004740', ('176', '180'))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('pen', 'Gene', '232670', (232, 235))	('pen', 'Gene', (232, 235))	('Akt1', 'Gene', (182, 186))	('PTEN', 'Gene', '19211', (290, 294))	('SHIP', 'Gene', (299, 303))	('transcription', 'biological_process', 'GO:0006351', ('240', '253'))	('PDK1', 'Gene', (176, 180))	('TSC', 'Gene', (191, 194))	('inhibition', 'Var', (276, 286))	('Akt1', 'Gene', '11651', (182, 186))	('NFkappaB', 'Gene', '18033', (221, 229))	('enhanced', 'PosReg', (195, 203))	('NFkappaB', 'Gene', (221, 229))
27550	27642729	Comparison of these genes between HPV+ and HPV- cohort showed that HPV- samples generally had significantly (p<0.05) lower expression of 42 genes in the antigen presentation and T cell activation classes, consistent with a pattern of adaptive immune suppression, and higher expression of genes in the innate immune response and cancer cell signaling class, which were negatively associated with survival.	('expression', 'MPA', (274, 284))	('HPV-', 'Var', (67, 71))	('higher', 'PosReg', (267, 273))	('expression', 'MPA', (123, 133))	('T cell activation', 'biological_process', 'GO:0042110', ('178', '195'))	('antigen presentation', 'biological_process', 'GO:0019882', ('153', '173'))	('lower', 'NegReg', (117, 122))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('signaling', 'biological_process', 'GO:0023052', ('340', '349'))	('innate immune response', 'biological_process', 'GO:0045087', ('301', '323'))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
27556	27642729	Wildtype or p110gamma-/- 6-8 week-old female or male syngeneic C57Bl/6J (LLC lung, PyMT breast, and MEER HPV+ HNSCC) or C3He/J (SSCVII HPV- HNSCC) mice were implanted with 1x106 tumor cells by subcutaneous injection (LLC, MEER, SCCVII) or by orthotopic injection (PyMT) (n=10-15) and tumor growth was monitored for up to 30 days.	('p110gamma', 'Gene', (12, 21))	('p110gamma', 'Gene', '30955', (12, 21))	('mice', 'Species', '10090', (147, 151))	('tumor', 'Disease', (178, 183))	('LLC', 'cellular_component', 'GO:0038045', ('217', '220'))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('C57Bl/6J', 'Var', (63, 71))	('LLC', 'cellular_component', 'GO:0038045', ('73', '76'))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('HNSCC', 'Phenotype', 'HP:0012288', (140, 145))	('tumor', 'Disease', (284, 289))
27564	27642729	Enzymatic and cellular assays confirmed the selectivity of IPI-549 for PI3Kgamma (>200-fold in enzymatic assays and >140-fold in cellular assays over other Class I PI3K isoforms.	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('IPI-549', 'Var', (59, 66))	('PI3Kgamma', 'Disease', (71, 80))	('IPI-549', 'CellLine', 'CVCL:3825', (59, 66))
27575	27642729	Wildtype mice bearing HPV+ tumors were also treated with the p110gamma inhibitor TG100-11543 b.i.d.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('p110gamma', 'Gene', (61, 70))	('p110gamma', 'Gene', '30955', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('TG100', 'Chemical', '-', (81, 86))	('HPV+ tumors', 'Disease', 'MESH:D030361', (22, 33))	('mice', 'Species', '10090', (9, 13))	('HPV+ tumors', 'Disease', (22, 33))	('TG100-11543', 'Var', (81, 92))
27626	27642729	For cell sorting, single cell suspensions were stained with Aqua Live Dead fixable stain (Life Technologies) to exclude dead cells and anti-CD11b-APC (M1/70, eBioscience) and anti-Gr1-FITC (RB6-8C5, eBioscience) antibodies.	('Gr1', 'Gene', (180, 183))	('Gr1', 'Gene', '546644', (180, 183))	('pen', 'Gene', (33, 36))	('APC', 'cellular_component', 'GO:0005680', ('146', '149'))	('pen', 'Gene', '232670', (33, 36))	('anti-CD11b-APC', 'Var', (135, 149))	('M1/70', 'Gene', (151, 156))	('M1/70', 'Gene', '12669', (151, 156))
27639	27642729	Freshly isolated mouse bone marrow cells from 9 WT and 9 p110gamma-/- mice were pooled into 3 replicates sets of WT or p110g-/- cells and differentiated into macrophages for six days in RPMI + 20% FBS+ 1%Pen/Strep+ 50 ng/ml M-CSF.	('p110gamma', 'Gene', (57, 66))	('RPMI', 'Chemical', '-', (186, 190))	('FBS+ 1', 'Gene', '230904', (197, 203))	('mouse', 'Species', '10090', (17, 22))	('p110gamma', 'Gene', '30955', (57, 66))	('Pen', 'Gene', (204, 207))	('mice', 'Species', '10090', (70, 74))	('Pen', 'Gene', '232670', (204, 207))	('p110g-/-', 'Var', (119, 127))	('FBS+ 1', 'Gene', (197, 203))
27664	27642729	Primary antibodies directed against Akt (11E7), p-Akt (244F9), IkBa (L35A5), IKKb (D30C6), p-IKKa/b (16A6), NFkBp65 (D14E12), pNFkBp65 (93H1), C/EBPb (#3087), p-CEBPb (#3082), IRAK1 (D51G7), TBK1 (D1B4), and p110gamma (#4252) were from Cell Signaling Technology and pTBK1 (EPR2867(2)) was from Abcam.	('IKKa', 'Gene', '12675', (93, 97))	('p110gamma', 'Gene', '30955', (208, 217))	('#3087', 'Var', (151, 156))	('p65', 'Gene', '19697', (112, 115))	('TBK1', 'Gene', (191, 195))	('TBK1', 'Gene', '56480', (267, 271))	('p110gamma', 'Gene', (208, 217))	('p65', 'Gene', (131, 134))	('IRAK1', 'Gene', (176, 181))	('D30C6', 'Var', (83, 88))	('Signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('Akt', 'Gene', (36, 39))	('IRAK1', 'Gene', '16179', (176, 181))	('Akt', 'Gene', '11651', (36, 39))	('IKKa', 'Gene', (93, 97))	('IKKb', 'Gene', '16150', (77, 81))	('p65', 'Gene', (112, 115))	('Akt', 'Gene', (50, 53))	('TBK1', 'Gene', '56480', (191, 195))	('L35A5', 'Var', (69, 74))	('TBK1', 'molecular_function', 'GO:0008384', ('191', '195'))	('#3082', 'Var', (168, 173))	('C/EBPb', 'Gene', (143, 149))	('TBK1', 'Gene', (267, 271))	('p65', 'Gene', '19697', (131, 134))	('Akt', 'Gene', '11651', (50, 53))	('C/EBPb', 'Gene', '12608', (143, 149))	('IKKb', 'Gene', (77, 81))	('CEBPb', 'Gene', (161, 166))	('CEBPb', 'Gene', '12608', (161, 166))	('D51G7', 'Var', (183, 188))
27665	27642729	CD90.2+ tumor derived T cells were purified from LLC tumor-bearing WT and p110gamma-/- or TG100-115 and control treated mice and then co-incubated with LLC tumor cells (target cells) at 2.5:1, 5:1 and 10:1 ratios of T cells to tumor cells (2x103 LLC tumor cells per well) for 6 hours.	('p110gamma', 'Gene', (74, 83))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('rat', 'Species', '10116', (206, 209))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (250, 255))	('TG100-115', 'Var', (90, 99))	('LLC tumor', 'Disease', (49, 58))	('TG100', 'Chemical', '-', (90, 95))	('LLC tumor', 'Disease', (246, 255))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('LLC', 'cellular_component', 'GO:0038045', ('49', '52'))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('LLC tumor', 'Disease', 'MESH:D009369', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('LLC tumor', 'Disease', 'MESH:D009369', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('LLC', 'cellular_component', 'GO:0038045', ('152', '155'))	('tumor', 'Disease', (8, 13))	('LLC tumor', 'Disease', 'MESH:D009369', (246, 255))	('p110gamma', 'Gene', '30955', (74, 83))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('LLC', 'cellular_component', 'GO:0038045', ('246', '249'))	('tumor', 'Disease', (53, 58))	('LLC tumor', 'Disease', (152, 161))
27677	28202515	Systematic in vivo inactivation of chromatin regulating enzymes identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma Chromatin modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood.	('human', 'Species', '9606', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Chromatin', 'cellular_component', 'GO:0000785', ('133', '142'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 132))	('tumor', 'Disease', (93, 98))	('lung adenocarcinoma', 'Disease', (191, 210))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (191, 210))	('Setd2', 'Gene', (75, 80))	('lung adenocarcinoma', 'Disease', (113, 132))	('Setd2', 'Gene', '235626', (75, 80))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (113, 132))	('inactivation', 'Var', (19, 31))	('chromatin', 'cellular_component', 'GO:0000785', ('35', '44'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
27679	28202515	Targeted inactivation of SWI/SNF nucleosome remodeling complex members Smarca4 (Brg1) or Arid1a had complex effects on lung adenocarcinoma initiation and progression.	('lung adenocarcinoma initiation', 'Disease', (119, 149))	('SWI/SNF', 'Gene', (25, 32))	('effects', 'Reg', (108, 115))	('lung adenocarcinoma initiation', 'Disease', 'MESH:D000077192', (119, 149))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('Smarca4', 'Gene', (71, 78))	('nucleosome remodeling complex', 'cellular_component', 'GO:0016585', ('33', '62'))	('Smarca4', 'Gene', '20586', (71, 78))	('inactivation', 'Var', (9, 21))	('Arid1a', 'Gene', (89, 95))
27680	28202515	Loss of either Brg1 or Arid1a were selected against in early stage tumors, but Brg1 loss continued to limit disease progression over time, whereas loss of Arid1a eventually promoted development of higher grade lesions.	('Arid1a', 'Gene', (155, 161))	('promoted', 'PosReg', (173, 181))	('stage tumors', 'Disease', (61, 73))	('loss', 'NegReg', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('Brg1', 'Gene', (79, 83))	('stage tumors', 'Disease', 'MESH:D062706', (61, 73))	('loss', 'Var', (147, 151))
27681	28202515	In contrast to these stage-specific effects, loss of the histone methyltransferase Setd2 had robust tumor promoting consequences.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Setd2', 'Gene', (83, 88))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('loss', 'Var', (45, 49))
27683	28202515	Setd2 inactivation and subsequent loss of H3K36me3 led to the swift expansion and accelerated progression of both early and late stage tumors.	('late stage tumors', 'Disease', 'MESH:D062706', (124, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('inactivation', 'Var', (6, 18))	('late stage tumors', 'Disease', (124, 141))	('accelerated', 'PosReg', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('H3K36me3', 'Protein', (42, 50))	('loss', 'NegReg', (34, 38))	('Setd2', 'Gene', (0, 5))
27690	28202515	The chromatin regulators SMARCA4 (BRG1), ARID1A, and SETD2 have been found to contain recurrent inactivating mutations in multiple tumor types including lung adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('inactivating mutations', 'Var', (96, 118))	('SMARCA4', 'Gene', (25, 32))	('lung adenocarcinoma', 'Disease', (153, 172))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 172))	('chromatin', 'cellular_component', 'GO:0000785', ('4', '13'))	('tumor', 'Disease', (131, 136))	('SMARCA4', 'Gene', '20586', (25, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))
27694	28202515	Loss of either Brg1 or Arid1a has been linked to multiple activities that promote cancer including pathological Myc signaling, defects in DNA repair, and impairment of cell cycle control.	('cell cycle control', 'biological_process', 'GO:1901987', ('168', '186'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Brg1', 'Gene', (15, 19))	('Myc', 'Gene', (112, 115))	('Myc', 'Gene', '17869', (112, 115))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('cell cycle control', 'CPA', (168, 186))	('promote', 'PosReg', (74, 81))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('linked', 'Reg', (39, 45))	('Arid1a', 'Gene', (23, 29))	('defects', 'NegReg', (127, 134))	('DNA repair', 'MPA', (138, 148))	('Loss', 'Var', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('DNA repair', 'biological_process', 'GO:0006281', ('138', '148'))
27695	28202515	While loss of Arid1a has yet to be studied in mouse models of lung adenocarcinoma, widespread loss of Brg1 in the lung limits tumor development in a model of carcinogen-induced lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('tumor', 'Disease', (126, 131))	('Brg1', 'Gene', (102, 106))	('loss', 'Var', (94, 98))	('lung adenocarcinoma', 'Disease', (177, 196))	('mouse', 'Species', '10090', (46, 51))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('limits', 'NegReg', (119, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))	('lung adenocarcinoma', 'Disease', (62, 81))
27696	28202515	Conversely loss of Brg1 throughout the lung epithelium promoted the growth of established carcinogen-induced tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('Brg1', 'Gene', (19, 23))	('loss', 'Var', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('promoted', 'PosReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
27697	28202515	Thus, loss of Brg1 is likely to have context-specific effects, but it remains unclear whether these effects of Brg1 loss are cancer cell autonomous or due to secondary effects of SWI/SNF disruption throughout lung tissue.	('Brg1', 'Gene', (111, 115))	('loss', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('loss', 'NegReg', (116, 120))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
27701	28202515	SETD2 encodes a histone methyltransferase that is unique in its ability to specifically catalyze histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is absent or dramatically reduced in cells that have lost normal Setd2 expression.	('Setd2', 'Gene', (223, 228))	('lysine', 'Chemical', 'MESH:D008239', (108, 114))	('reduced', 'NegReg', (184, 191))	('SETD2', 'Gene', (0, 5))	('H3K36me3', 'Var', (149, 157))
27703	28202515	KrasLSL-G12D/+ and KrasLSL-G12D/+;p53flox/flox mice form the basis of two well-characterized models of lung adenocarcinoma in which inhalation of Cre-expressing lentiviral vectors induces expression of oncogenic KrasG12D alone, or in combination with p53 deletion in infected lung epithelial cells.	('Kras', 'Gene', (19, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('G12D', 'Mutation', 'rs121913529', (216, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('p53', 'Gene', (34, 37))	('Kras', 'Gene', '16653', (19, 23))	('p53', 'Gene', '22060', (34, 37))	('Kras', 'Gene', (0, 4))	('G12D', 'Mutation', 'rs121913529', (8, 12))	('Kras', 'Gene', (212, 216))	('induces', 'PosReg', (180, 187))	('Kras', 'Gene', '16653', (0, 4))	('oncogenic', 'MPA', (202, 211))	('p53', 'Gene', (251, 254))	('expression', 'MPA', (188, 198))	('p53', 'Gene', '22060', (251, 254))	('lung adenocarcinoma', 'Disease', (103, 122))	('Kras', 'Gene', '16653', (212, 216))	('deletion', 'Var', (255, 263))	('mice', 'Species', '10090', (47, 51))	('G12D', 'Mutation', 'rs121913529', (27, 31))
27705	28202515	As KRAS and TP53 are the most frequently mutated genes in human lung adenocarcinoma, and often co-occur with mutations in BRG1, ARID1A, or SETD2, the KrasLSL-G12D/+ and KrasLSL-G12D/+;p53flox/flox models represent highly attractive and physiologically relevant systems to determine how loss of these chromatin regulators impacts tumor progression (Supplementary Fig.	('SETD2', 'Gene', (139, 144))	('human', 'Species', '9606', (58, 63))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('chromatin', 'cellular_component', 'GO:0000785', ('300', '309'))	('impacts tumor', 'Disease', (321, 334))	('loss', 'Var', (286, 290))	('Kras', 'Gene', (169, 173))	('p53', 'Gene', (184, 187))	('BRG1', 'Gene', (122, 126))	('G12D', 'Mutation', 'rs121913529', (177, 181))	('ARID1A', 'Gene', (128, 134))	('TP53', 'Gene', (12, 16))	('p53', 'Gene', '22060', (184, 187))	('Kras', 'Gene', '16653', (169, 173))	('Kras', 'Gene', (150, 154))	('mutations', 'Var', (109, 118))	('lung adenocarcinoma', 'Disease', (64, 83))	('G12D', 'Mutation', 'rs121913529', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('TP53', 'Gene', '7157', (12, 16))	('Kras', 'Gene', '16653', (150, 154))	('impacts tumor', 'Disease', 'MESH:D004834', (321, 334))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 83))
27739	28202515	Because CRISPR-mediated gene disruption is dependent on error-prone DNA repair after Cas9 nuclease activity, complete inactivation of target genes is not expected to occur in all tumors.	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('DNA repair', 'MPA', (68, 78))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('nuclease activity', 'molecular_function', 'GO:0004518', ('90', '107'))	('error-prone DNA repair', 'biological_process', 'GO:0045020', ('56', '78'))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('Cas', 'cellular_component', 'GO:0005650', ('85', '88'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('disruption', 'Var', (29, 39))
27746	28202515	However, tumors that were negative or mixed for H3K36me3 were significantly larger and showed higher rates of proliferation, with no difference in rates of apoptosis, than tumors that maintained normal H3K36me3 levels (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('H3K36me3', 'Var', (48, 56))	('proliferation', 'CPA', (110, 123))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('higher', 'PosReg', (94, 100))
27747	28202515	The spectrum of tumor grades in KrasLSL-G12D/+ mice were not affected by loss of Arid1a or Brg1 expression, but tumors with inactivated Setd2 displayed a shift towards more grade 2 adenomas (Fig.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Kras', 'Gene', (32, 36))	('Setd2', 'Gene', (136, 141))	('Kras', 'Gene', '16653', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('G12D', 'Mutation', 'rs121913529', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Brg1', 'Gene', (91, 95))	('adenomas', 'Disease', 'MESH:D000236', (181, 189))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (112, 117))	('inactivated', 'Var', (124, 135))	('adenomas', 'Disease', (181, 189))	('mice', 'Species', '10090', (47, 51))	('tumors', 'Disease', (112, 118))
27748	28202515	Interestingly, despite the clear increase in grade 2 adenomas after Setd2 inactivation, we never observed grade 3 tumors in KrasLSL-G12D/+ mice at this time point (Fig.	('G12D', 'Mutation', 'rs121913529', (132, 136))	('adenomas', 'Disease', 'MESH:D000236', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('adenomas', 'Disease', (53, 61))	('increase', 'PosReg', (33, 41))	('tumors', 'Disease', (114, 120))	('Kras', 'Gene', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('mice', 'Species', '10090', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('Kras', 'Gene', '16653', (124, 128))	('Setd2', 'Gene', (68, 73))	('inactivation', 'Var', (74, 86))
27749	28202515	These results indicate that although loss of Setd2 promotes the growth of early stage lung adenomas by increasing proliferation rates, Setd2 loss alone is insufficient to overcome the p53-regulated barrier that suppresses the formation of grade 3 adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (247, 262))	('Setd2', 'Gene', (45, 50))	('loss', 'NegReg', (141, 145))	('adenocarcinomas', 'Disease', (247, 262))	('growth', 'MPA', (64, 70))	('Setd2', 'Gene', (135, 140))	('p53', 'Gene', (184, 187))	('proliferation rates', 'CPA', (114, 133))	('lung adenomas', 'Disease', (86, 99))	('insufficient', 'Disease', (155, 167))	('insufficient', 'Disease', 'MESH:D000309', (155, 167))	('increasing', 'PosReg', (103, 113))	('promotes', 'PosReg', (51, 59))	('loss', 'Var', (37, 41))	('formation', 'biological_process', 'GO:0009058', ('226', '235'))	('p53', 'Gene', '22060', (184, 187))	('lung adenomas', 'Disease', 'MESH:D000236', (86, 99))
27761	28202515	These data demonstrate that while loss of Arid1a and Setd2 in KrasG12D-driven lung cancer drives a dramatically different number of gene expression changes, many of these genes are altered in both conditions, and may potentially reveal pathways of tumor suppression that are shared amongst these mechanistically distinct chromatin regulating enzymes.	('altered', 'Reg', (181, 188))	('suppression', 'NegReg', (254, 265))	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('tumor', 'Disease', (248, 253))	('loss', 'Var', (34, 38))	('gene expression changes', 'MPA', (132, 155))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('Setd2', 'Gene', (53, 58))	('reveal', 'Reg', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('chromatin', 'cellular_component', 'GO:0000785', ('321', '330'))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('Arid1a', 'Gene', (42, 48))
27762	28202515	To determine the impact of inactivating Brg1, Arid1a, and Setd2 in combination with p53 loss in more advanced KrasG12D-driven lung adenocarcinoma, we assessed tumors in KrasLSL-G12D/+;p53flox/flox mice 12 weeks after tumor initiation with LentiCRISPRv2Cre.	('p53', 'Gene', '22060', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('mice', 'Species', '10090', (197, 201))	('Kras', 'Gene', (169, 173))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 145))	('G12D', 'Mutation', 'rs121913529', (114, 118))	('p53', 'Gene', (184, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (126, 145))	('G12D', 'Mutation', 'rs121913529', (177, 181))	('Kras', 'Gene', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('p53', 'Gene', '22060', (184, 187))	('tumor initiation', 'Disease', 'MESH:D009369', (217, 233))	('Kras', 'Gene', '16653', (169, 173))	('tumor initiation', 'Disease', (217, 233))	('loss', 'NegReg', (88, 92))	('Kras', 'Gene', '16653', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('p53', 'Gene', (84, 87))	('inactivating', 'Var', (27, 39))	('lung adenocarcinoma', 'Disease', (126, 145))
27764	28202515	However, fewer tumors were present in mice infected with LentiCRISPRv2Cre targeting Brg1 and these tumors demonstrated a significant increase in apoptotic rates, again suggesting that Brg1 is required for efficient tumor formation (Fig.4A, and Supplementary Figure S7A-B).	('formation', 'biological_process', 'GO:0009058', ('221', '230'))	('mice', 'Species', '10090', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', (99, 104))	('LentiCRISPRv2Cre targeting', 'Var', (57, 83))	('apoptotic rates', 'CPA', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Brg1', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
27765	28202515	While tumor size was unchanged in Arid1a or Brg1 mixed and negative tumors, tumors with mixed or no H3K36me3 staining were significantly larger and had higher proliferation rates, with no change in the rate of apoptosis, than those that retained normal H3K36me3 levels (Fig.	('higher', 'PosReg', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Disease', (76, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (68, 73))	('proliferation rates', 'CPA', (159, 178))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('H3K36me3 staining', 'Var', (100, 117))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (6, 11))	('tumors', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('larger', 'PosReg', (137, 143))
27767	28202515	Loss of Brg1 however did not promote the acquisition of advanced grade disease in KrasLSL-G12D/+;p53flox/flox mice, but instead significantly increased the proportion of adenomatous alveolar hyperplasias (AAH) detected.	('alveolar hyperplasias', 'Phenotype', 'HP:0009085', (182, 203))	('p53', 'Gene', (97, 100))	('Brg1', 'Gene', (8, 12))	('increased', 'PosReg', (142, 151))	('Kras', 'Gene', (82, 86))	('Kras', 'Gene', '16653', (82, 86))	('G12D', 'Mutation', 'rs121913529', (90, 94))	('mice', 'Species', '10090', (110, 114))	('adenomatous alveolar hyperplasias', 'Disease', 'MESH:D011125', (170, 203))	('p53', 'Gene', '22060', (97, 100))	('AAH', 'Phenotype', 'HP:0009085', (205, 208))	('adenomatous alveolar hyperplasias', 'Disease', (170, 203))	('Loss', 'Var', (0, 4))
27768	28202515	In contrast to the subtle effects of targeting Arid1a in tumors expressing wildtype p53, loss of Arid1a significantly accelerated lung tumor progression in KrasLSL-G12D/+;p53flox/flox mice.	('p53', 'Gene', '22060', (84, 87))	('loss', 'Var', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('p53', 'Gene', '22060', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('accelerated', 'PosReg', (118, 129))	('Arid1a', 'Gene', (97, 103))	('lung tumor', 'Disease', 'MESH:D008175', (130, 140))	('mice', 'Species', '10090', (184, 188))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('Kras', 'Gene', (156, 160))	('lung tumor', 'Disease', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p53', 'Gene', (84, 87))	('tumors', 'Disease', (57, 63))	('G12D', 'Mutation', 'rs121913529', (164, 168))	('p53', 'Gene', (171, 174))	('lung tumor', 'Phenotype', 'HP:0100526', (130, 140))	('Kras', 'Gene', '16653', (156, 160))
27770	28202515	Inactivation of Setd2 also resulted in a dramatic shift in tumor grade, as the majority of H3K36me3 mixed and negative tumors were grade 3 or 4, in contrast to lower grade H3K36me3 positive tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (59, 64))	('shift', 'Reg', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Setd2', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Disease', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('H3K36me3', 'Protein', (91, 99))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Inactivation', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('negative', 'NegReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
27773	28202515	To determine whether loss of Brg1, Arid1a or Setd2 altered cellular fates after tumor initiation or during tumor progression as has been reported in other contexts, we measured the expression of cellular lineage markers in extant tumors at early (8-12 week) and late (16 week) time points.	('Arid1a', 'Gene', (35, 41))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cellular fates', 'CPA', (59, 73))	('loss', 'Var', (21, 25))	('tumors', 'Disease', (230, 236))	('tumor', 'Disease', (230, 235))	('expression', 'MPA', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Setd2', 'Gene', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('altered', 'Reg', (51, 58))	('Brg1', 'Gene', (29, 33))	('tumor initiation', 'Disease', 'MESH:D009369', (80, 96))	('tumor initiation', 'Disease', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
27776	28202515	The development of poorly differentiated late stage metastatic disease (Grade 5), is marked by loss of the lung cell fate-determining transcription factor Nkx2-1 and derepression of Hmga2, an embryonic-restricted regulator of chromatin architecture.	('Hmga2', 'Gene', '15364', (182, 187))	('Hmga2', 'Gene', (182, 187))	('Nkx2-1', 'Gene', (155, 161))	('chromatin', 'cellular_component', 'GO:0000785', ('226', '235'))	('transcription factor', 'molecular_function', 'GO:0000981', ('134', '154'))	('Nkx2-1', 'Gene', '21869', (155, 161))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('loss', 'NegReg', (95, 99))	('derepression', 'Var', (166, 178))
27780	28202515	In contrast, H3K36me3 negative tumor cells display severe nuclear and cellular pleomorphism with increased nuclear to cytoplasmic ratio (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (31, 36))	('nuclear to cytoplasmic ratio', 'MPA', (107, 135))	('H3K36me3 negative', 'Var', (13, 30))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
27785	28202515	We examined lung tumors from KrasLSL-G12D/+;p53flox/flox mice infected with LentiCRISPRv2Cre targeting Brg1, Arid1a, or Setd2 at 8, 12, and 16 weeks post tumor initiation.	('p53', 'Gene', '22060', (44, 47))	('Kras', 'Gene', (29, 33))	('Kras', 'Gene', '16653', (29, 33))	('mice', 'Species', '10090', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('lung tumors', 'Phenotype', 'HP:0100526', (12, 23))	('tumor initiation', 'Disease', (154, 170))	('LentiCRISPRv2Cre', 'Var', (76, 92))	('G12D', 'Mutation', 'rs121913529', (37, 41))	('p53', 'Gene', (44, 47))	('lung tumors', 'Disease', 'MESH:D008175', (12, 23))	('lung tumor', 'Phenotype', 'HP:0100526', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Brg1', 'Gene', (103, 107))	('tumor initiation', 'Disease', 'MESH:D009369', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('lung tumors', 'Disease', (12, 23))
27795	28202515	These data reflect patient outcomes for human LUAD, for whom low Setd2 expression is associated with dramatically reduced overall survival (Fig.	('expression', 'MPA', (71, 81))	('Setd2', 'Gene', (65, 70))	('patient', 'Species', '9606', (19, 26))	('reduced', 'NegReg', (114, 121))	('low', 'Var', (61, 64))	('overall survival', 'MPA', (122, 138))	('human', 'Species', '9606', (40, 45))
27796	28202515	To further demonstrate the relationship between SETD2 loss and lung adenocarcinoma amongst human patient samples, we stained 60 human tumors (~6 cores per tumor sample) with known KRAS or EGFR mutations for H3K36me3 deposition (Fig.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('KRAS', 'Gene', (180, 184))	('H3K36me3 deposition', 'MPA', (207, 226))	('tumor', 'Disease', (155, 160))	('mutations', 'Var', (193, 202))	('patient', 'Species', '9606', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumors', 'Disease', (134, 140))	('human', 'Species', '9606', (128, 133))	('SETD2', 'Gene', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('EGFR', 'Gene', (188, 192))	('tumor', 'Disease', (134, 139))	('lung adenocarcinoma', 'Disease', (63, 82))	('loss', 'NegReg', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('human', 'Species', '9606', (91, 96))
27798	28202515	Interestingly, we found that KRAS mutant tumors were significantly more likely than EGFR mutant tumors to have reduced or absent staining for H3K36me3 (p=0.02, Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('KRAS mutant', 'Var', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('reduced', 'NegReg', (111, 118))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('staining for', 'MPA', (129, 141))	('H3K36me3', 'Protein', (142, 150))	('absent', 'NegReg', (122, 128))	('mutant', 'Var', (34, 40))
27800	28202515	Cancer genome sequencing studies of diverse malignancies have uncovered a surprising enrichment of mutations in genes that regulate chromatin structure and function.	('chromatin', 'cellular_component', 'GO:0000785', ('132', '141'))	('malignancies', 'Disease', (44, 56))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (99, 108))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))	('chromatin', 'MPA', (132, 141))
27804	28202515	Based on this human sequencing data, mutations of these chromatin regulators were predicted to facilitate lung adenocarcinoma development.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('human', 'Species', '9606', (14, 19))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('chromatin', 'cellular_component', 'GO:0000785', ('56', '65'))	('mutations', 'Var', (37, 46))	('facilitate', 'PosReg', (95, 105))	('lung adenocarcinoma', 'Disease', (106, 125))
27805	28202515	However, we observed that inactivation of these genes in vivo had variable effects on tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('inactivation', 'Var', (26, 38))	('tumor initiation', 'Disease', (86, 102))	('progression', 'CPA', (107, 118))	('tumor initiation', 'Disease', 'MESH:D009369', (86, 102))
27807	28202515	Despite the high frequency of BRG1 and ARID1A mutations in human lung adenocarcinoma, we were unable to detect tumors that had lost Brg1 and few that had lost Arid1a expression during the earliest stages of tumor initiation, demonstrating that SWI/SNF chromatin remodeling activity is required at early disease stages.	('human', 'Species', '9606', (59, 64))	('chromatin', 'cellular_component', 'GO:0000785', ('252', '261'))	('mutations', 'Var', (46, 55))	('lost', 'NegReg', (127, 131))	('tumor initiation', 'Disease', 'MESH:D009369', (207, 223))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('BRG1', 'Gene', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor initiation', 'Disease', (207, 223))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('252', '272'))	('ARID1A', 'Gene', (39, 45))	('Brg1', 'Gene', (132, 136))	('lung adenocarcinoma', 'Disease', (65, 84))
27809	28202515	That ARID1A mutations are present in these early lesions in the mouse, but do not act as a significant driver of tumor progression in those cells, is consistent with the recent identification of ARID1A mutations in incidental pre-neoplastic lesions discovered in lung resection patients.	('tumor', 'Disease', (113, 118))	('ARID1A', 'Gene', (5, 11))	('ARID1A', 'Gene', (195, 201))	('mutations', 'Var', (12, 21))	('pre', 'molecular_function', 'GO:0003904', ('226', '229'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('patients', 'Species', '9606', (278, 286))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (230, 248))	('mouse', 'Species', '10090', (64, 69))	('mutations', 'Var', (202, 211))
27810	28202515	This suggests that once tumors attain a cellular state associated with more advanced disease, loss of Arid1a promotes disease progression.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('disease progression', 'CPA', (118, 137))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('loss', 'Var', (94, 98))	('Arid1a', 'Gene', (102, 108))	('promotes', 'PosReg', (109, 117))
27812	28202515	These context-specific roles are interesting in light of work in KrasG12D-driven pancreatic cancer models, where loss of Brg1 expression opposes the development of one disease subtype but promotes the development of another depending on the initiating cell of origin and the stage of tumor progression.	('tumor', 'Disease', (284, 289))	('opposes', 'NegReg', (137, 144))	('promotes', 'PosReg', (188, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('loss', 'Var', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('Brg1', 'Gene', (121, 125))	('pancreatic cancer', 'Disease', (81, 98))
27814	28202515	Because of the strong selective disadvantage of SWI/SNF deregulation during early stages of tumor initiation in our model, systems which limit inactivation of SWI/SNF complex members to tumors after they are established are needed to better understand the individual role each complex member plays in particular stages of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SWI/SNF', 'Gene', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('deregulation', 'Var', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor initiation', 'Disease', 'MESH:D009369', (92, 108))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (322, 327))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('159', '174'))	('tumor initiation', 'Disease', (92, 108))
27815	28202515	In contrast to the modest effects of SWI/SNF complex mutations, CRISPR-mediated disruption of Setd2 profoundly affected KrasG12D-driven tumors in the lung.	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('Setd2', 'Gene', (94, 99))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('37', '52'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('affected', 'Reg', (111, 119))	('disruption', 'Var', (80, 90))
27818	28202515	However, despite the rapid expansion and progression of tumors upon Setd2 inactivation, these tumors were still limited by well-defined progression checkpoints characteristic of the KrasLSL-G12D/+ and KrasLSL-G12D/+;p53flox/flox tumor models.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('G12D', 'Mutation', 'rs121913529', (209, 213))	('Kras', 'Gene', '16653', (201, 205))	('p53', 'Gene', (216, 219))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('p53', 'Gene', '22060', (216, 219))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', (94, 100))	('inactivation', 'Var', (74, 86))	('G12D', 'Mutation', 'rs121913529', (190, 194))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (229, 234))	('Kras', 'Gene', (182, 186))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Setd2', 'Gene', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('Kras', 'Gene', '16653', (182, 186))	('Kras', 'Gene', (201, 205))
27819	28202515	The transition to malignancy (grade 3) is opposed by the p53 pathway in KrasG12D/+ lung tumors, and within the 16 week time course of our experiments, Setd2 loss was not sufficient to overcome this barrier to malignant lung tumor progression.	('malignant lung tumor', 'Disease', (209, 229))	('p53', 'Gene', '22060', (57, 60))	('lung tumor', 'Phenotype', 'HP:0100526', (219, 229))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('malignancy', 'Disease', 'MESH:D009369', (18, 28))	('Setd2', 'Gene', (151, 156))	('lung tumors', 'Disease', 'MESH:D008175', (83, 94))	('lung tumor', 'Phenotype', 'HP:0100526', (83, 93))	('malignancy', 'Disease', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('lung tumors', 'Phenotype', 'HP:0100526', (83, 94))	('p53', 'Gene', (57, 60))	('KrasG12D/+', 'Var', (72, 82))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('malignant lung tumor', 'Disease', 'MESH:D018198', (209, 229))	('lung tumors', 'Disease', (83, 94))	('loss', 'NegReg', (157, 161))
27826	28202515	Yet these defects likely limit cell fitness, and thus appear to be at odds with the immediate and widespread proliferation that occurs with Setd2 loss in tumors.	('loss', 'NegReg', (146, 150))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('limit', 'NegReg', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cell fitness', 'CPA', (31, 43))	('Setd2', 'Gene', (140, 145))	('defects', 'Var', (10, 17))
27827	28202515	In light of the distinct overlap of differentially expressed genes regulating alternative splicing in both Arid1a and Setd2 deficient tumors, and the common occurrence of somatic alterations in spliceosomal components across multiple cancer types, it is intriguing to speculate that defective alternative splicing could be a common driving force of tumor progression after loss of proper chromatin regulation.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('chromatin', 'cellular_component', 'GO:0000785', ('388', '397'))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('regulation', 'biological_process', 'GO:0065007', ('398', '408'))	('deficient tumors', 'Disease', (124, 140))	('Setd2', 'Gene', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('deficient tumors', 'Disease', 'MESH:D009369', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('splicing', 'biological_process', 'GO:0045292', ('305', '313'))	('defective alternative', 'Var', (283, 304))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (234, 240))	('splicing', 'biological_process', 'GO:0045292', ('90', '98'))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (349, 354))
27830	28367247	Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('over-expressed', 'PosReg', (158, 172))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('Aberrant', 'Var', (21, 29))	('Tumors', 'Disease', (44, 50))	('Fibronectin', 'Gene', (85, 96))	('cancers', 'Disease', (184, 191))	('Tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Disease', (247, 252))	('participate', 'Reg', (215, 226))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('Tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Fibronectin', 'Gene', '2335', (0, 11))	('Tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Fibronectin', 'Gene', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('Fibronectin', 'Gene', '2335', (85, 96))
27831	28367247	The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance.	('invasion', 'CPA', (105, 113))	('metastasis', 'CPA', (115, 125))	('fibronectin', 'Protein', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('influences', 'Reg', (80, 90))	('aberrant', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('therapy resistance', 'CPA', (130, 148))	('tumor', 'Disease', (91, 96))
27837	28367247	With regard to cancer, fibronectin is not only increased in tumors where its altered expression has been shown to promote tumor growth, migration and invasion but fibronectin has also been reported to limit tumor cell responsiveness to therapy  (Figure 1).	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('altered', 'Var', (77, 84))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('promote', 'PosReg', (114, 121))	('limit', 'NegReg', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', (60, 66))	('expression', 'MPA', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('invasion', 'CPA', (150, 158))	('increased', 'PosReg', (47, 56))	('migration', 'CPA', (136, 145))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
27840	28367247	Work in our lab has shown that loss of caveolin-1, the main structural protein of caveolae, results in increased expression of fibronectin, tenascin-C and collagen in murine mammary glands (Thompson et al, unpublished data).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('expression', 'MPA', (113, 123))	('caveolae', 'cellular_component', 'GO:0005901', ('82', '90'))	('increased expression of fibronectin', 'Phenotype', 'HP:0032463', (103, 138))	('increased', 'PosReg', (103, 112))	('murine', 'Species', '10090', (167, 173))	('loss', 'Var', (31, 35))	('tenascin-C', 'cellular_component', 'GO:0090733', ('140', '150'))	('caveolin-1', 'Gene', (39, 49))	('tenascin-C', 'Protein', (140, 150))	('collagen', 'Protein', (155, 163))	('collagen', 'molecular_function', 'GO:0005202', ('155', '163'))	('fibronectin', 'Protein', (127, 138))	('caveolin-1', 'Gene', '12389', (39, 49))
27841	28367247	The purpose of this review is to illustrate the mechanisms in which aberrant fibronectin expression influences tumorigenesis and therapy resistance.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('influences', 'Reg', (100, 110))	('tumor', 'Disease', (111, 116))	('fibronectin', 'Protein', (77, 88))	('therapy resistance', 'CPA', (129, 147))	('aberrant', 'Var', (68, 76))
27856	28367247	In an effort to delineate a role for fibronectin-integrin interactions on tumor cell resistance to apoptosis, Han et al used Wortmannin to block PI3-K in human bronchial epithelial BEAS-2B and 16-HBE cell lines following alpha5beta1 cellular engagement with fibronectin.	('human', 'Species', '9606', (154, 159))	('16-HBE', 'CellLine', 'CVCL:0112', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('PI3-K', 'Var', (145, 150))	('interactions', 'Interaction', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('BEAS-2B', 'CellLine', 'CVCL:0168', (181, 188))	('Wortmannin', 'Chemical', 'MESH:D000077191', (125, 135))	('tumor', 'Disease', (74, 79))	('beta1', 'Gene', '146712', (227, 232))	('beta1', 'Gene', (227, 232))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('PI3-K', 'molecular_function', 'GO:0016303', ('145', '150'))
27867	28367247	While the full length form of fibronectin plays an important role in tumorigenesis, isoforms of fibronectin, such as the ED-A and ED-B variants, have been reported to regulate tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ED-B', 'Gene', '2335', (130, 134))	('ED-A', 'Gene', (121, 125))	('tumor', 'Disease', (69, 74))	('regulate', 'Reg', (167, 175))	('tumor', 'Disease', (176, 181))	('ED-B', 'Gene', (130, 134))	('variants', 'Var', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
27872	28367247	Aside from a role in angiogenesis, ED-A fibronectin was reported to be upregulated in patient colorectal tumors, especially those that were of advanced stage.	('colorectal tumors', 'Disease', 'MESH:D015179', (94, 111))	('angiogenesis', 'biological_process', 'GO:0001525', ('21', '33'))	('colorectal tumors', 'Disease', (94, 111))	('patient', 'Species', '9606', (86, 93))	('ED-A', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('upregulated', 'PosReg', (71, 82))
27875	28367247	In a more recent study, ED-A fibronectin was shown to increase the population of myeloid derived cells, known to impair immune responses to cancer cells, from osteoblasts.	('ED-A fibronectin', 'Var', (24, 40))	('increase', 'PosReg', (54, 62))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('population of myeloid derived cells', 'CPA', (67, 102))
27876	28367247	To determine whether the absence of fibronectin impaired myeloid cell numbers and thus tumor formation, the authors subcutaneously injected melanoma cells into either a fibronectin knock out model (cKO) in which fibronectin expression in differentiating osteoblasts was conditionally deleted or a wild type animal (WT) and evaluated for tumor formation.	('fibronectin', 'Gene', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('formation', 'biological_process', 'GO:0009058', ('343', '352'))	('tumor', 'Disease', (337, 342))	('impaired myeloid cell numbers', 'Disease', (48, 77))	('tumor', 'Disease', (87, 92))	('fibronectin impaired', 'Phenotype', 'HP:0032463', (36, 56))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('absence', 'Var', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('impaired myeloid cell numbers', 'Disease', 'MESH:D009422', (48, 77))
27877	28367247	Tumor growth and the presence of myeloid cells in tumors were reduced in cKO animals but not in WT animals.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cKO', 'Var', (73, 76))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('Tumor growth', 'CPA', (0, 12))	('reduced', 'NegReg', (62, 69))
27878	28367247	Although the authors don't attribute these findings to a specific reduction in the ED-A fibronectin isoform, they go on to demonstrate that culture of myeloid cells from cKO animals with ED-A fibronectin resulted in a reduction of melanoma apoptosis, suggesting that this pro-tumor effect results from ED-A activation of myeloid cells.	('apoptosis', 'biological_process', 'GO:0097194', ('240', '249'))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('apoptosis', 'biological_process', 'GO:0006915', ('240', '249'))	('melanoma apoptosis', 'Disease', 'MESH:D008545', (231, 249))	('reduction', 'NegReg', (218, 227))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('ED-A', 'Var', (187, 191))	('tumor', 'Disease', (276, 281))	('melanoma apoptosis', 'Disease', (231, 249))
27892	28367247	The authors found that inhibiting 7-nAChR and COX-2 not only limited fibronectin expression, but also increased E-cadherin expression, reducing SW480 cell migration.	('limited', 'NegReg', (61, 68))	('reducing', 'NegReg', (135, 143))	('COX-2', 'Gene', '4513', (46, 51))	('fibronectin', 'Protein', (69, 80))	('expression', 'MPA', (123, 133))	('COX-2', 'Gene', (46, 51))	('nAChR', 'Gene', (36, 41))	('E-cadherin', 'Gene', (112, 122))	('SW480', 'CellLine', 'CVCL:0546', (144, 149))	('E-cadherin', 'Gene', '999', (112, 122))	('nAChR', 'molecular_function', 'GO:0022848', ('36', '41'))	('cell migration', 'biological_process', 'GO:0016477', ('150', '164'))	('cadherin', 'molecular_function', 'GO:0008014', ('114', '122'))	('SW480 cell migration', 'CPA', (144, 164))	('increased', 'PosReg', (102, 111))	('inhibiting', 'Var', (23, 33))	('nAChR', 'Gene', '1137', (36, 41))
27896	28367247	Here, the authors first showed that 3D co-culture of ovarian cancer cells with mesothelial cells supported fibronectin expression from mesothelial cells via activation of a TGF-betaR1/RAC1/SMAD3 signaling pathway, a phenomenon which was important for cancer cell adhesion, proliferation and invasion as silencing of fibronectin reduced these cellular responses.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('ovarian cancer', 'Disease', (53, 67))	('TGF-beta', 'Gene', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('reduced', 'NegReg', (328, 335))	('RAC1', 'Gene', (184, 188))	('expression', 'MPA', (119, 129))	('RAC1', 'Gene', '5879', (184, 188))	('SMAD3', 'Gene', '4088', (189, 194))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('fibronectin', 'MPA', (107, 118))	('cancer', 'Disease', (251, 257))	('cell adhesion', 'biological_process', 'GO:0007155', ('258', '271'))	('silencing', 'Var', (303, 312))	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('SMAD3', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('TGF-beta', 'Gene', '7040', (173, 181))	('activation', 'PosReg', (157, 167))	('signaling pathway', 'biological_process', 'GO:0007165', ('195', '212'))
27898	28367247	In-vivo, the authors found that treatment of mice with antibodies against alpha5 and beta1 reduced the number of metastases and tumor weight from orthotopically injected ovarian cancer cell lines.	('ovarian cancer', 'Disease', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mice', 'Species', '10090', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('alpha5', 'Protein', (74, 80))	('metastases', 'Disease', (113, 123))	('beta1', 'Gene', (85, 90))	('reduced', 'NegReg', (91, 98))	('beta1', 'Gene', '146712', (85, 90))	('antibodies', 'Var', (55, 65))	('tumor', 'Disease', (128, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
27900	28367247	In a similar study, it was shown that inhibition of alpha5 and beta1 integrins significantly reduced ovarian tumor cell adhesion to a 3D model consisting of primary human mesothelial cells and fibroblasts and additionally limited the number of metastases in ovarian cancer xenografts.	('ovarian tumor', 'Phenotype', 'HP:0100615', (101, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (258, 272))	('beta1 integrin', 'Gene', '3688', (63, 77))	('human', 'Species', '9606', (165, 170))	('limited', 'NegReg', (222, 229))	('ovarian tumor', 'Disease', 'MESH:D010051', (101, 114))	('cell adhesion', 'biological_process', 'GO:0007155', ('115', '128'))	('beta1 integrin', 'Gene', (63, 77))	('reduced', 'NegReg', (93, 100))	('inhibition', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('metastases in ovarian cancer', 'Disease', 'MESH:D009362', (244, 272))	('metastases in ovarian cancer', 'Disease', (244, 272))	('ovarian tumor', 'Disease', (101, 114))
27901	28367247	Downregulation of E-cadherin on ovarian cancer cells was specifically shown to augment alpha5 integrin expression via activation of FAK and Erk1.	('FAK', 'Gene', (132, 135))	('activation', 'PosReg', (118, 128))	('FAK', 'molecular_function', 'GO:0004717', ('132', '135'))	('E-cadherin', 'Gene', '999', (18, 28))	('ovarian cancer', 'Disease', (32, 46))	('Downregulation', 'Var', (0, 14))	('augment', 'PosReg', (79, 86))	('Erk1', 'Gene', '5595', (140, 144))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('Erk1', 'molecular_function', 'GO:0004707', ('140', '144'))	('Erk1', 'Gene', (140, 144))	('FAK', 'Gene', '5747', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))	('E-cadherin', 'Gene', (18, 28))	('alpha5 integrin', 'Protein', (87, 102))
27915	28367247	Inhibition of ERK1/2 and PI3K resulted in a reduction of migrating and invasive A549 cells as a result of downregulation of MMP9, implicating a role for fibronectin-FAK-MMP9 in lung cancer invasion.	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('MMP9', 'molecular_function', 'GO:0004229', ('169', '173'))	('FAK', 'Gene', '5747', (165, 168))	('FAK', 'molecular_function', 'GO:0004717', ('165', '168'))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('PI3K', 'Var', (25, 29))	('MMP9', 'Gene', '4318', (124, 128))	('MMP9', 'Gene', (124, 128))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('MMP9', 'molecular_function', 'GO:0004229', ('124', '128'))	('reduction', 'NegReg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('downregulation', 'NegReg', (106, 120))	('lung cancer', 'Disease', (177, 188))	('ERK1/2', 'Gene', (14, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('25', '29'))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('MMP9', 'Gene', '4318', (169, 173))	('FAK', 'Gene', (165, 168))	('MMP9', 'Gene', (169, 173))	('ERK1', 'molecular_function', 'GO:0004707', ('14', '18'))
27922	28367247	Disrupting the interaction between the beta1-integrin and fibronectin reversed the conferred resistance, leading to drug-induced apoptosis of the tumor cells.	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('resistance', 'MPA', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('leading to', 'Reg', (105, 115))	('tumor', 'Disease', (146, 151))	('beta1-integrin', 'Gene', '3688', (39, 53))	('Disrupting', 'Var', (0, 10))	('beta1-integrin', 'Gene', (39, 53))	('interaction', 'Interaction', (15, 26))	('drug-induced apoptosis', 'CPA', (116, 138))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
27925	28367247	Inhibition of beta1 improved tamoxifen sensitivity of resistant MCF7 cells and further reduced cellular migration following culture in the presence of conditioned media from carcinoma associated fibroblasts (CAFs).	('improved', 'PosReg', (20, 28))	('carcinoma', 'Disease', (174, 183))	('tamoxifen', 'Chemical', 'MESH:D013629', (29, 38))	('CAF', 'Gene', (208, 211))	('reduced', 'NegReg', (87, 94))	('CAF', 'Gene', '8850', (208, 211))	('carcinoma', 'Disease', 'MESH:D002277', (174, 183))	('MCF7', 'CellLine', 'CVCL:0031', (64, 68))	('Inhibition', 'Var', (0, 10))	('beta1', 'Gene', (14, 19))	('beta1', 'Gene', '146712', (14, 19))	('cellular migration', 'CPA', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('tamoxifen sensitivity', 'MPA', (29, 50))
27929	28367247	The observed reduction of cytotoxicity was a result of tumor cell alpha5beta1 integrin engagement with fibronectin as silencing these integrins restored tumor cell sensitivity to cetuximab.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('restored', 'PosReg', (144, 152))	('cytotoxicity', 'Disease', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cetuximab', 'Chemical', 'MESH:D000068818', (179, 188))	('beta1 integrin', 'Gene', (72, 86))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (153, 158))	('silencing', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('reduction', 'NegReg', (13, 22))	('beta1 integrin', 'Gene', '3688', (72, 86))
27930	28367247	Interestingly, cetuximab was also shown to promote increased fibronectin expression from both tumor cell lines, a finding which was reported to result from activation of the p38-MAPK-ATF2 signaling pathway.	('cetuximab', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('promote increased', 'PosReg', (43, 60))	('ATF2', 'Gene', (183, 187))	('MAPK', 'molecular_function', 'GO:0004707', ('178', '182'))	('signaling pathway', 'biological_process', 'GO:0007165', ('188', '205'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('p38', 'Gene', '5594', (174, 177))	('fibronectin', 'Protein', (61, 72))	('cetuximab', 'Chemical', 'MESH:D000068818', (15, 24))	('tumor', 'Disease', (94, 99))	('ATF2', 'Gene', '1386', (183, 187))	('increased fibronectin', 'Phenotype', 'HP:0032463', (51, 72))	('p38', 'Gene', (174, 177))
27931	28367247	siRNA silencing of fibronectin improved cytotoxicity of cetuximab in H1299 and A549 tumor cell lines, demonstrating that excess fibronectin in combination with alpha5beta1 integrin engagement with fibronectin facilitates cetuximab resistance.	('A549 tumor', 'Disease', (79, 89))	('cytotoxicity', 'Disease', (40, 52))	('beta1 integrin', 'Gene', '3688', (166, 180))	('facilitates', 'PosReg', (209, 220))	('cetuximab', 'Chemical', 'MESH:D000068818', (56, 65))	('cetuximab', 'Chemical', 'MESH:D000068818', (221, 230))	('A549 tumor', 'Disease', 'MESH:D009369', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('cetuximab', 'MPA', (221, 230))	('beta1 integrin', 'Gene', (166, 180))	('silencing', 'Var', (6, 15))	('H1299', 'CellLine', 'CVCL:0060', (69, 74))
27936	28367247	To overcome chemotherapy resistance from integrin-fibronectin interactions, Nam et al showed that disrupting the peptide bond between fibronectin and alpha5beta1-integrin in combination with radiation therapy promoted apoptosis and reduced the expression of alpha5beta1 in cultures of malignant human breast cancer cells cultured atop a 3D Matrigel.	('beta1', 'Gene', '146712', (156, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (301, 314))	('reduced', 'NegReg', (232, 239))	('beta1', 'Gene', '146712', (264, 269))	('beta1-integrin', 'Gene', (156, 170))	('disrupting', 'Var', (98, 108))	('breast cancer', 'Disease', 'MESH:D001943', (301, 314))	('radiation', 'Disease', 'MESH:D004194', (191, 200))	('Nam', 'Gene', (76, 79))	('human', 'Species', '9606', (295, 300))	('apoptosis', 'biological_process', 'GO:0097194', ('218', '227'))	('breast cancer', 'Disease', (301, 314))	('apoptosis', 'biological_process', 'GO:0006915', ('218', '227'))	('radiation', 'Disease', (191, 200))	('Nam', 'Gene', '246329', (76, 79))	('apoptosis', 'CPA', (218, 227))	('peptide bond', 'MPA', (113, 125))	('beta1', 'Gene', (156, 161))	('beta1-integrin', 'Gene', '3688', (156, 170))	('beta1', 'Gene', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('promoted', 'PosReg', (209, 217))	('expression', 'MPA', (244, 254))
27939	28367247	To determine whether inhibition of beta1 integrin improved therapeutic responses, the authors treated subcutaneously grown U87MG glioblastomas with alternating doses of a beta1 inhibitor and low dose (1mg/kg) bevacizumab.	('beta1', 'Gene', (35, 40))	('glioblastomas', 'Phenotype', 'HP:0012174', (129, 142))	('glioblastomas', 'Disease', 'MESH:D005909', (129, 142))	('beta1 integrin', 'Gene', (35, 49))	('glioblastomas', 'Disease', (129, 142))	('therapeutic responses', 'CPA', (59, 80))	('inhibition', 'Var', (21, 31))	('beta1', 'Gene', (171, 176))	('bevacizumab', 'Chemical', 'MESH:D000068258', (209, 220))	('beta1', 'Gene', '146712', (171, 176))	('beta1 integrin', 'Gene', '3688', (35, 49))	('beta1', 'Gene', '146712', (35, 40))
27947	28367247	For instance, Ilic et al reported that fibronectin fibrils were more sparse and thinner in FAK null embryos compared to wildtype littermates and fibroblasts, a result which was demonstrated to be independent of fibronectin gene or protein expression and synthesis, suggesting that FAK activity is necessary for fibronectin matrix organization.	('thinner', 'NegReg', (80, 87))	('FAK', 'Gene', (91, 94))	('FAK', 'Gene', '5747', (91, 94))	('sparse', 'NegReg', (69, 75))	('FAK', 'molecular_function', 'GO:0004717', ('91', '94'))	('FAK', 'molecular_function', 'GO:0004717', ('281', '284'))	('fibronectin fibrils', 'CPA', (39, 58))	('FAK', 'Gene', '5747', (281, 284))	('FAK', 'Gene', (281, 284))	('synthesis', 'biological_process', 'GO:0009058', ('254', '263'))	('protein', 'cellular_component', 'GO:0003675', ('231', '238'))	('null', 'Var', (95, 99))
27951	28367247	Specifically, the authors reported that inhibition of Src resulted in decreased FAK phosphorylation suggesting that a reduction of FAK activity may be a useful strategy to reduce fibronectin mediated effects on tumor cell migration and invasion.	('cell migration', 'biological_process', 'GO:0016477', ('217', '231'))	('FAK', 'Gene', '5747', (80, 83))	('invasion', 'CPA', (236, 244))	('reduction', 'NegReg', (118, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('tumor', 'Disease', (211, 216))	('Src', 'Gene', (54, 57))	('FAK', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('FAK', 'molecular_function', 'GO:0004717', ('131', '134'))	('activity', 'MPA', (135, 143))	('reduce', 'NegReg', (172, 178))	('decreased FAK', 'Phenotype', 'HP:0032341', (70, 83))	('reduce fibronectin', 'Phenotype', 'HP:0032463', (172, 190))	('fibronectin', 'Protein', (179, 190))	('FAK', 'Gene', '5747', (131, 134))	('inhibition', 'Var', (40, 50))	('Src', 'Gene', '6714', (54, 57))	('FAK', 'molecular_function', 'GO:0004717', ('80', '83'))	('decreased', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('FAK', 'Gene', (80, 83))
27952	28367247	In addition to indirect targets of FAK, it may be possible to directly reduce FAK activity via use of a novel ATP competitive kinase inhibitor, PF-04554878, which was recently shown to promote apoptosis and reduce proliferation of pancreatic neuroendocrine tumor cells.	('reduce', 'NegReg', (207, 213))	('reduce', 'NegReg', (71, 77))	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('FAK', 'Gene', '5747', (78, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('193', '202'))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (231, 262))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (242, 262))	('proliferation', 'CPA', (214, 227))	('apoptosis', 'biological_process', 'GO:0006915', ('193', '202'))	('promote', 'PosReg', (185, 192))	('FAK', 'Gene', (35, 38))	('pancreatic neuroendocrine tumor', 'Disease', (231, 262))	('FAK', 'molecular_function', 'GO:0004717', ('78', '81'))	('FAK', 'Gene', '5747', (35, 38))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (231, 262))	('PF-04554878', 'Chemical', 'MESH:C584510', (144, 155))	('PF-04554878', 'Var', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('apoptosis', 'CPA', (193, 202))	('FAK', 'Gene', (78, 81))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('126', '142'))	('activity', 'MPA', (82, 90))	('ATP', 'Chemical', 'MESH:D000255', (110, 113))
27954	28367247	Levental et al demonstrated that expression of lysyl oxidase (LOX), an enzyme which cross-links collagen fibers, not only increased FAK expression, but augmented matrix rigidity and breast tumor progression, a phenomenon which was reversed upon treatment with an inhibitor of LOX.	('FAK', 'Gene', (132, 135))	('augmented', 'PosReg', (152, 161))	('breast tumor', 'Disease', 'MESH:D001943', (182, 194))	('FAK', 'Gene', '5747', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('LOX', 'Gene', '4015', (62, 65))	('rigidity', 'Disease', 'MESH:D009127', (169, 177))	('lysyl oxidase', 'Gene', '4015', (47, 60))	('breast tumor', 'Phenotype', 'HP:0100013', (182, 194))	('LOX', 'Gene', '4015', (276, 279))	('rigidity', 'Disease', (169, 177))	('increased', 'PosReg', (122, 131))	('breast tumor', 'Disease', (182, 194))	('LOX', 'Gene', (62, 65))	('expression', 'Var', (33, 43))	('FAK', 'molecular_function', 'GO:0004717', ('132', '135'))	('rigidity', 'Phenotype', 'HP:0002063', (169, 177))	('LOX', 'Gene', (276, 279))	('collagen', 'molecular_function', 'GO:0005202', ('96', '104'))	('lysyl oxidase', 'Gene', (47, 60))
27957	28367247	Although this work was conducted in cardiac fibroblasts, it's foreseeable that inhibiting LOX may be a means to reduce tumoral fibronectin expression.	('inhibiting', 'Var', (79, 89))	('LOX', 'Gene', '4015', (90, 93))	('tumoral', 'Disease', (119, 126))	('reduce', 'NegReg', (112, 118))	('tumoral', 'Disease', 'MESH:D009369', (119, 126))	('LOX', 'Gene', (90, 93))	('reduce tumoral fibronectin expression', 'Phenotype', 'HP:0032463', (112, 149))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
27960	28367247	Furthermore, Hielscher et al demonstrated that treatment of co-cultures of fibroblasts and breast cancer cells with pUR4B not only reduced fibronectin deposition and organization in the ECM, but also inhibited the deposition of other matrix proteins.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('fibronectin deposition', 'MPA', (139, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('organization in the ECM', 'CPA', (166, 189))	('reduced fibronectin deposition', 'Phenotype', 'HP:0032463', (131, 161))	('reduced', 'NegReg', (131, 138))	('deposition of other matrix proteins', 'MPA', (214, 249))	('pUR4B', 'Var', (116, 121))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('inhibited', 'NegReg', (200, 209))
27961	28367247	As such, direct inhibition of fibronectin polymerization via a small peptide may impair the assembly of other matrix proteins and capillaries, thus depriving tumors of a supportive scaffold and the oxygen and nutrients necessary for continued growth.	('assembly', 'MPA', (92, 100))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('small peptide', 'Var', (63, 76))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('inhibition', 'NegReg', (16, 26))	('fibronectin polymerization', 'Protein', (30, 56))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('oxygen', 'Chemical', 'MESH:D010100', (198, 204))	('depriving', 'NegReg', (148, 157))	('impair', 'NegReg', (81, 87))
27966	28367247	Previous studies have shown that silencing fibronectin reduced tumor cell proliferation and growth and tumor cell migration.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('reduced', 'NegReg', (55, 62))	('tumor', 'Disease', (103, 108))	('silencing', 'Var', (33, 42))	('cell migration', 'biological_process', 'GO:0016477', ('109', '123'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('growth', 'CPA', (92, 98))	('fibronectin', 'Protein', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
28017	28078088	The pulmonary nodule associated with IgG4-RD can have a margin that is not well-demarcated and rather irregular, which makes it difficult to distinguish these lesions from lung cancer.	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('IgG4', 'cellular_component', 'GO:0071735', ('37', '41'))	('IgG4-RD', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pulmonary nodule', 'Disease', (4, 20))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
28038	33332677	20  There are also many examples of miRNAs acting as oncogenes (oncomiRs) in tumourigenesis.	('miRNAs', 'Var', (36, 42))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (77, 83))
28053	33332677	25  Hsa-miR-125b-1 is implicated in t(11;14)(q24;q32) and t(2;11)(p21;q23) chromosomal translocations, which leads to B-cell acute lymphoid leukaemia (B-ALL) and acute myeloid leukaemia (AML), respectively.	('lymphoid leukaemia', 'Phenotype', 'HP:0005526', (131, 149))	('t(2;11)(p21;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (58, 74))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (162, 185))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (162, 185))	('t(2;11)(p21;q23', 'Var', (58, 73))	('Hsa-miR-125b-1', 'Gene', '406911', (4, 18))	('ALL', 'Phenotype', 'HP:0006721', (153, 156))	('t(11;14)(q24;q32', 'Var', (36, 52))	('lymphoid leukaemia', 'Disease', (131, 149))	('cel', 'Gene', (120, 123))	('t(11;14)(q24;q32)', 'STRUCTURAL_ABNORMALITY', 'None', (36, 53))	('acute myeloid leukaemia', 'Disease', (162, 185))	('leads to', 'Reg', (109, 117))	('Hsa-miR-125b-1', 'Gene', (4, 18))	('acute lymphoid leukaemia', 'Phenotype', 'HP:0006721', (125, 149))	('AML', 'Disease', 'MESH:D015470', (187, 190))	('lymphoid leukaemia', 'Disease', 'MESH:D007945', (131, 149))	('AML', 'Phenotype', 'HP:0004808', (187, 190))	('AML', 'Disease', (187, 190))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (168, 185))	('cel', 'Gene', '1056', (120, 123))
28061	33332677	37 ,  38  One of miR-125b downstream targets is the tumour suppressor, adenomatous polyposis coli (APC), and loss-of-function mutations in APC have been linked to the progression of cancer.	('miR-125b', 'Gene', '100033636', (17, 25))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (71, 97))	('tumour', 'Disease', (52, 58))	('adenomatous polyposis coli', 'Gene', (71, 97))	('cancer', 'Disease', (182, 188))	('mutations', 'Var', (126, 135))	('APC', 'Phenotype', 'HP:0005227', (99, 102))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('APC', 'Disease', (99, 102))	('adenomatous polyposis coli', 'Gene', '324', (71, 97))	('APC', 'cellular_component', 'GO:0005680', ('99', '102'))	('APC', 'cellular_component', 'GO:0005680', ('139', '142'))	('APC', 'Phenotype', 'HP:0005227', (139, 142))	('APC', 'Disease', 'MESH:D011125', (139, 142))	('loss-of-function', 'NegReg', (109, 125))	('APC', 'Disease', (139, 142))	('miR-125b', 'Gene', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (182, 188))
28066	33332677	43   Similarly, the dysregulated activation of the PI3K/Akt signalling pathway is commonly associated with the proliferative ability of tumour cells in cancer progression, and miR-125b is also implicated in this signalling pathway (Figure 1).	('Akt', 'Gene', (56, 59))	('miR-125b', 'Gene', '100033636', (176, 184))	('Akt', 'Gene', '207', (56, 59))	('dysregulated', 'Var', (20, 32))	('cancer', 'Disease', (152, 158))	('activation', 'PosReg', (33, 43))	('cel', 'Gene', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('proliferative ability', 'CPA', (111, 132))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('signalling pathway', 'biological_process', 'GO:0007165', ('212', '230'))	('tumour', 'Disease', (136, 142))	('associated', 'Reg', (91, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('signalling pathway', 'biological_process', 'GO:0007165', ('60', '78'))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('miR-125b', 'Gene', (176, 184))	('cel', 'Gene', '1056', (143, 146))
28076	33332677	50 ,  51  For example, the ectopic expression of miR-125b in human osteosarcoma cells can reverse their high rate of proliferation, migration and tumour formation by targeting STAT3.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('miR-125b', 'Gene', '100033636', (49, 57))	('cel', 'Gene', '1056', (80, 83))	('formation', 'biological_process', 'GO:0009058', ('153', '162'))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('ectopic expression', 'Var', (27, 45))	('osteosarcoma', 'Disease', (67, 79))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('cel', 'Gene', (80, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('tumour', 'Disease', (146, 152))	('STAT3', 'Gene', '6774', (176, 181))	('migration', 'CPA', (132, 141))	('human', 'Species', '9606', (61, 66))	('targeting', 'Reg', (166, 175))	('STAT3', 'Gene', (176, 181))	('reverse', 'NegReg', (90, 97))	('miR-125b', 'Gene', (49, 57))	('high rate', 'MPA', (104, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
28092	33332677	For example, in glioblastoma cells, miR-125b down-regulates p53 and the knockdown of miR-125b can lead to the activation of p53-related apoptosis.	('miR-125b', 'Gene', (36, 44))	('cel', 'Gene', (29, 32))	('activation', 'PosReg', (110, 120))	('miR-125b', 'Gene', '100033636', (85, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('p53', 'Protein', (60, 63))	('p53-related apoptosis', 'CPA', (124, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('miR-125b', 'Gene', (85, 93))	('down-regulates', 'NegReg', (45, 59))	('miR-125b', 'Gene', '100033636', (36, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('cel', 'Gene', '1056', (29, 32))	('glioblastoma', 'Disease', (16, 28))	('knockdown', 'Var', (72, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
28098	33332677	31 ,  32  The aberrant expression of miR-125b has been demonstrated to give rise to a wide range of malignancies.	('give rise to', 'Reg', (71, 83))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('malignancies', 'Disease', (100, 112))	('aberrant expression', 'Var', (14, 33))	('miR-125b', 'Gene', '100033636', (37, 45))	('miR-125b', 'Gene', (37, 45))
28101	33332677	62  In addition, the ectopic overexpression of the heavy chain of ferritin, a nanocage protein, leads to the down-regulation of miR-125b in NSCLC via hypermethylation in the miR-125b promoter region (Figure 2).	('overexpression', 'PosReg', (29, 43))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('miR-125b', 'Gene', (174, 182))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('miR-125b', 'Gene', '100033636', (128, 136))	('down-regulation', 'NegReg', (109, 124))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('miR-125b', 'Gene', (128, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('hypermethylation', 'Var', (150, 166))	('miR-125b', 'Gene', '100033636', (174, 182))	('regulation', 'biological_process', 'GO:0065007', ('114', '124'))	('NSCLC', 'Disease', (140, 145))
28111	33332677	67  The subsequent knockdown of lncRNA HOXA-AS2 inhibits the capability of bladder cancer cell lines to proliferate and migrate in vitro as well as tumour development in vivo.	('tumour', 'Disease', (148, 154))	('HOXA-AS2', 'Gene', (39, 47))	('inhibits', 'NegReg', (48, 56))	('knockdown', 'Var', (19, 28))	('bladder cancer', 'Disease', (75, 89))	('cel', 'Gene', '1056', (90, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('HOXA-AS2', 'Gene', '285943', (39, 47))	('cel', 'Gene', (90, 93))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
28121	33332677	71  In addition, the expression of miR-125b is suppressed in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)+ systemic anaplastic large-cell lymphoma, due to hypermethylation of the miR-125b promoter region.	('cel', 'Gene', (139, 142))	('hypermethylation', 'Var', (161, 177))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (75, 94))	('miR-125b', 'Gene', '100033636', (185, 193))	('lymphoma', 'Disease', (86, 94))	('lymphoma', 'Disease', 'MESH:D008223', (86, 94))	('suppressed', 'NegReg', (47, 57))	('ALK', 'Gene', '238', (107, 110))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('cell lymphoma', 'Phenotype', 'HP:0012191', (139, 152))	('ALK', 'Gene', (107, 110))	('miR-125b', 'Gene', (35, 43))	('cel', 'Gene', '1056', (139, 142))	('NPM', 'Gene', (103, 106))	('NPM', 'Gene', '4869', (103, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('lymphoma', 'Disease', (144, 152))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (122, 152))	('miR-125b', 'Gene', '100033636', (35, 43))	('miR-125b', 'Gene', (185, 193))	('lymphoma', 'Disease', 'MESH:D008223', (144, 152))	('expression', 'MPA', (21, 31))
28124	33332677	Regarding the methylation of tumour suppressor genes, patients with promoter hypermethylation in genes such as PTEN and RASSF1A are also associated with down-regulated miR-125b levels.	('RASSF1A', 'Gene', (120, 127))	('tumour', 'Disease', (29, 35))	('PTEN', 'Gene', (111, 115))	('miR-125b', 'Gene', '100033636', (168, 176))	('PTEN', 'Gene', '5728', (111, 115))	('patients', 'Species', '9606', (54, 62))	('miR-125b', 'Gene', (168, 176))	('RASSF1A', 'Gene', '11186', (120, 127))	('promoter hypermethylation', 'Var', (68, 93))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('down-regulated', 'NegReg', (153, 167))	('tumour', 'Disease', 'MESH:D009369', (29, 35))
28127	33332677	75  In addition, the enhanced methylation of histones H3K9me3 and H3K27me3 is associated with the down-regulation of miR-125b-1 in breast cancer cells.	('histones H3K9me3', 'Protein', (45, 61))	('cel', 'Gene', '1056', (145, 148))	('enhanced', 'PosReg', (21, 29))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('miR-125b-1', 'Gene', '406911', (117, 127))	('miR-125b-1', 'Gene', (117, 127))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cel', 'Gene', (145, 148))	('down-regulation', 'NegReg', (98, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('breast cancer', 'Disease', (131, 144))	('H3K9me3', 'Protein', (54, 61))	('methylation', 'MPA', (30, 41))	('H3K27me3', 'Var', (66, 74))
28134	33332677	Hexokinase-2 (HK-2) is an enzyme involved in catalysing the first rate-limiting step in glycolysis, and it is targeted by miR-125b-5p.	('miR-125b-5p', 'Var', (122, 133))	('HK-2', 'Gene', '3099', (14, 18))	('glycolysis', 'biological_process', 'GO:0006096', ('88', '98'))	('HK-2', 'Gene', (14, 18))	('HK-2', 'molecular_function', 'GO:0008256', ('14', '18'))	('Hexokinase-2', 'Gene', (0, 12))	('miR-125b-5p', 'Chemical', '-', (122, 133))	('Hexokinase-2', 'Gene', '3099', (0, 12))
28135	33332677	44 ,  78  In laryngeal squamous cell carcinoma (LSCC) cells, miR-125b-5p overexpression leads to the down-regulation of HK-2 and thus results in a decrease in lactate production and glucose consumption.	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('cel', 'Gene', '1056', (54, 57))	('miR-125b-5p', 'Var', (61, 72))	('cel', 'Gene', (32, 35))	('decrease', 'NegReg', (147, 155))	('HK-2', 'Gene', '3099', (120, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('cel', 'Gene', (54, 57))	('glucose consumption', 'MPA', (182, 201))	('HK-2', 'molecular_function', 'GO:0008256', ('120', '124'))	('lactate production', 'MPA', (159, 177))	('down-regulation', 'NegReg', (101, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('overexpression', 'PosReg', (73, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))	('HK-2', 'Gene', (120, 124))	('miR-125b-5p', 'Chemical', '-', (61, 72))	('cel', 'Gene', '1056', (32, 35))	('glucose', 'Chemical', 'MESH:D005947', (182, 189))	('squamous cell carcinoma', 'Disease', (23, 46))	('lactate', 'Chemical', 'MESH:D019344', (159, 166))
28154	33332677	91  miR-125b overexpression or SIRT6 knockout leads to cellular senescence and apoptosis in hepatocellular carcinoma cells.	('cel', 'Gene', '1056', (55, 58))	('cel', 'Gene', (98, 101))	('knockout', 'Var', (37, 45))	('overexpression', 'PosReg', (13, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('cel', 'Gene', '1056', (117, 120))	('cel', 'Gene', (55, 58))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('SIRT6', 'Gene', (31, 36))	('miR-125b', 'Gene', (4, 12))	('SIRT6', 'Gene', '51548', (31, 36))	('cel', 'Gene', (117, 120))	('cellular senescence', 'biological_process', 'GO:0090398', ('55', '74'))	('hepatocellular carcinoma', 'Disease', (92, 116))	('cel', 'Gene', '1056', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('miR-125b', 'Gene', '100033636', (4, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('apoptosis', 'CPA', (79, 88))
28180	33332677	116  A number of investigations have reported that the deregulation of miR-125b influences critical developmental checkpoints during haematopoiesis and thus leads to the development of cancer (Table 1).	('miR-125b', 'Gene', '100033636', (71, 79))	('haematopoiesis', 'Disease', 'None', (133, 147))	('leads to', 'Reg', (157, 165))	('miR-125b', 'Gene', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('deregulation', 'Var', (55, 67))	('haematopoiesis', 'Disease', (133, 147))	('influences', 'Reg', (80, 90))	('critical developmental checkpoints', 'CPA', (91, 125))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
28185	33332677	105  In addition, the ectopic expression of miR-125b contributes to the development of leukaemia and accelerates the maturation arrest in T-ALL xenograft mouse models in part via the inhibition of the T-lineage regulators, Ets1 and CBFbeta.	('mouse', 'Species', '10090', (154, 159))	('miR-125b', 'Gene', (44, 52))	('leukaemia', 'Disease', (87, 96))	('inhibition', 'NegReg', (183, 193))	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('cel', 'Gene', '1056', (103, 106))	('ectopic expression', 'Var', (22, 40))	('Ets1', 'Gene', (223, 227))	('Ets1', 'Gene', '23871', (223, 227))	('ALL', 'Phenotype', 'HP:0006721', (140, 143))	('cel', 'Gene', (103, 106))	('arrest', 'Disease', (128, 134))	('leukaemia', 'Disease', 'MESH:D007938', (87, 96))	('CBFbeta', 'Gene', (232, 239))	('miR-125b', 'Gene', '100033636', (44, 52))	('CBFbeta', 'Gene', '12606', (232, 239))
28190	33332677	108  In addition, dysregulated expression of miR-125b initially reduces the production of B cells in the blood and spleen, and of pre-B cells in the bone marrow, by targeting S1PR1, but later promotes pre-B-cell lymphoma via the inhibition of IRF4 (Table 1).	('cel', 'Gene', '1056', (136, 139))	('targeting', 'NegReg', (165, 174))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (205, 220))	('IRF4', 'Gene', (243, 247))	('cel', 'Gene', (207, 210))	('pre', 'molecular_function', 'GO:0003904', ('130', '133'))	('miR-125b', 'Gene', (45, 53))	('cel', 'Gene', (136, 139))	('inhibition', 'NegReg', (229, 239))	('B-cell lymphoma', 'Disease', (205, 220))	('cel', 'Gene', '1056', (92, 95))	('reduces', 'NegReg', (64, 71))	('dysregulated', 'Var', (18, 30))	('miR-125b', 'Gene', '100033636', (45, 53))	('promotes', 'PosReg', (192, 200))	('lymphoma', 'Phenotype', 'HP:0002665', (212, 220))	('cell lymphoma', 'Phenotype', 'HP:0012191', (207, 220))	('pre', 'molecular_function', 'GO:0003904', ('201', '204'))	('cel', 'Gene', (92, 95))	('cel', 'Gene', '1056', (207, 210))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (205, 220))	('S1PR1', 'Gene', (175, 180))
28191	33332677	108  Besides that, miR-125b overexpression increases the number of early B-progenitor cells and induces the expansion and enrichment of the lymphoid-balanced and lymphoid-biased haematopoietic stem cell subset via negatively regulating pro-apoptotic targets, Bmf and KLF3, thereby conferring lymphoproliferative neoplasm.	('cel', 'Gene', '1056', (86, 89))	('Bmf', 'Gene', (259, 262))	('overexpression', 'Var', (28, 42))	('KLF3', 'Gene', (267, 271))	('lymphoproliferative neoplasm', 'Phenotype', 'HP:0005523', (292, 320))	('increases', 'PosReg', (43, 52))	('cel', 'Gene', '1056', (198, 201))	('conferring', 'Reg', (281, 291))	('KLF3', 'Gene', '16599', (267, 271))	('expansion', 'CPA', (108, 117))	('Bmf', 'Gene', '171543', (259, 262))	('lymphoproliferative neoplasm', 'Disease', 'MESH:D008232', (292, 320))	('cel', 'Gene', (86, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (312, 320))	('cel', 'Gene', (198, 201))	('negatively', 'NegReg', (214, 224))	('regulating', 'Reg', (225, 235))	('enrichment', 'CPA', (122, 132))	('miR-125b', 'Gene', (19, 27))	('lymphoproliferative neoplasm', 'Disease', (292, 320))	('induces', 'Reg', (96, 103))	('miR-125b', 'Gene', '100033636', (19, 27))
28255	33332677	158  Furthermore, miRNA expression microarray analysis indicated that miR-125b is up-regulated in patient tissue samples containing EGFR mutation for gefitinib resistance as compared with samples containing EGFR mutation for gefitinib sensitivity.	('patient', 'Species', '9606', (98, 105))	('mutation', 'Var', (137, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('miR-125b', 'Gene', '100033636', (70, 78))	('EGFR', 'Gene', (132, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('gefitinib', 'Chemical', 'MESH:D000077156', (225, 234))	('miR-125b', 'Gene', (70, 78))	('up-regulated', 'PosReg', (82, 94))	('gefitinib', 'Chemical', 'MESH:D000077156', (150, 159))	('gefitinib resistance', 'MPA', (150, 170))
28299	33148544	These include increasing the minimum age of sale for tobacco products as well as the selling prices of tobacco products; carrying out public campaign to decrease tobacco promotions, buoying up the establishment of tobacco-free places, involving their idols in these programmes and forbidding smoking in indoor and mutual places.	('tobacco', 'Species', '4097', (53, 60))	('tobacco', 'Species', '4097', (214, 221))	('age', 'Gene', (37, 40))	('age', 'Gene', '5973', (37, 40))	('tobacco promotions', 'MPA', (162, 180))	('buoying', 'Var', (182, 189))	('tobacco', 'Species', '4097', (103, 110))	('tobacco', 'Species', '4097', (162, 169))	('increasing', 'PosReg', (14, 24))	('men', 'Species', '9606', (206, 209))	('decrease', 'NegReg', (153, 161))
28342	33148544	Furthermore, among northeast Chinese female non-smokers, two single nucleotide polymorphisms, rs4787050 and rs8045980 were associated with a significantly increased risk of lung cancer, a risk further exacerbated by exposure to cooking oil fumes.	('rs8045980', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('rs8045980', 'Mutation', 'rs8045980', (108, 117))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('rs4787050', 'Var', (94, 103))	('rs4787050', 'Mutation', 'rs4787050', (94, 103))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))
28343	33148544	Somatic driver genetic alterations, including epidermal growth factor receptor (EGFR) mutations, occur more frequently in non-smokers, and particularly, women with ADC.	('mutations', 'Var', (86, 95))	('ADC', 'Disease', (164, 167))	('epidermal growth factor receptor', 'Gene', '1956', (46, 78))	('women', 'Species', '9606', (153, 158))	('EGFR', 'Gene', '1956', (80, 84))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('46', '69'))	('EGFR', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('rat', 'Species', '10116', (27, 30))	('epidermal growth factor receptor', 'Gene', (46, 78))
28344	33148544	Mutations in human epidermal growth factor receptor 2 (HER-2) exon 20 occur in 1%-5% of patients, particularly young never-smoker women.	('HER-2', 'Gene', (55, 60))	('human', 'Species', '9606', (13, 18))	('patients', 'Species', '9606', (88, 96))	('women', 'Species', '9606', (130, 135))	('occur', 'Reg', (70, 75))	('Mutations', 'Var', (0, 9))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('19', '42'))	('epidermal growth factor receptor 2', 'Gene', (19, 53))	('epidermal growth factor receptor 2', 'Gene', '2064', (19, 53))	('HER-2', 'Gene', '2064', (55, 60))
28350	33148544	A prospective, observational study, the French Collaborative Intergroup for Thoracic Cancer Research, (IFCT-1002) BioCAST study, in 260 female never-smokers with lung cancer showed that reproductive factors were associated significantly with specific lung cancer mutations.	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('Cancer', 'Disease', (85, 91))	('associated', 'Reg', (212, 222))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (263, 272))	('rat', 'Species', '10116', (54, 57))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('lung cancer', 'Disease', (251, 262))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('lung cancer', 'Disease', 'MESH:D008175', (251, 262))
28351	33148544	In particular, EGFR mutations were correlated significantly with increasing age at menarche and age at first birth.	('age', 'Gene', '5973', (76, 79))	('menarche', 'Disease', (83, 91))	('menarche', 'Disease', 'None', (83, 91))	('age', 'Gene', (96, 99))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('age', 'Gene', (76, 79))	('age', 'Gene', '5973', (96, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('mutations', 'Var', (20, 29))	('menarche', 'biological_process', 'GO:0042696', ('83', '91'))
28352	33148544	In addition, ALK alterations were associated with both parity and number of pregnancies.	('associated', 'Reg', (34, 44))	('ALK', 'Gene', (13, 16))	('rat', 'Species', '10116', (21, 24))	('ALK', 'Gene', '238', (13, 16))	('alterations', 'Var', (17, 28))	('parity', 'Disease', (55, 61))
28367	33148544	The stronger immune responses reported in women have been attributed to sex chromosome linked genes and miRNA, coding for proteins involved in the regulation of the innate and acquired immunity; differences in microbial composition, in programmed death-ligand 1 (PD-L1) expression, hypothetically modulated in an oestrogen-dependent manner (evidence-based in preclinical studies); and proportion of intratumoural immune infiltrates.	('differences', 'Var', (195, 206))	('tumour', 'Disease', 'MESH:D009369', (404, 410))	('PD-L1', 'Gene', (263, 268))	('ligand', 'molecular_function', 'GO:0005488', ('253', '259'))	('tumour', 'Disease', (404, 410))	('tumour', 'Phenotype', 'HP:0002664', (404, 410))	('immune', 'MPA', (13, 19))	('stronger', 'PosReg', (4, 12))	('PD-L1', 'Gene', '29126', (263, 268))	('sex chromosome', 'cellular_component', 'GO:0000803', ('72', '86'))	('rat', 'Species', '10116', (426, 429))	('women', 'Species', '9606', (42, 47))	('programmed death-ligand 1', 'Gene', (236, 261))	('programmed death-ligand 1', 'Gene', '29126', (236, 261))	('regulation', 'biological_process', 'GO:0065007', ('147', '157'))	('rat', 'Species', '10116', (402, 405))
28421	33148544	Women with stage IV NSCLC harbouring an EGFR sensitising mutation were found to outlive men as well, with men and women having median survival of 19 and 32 months, respectively.	('mutation', 'Var', (57, 65))	('women', 'Species', '9606', (114, 119))	('Women', 'Species', '9606', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('age', 'Gene', (13, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('men', 'Species', '9606', (2, 5))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('men', 'Species', '9606', (88, 91))	('age', 'Gene', '5973', (13, 16))	('men', 'Species', '9606', (116, 119))	('NSCLC', 'Disease', (20, 25))	('men', 'Species', '9606', (106, 109))
28467	32872022	Participants meeting all the following criteria will be enrolled: Histologically or cytologically confirmed NSCLC and clinical-stage IIIB or IV; (2) Conform to TCM syndrome differentiation; Lesion >= 2 cm in diameter; Eastern Cooperative Oncology Group score <= 2; Expected survival >= 3 months; Age >= 18; Participate the trial voluntarily and sign written informed consent.	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('Lesion >=', 'Var', (190, 199))	('TC', 'Chemical', 'MESH:D013667', (160, 162))	('Conform', 'Reg', (149, 156))	('NSCLC', 'Disease', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('Participants', 'Species', '9606', (0, 12))	('Oncology', 'Phenotype', 'HP:0002664', (238, 246))
28473	32872022	Participants allocated to the study group will receive cryoablation and TCM syndrome differentiation and treatment, while chemotherapy will be applied in the control group.	('TC', 'Chemical', 'MESH:D013667', (72, 74))	('TCM syndrome', 'Gene', (72, 84))	('Participants', 'Species', '9606', (0, 12))	('cryoablation', 'Var', (55, 67))
28516	32633324	Furthermore, the aberrant expression of lncRNA was shown to be associated with the onset and development of cancers.	('lncRNA', 'Protein', (40, 46))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('associated', 'Reg', (63, 73))	('aberrant expression', 'Var', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
28522	32633324	The abnormal expression of SNHG15 promoted the proliferation, invasion and epithelial-mesenchymal transition (EMT) of tumor cells as well.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('75', '108'))	('SNHG15', 'Gene', (27, 33))	('abnormal', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('EMT', 'biological_process', 'GO:0001837', ('110', '113'))	('promoted', 'PosReg', (34, 42))	('tumor', 'Disease', (118, 123))	('invasion', 'CPA', (62, 70))	('proliferation', 'CPA', (47, 60))	('SNHG15', 'Gene', '285958', (27, 33))
28538	32633324	Pooled HRs indicated an association between the high expression of SNHG15 and overall survival (HR = 2.07, 95% CI, 1.48-2.88; P<0.0001).	('SNHG15', 'Gene', '285958', (67, 73))	('association', 'Interaction', (24, 35))	('SNHG15', 'Gene', (67, 73))	('high expression', 'Var', (48, 63))	('overall survival', 'CPA', (78, 94))
28548	32633324	The combined results indicated a significantly positive correlation between the high expression of SNHG15 and positive lymph node metastasis (HR = 2.41, 95%CI, 0.99-5.87; P=0.05).	('positive', 'PosReg', (47, 55))	('positive lymph node metastasis', 'CPA', (110, 140))	('SNHG15', 'Gene', '285958', (99, 105))	('high', 'Var', (80, 84))	('SNHG15', 'Gene', (99, 105))
28560	32633324	The abnormal expression of non-coding RNA was reported to be closely related to diseases, such as cancer, cardiovascular disease, inflammatory bowel disease and metabolic disease.	('metabolic disease', 'Disease', (161, 178))	('non-coding', 'Var', (27, 37))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (106, 128))	('abnormal', 'Var', (4, 12))	('inflammatory bowel disease', 'Disease', (130, 156))	('cardiovascular disease', 'Disease', 'MESH:D002318', (106, 128))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('metabolic disease', 'Disease', 'MESH:D008659', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('RNA', 'Gene', (38, 41))	('cardiovascular disease', 'Disease', (106, 128))	('related', 'Reg', (69, 76))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (130, 156))
28573	32633324	discovered that SNHG15 regulated YAP1-Hippo signaling pathway by sponging miR-200a-3p, inducing the growth and migration of papillary thyroid carcinoma cells.	('papillary thyroid carcinoma', 'Disease', (124, 151))	('sponging', 'Var', (65, 73))	('inducing', 'PosReg', (87, 95))	('SNHG15', 'Gene', '285958', (16, 22))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (124, 151))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('38', '61'))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (124, 151))	('YAP1', 'Gene', '10413', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (134, 151))	('YAP1', 'Gene', (33, 37))	('SNHG15', 'Gene', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
28576	32633324	demonstrated that MYC protein increased the expression of SNHG15 through binding to the transcription start point of SNHG15, and the high expression of SNHG15 activated the apoptosis induced factor (AIF) protein, thus promoting the proliferation, invasion and chemotherapy resistance in colorectal cancer.	('chemotherapy resistance', 'CPA', (260, 283))	('expression', 'MPA', (44, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (287, 304))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('increased', 'PosReg', (30, 39))	('SNHG15', 'Gene', (152, 158))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('colorectal cancer', 'Disease', (287, 304))	('SNHG15', 'Gene', (117, 123))	('SNHG15', 'Gene', '285958', (152, 158))	('MYC', 'Gene', (18, 21))	('invasion', 'CPA', (247, 255))	('promoting', 'PosReg', (218, 227))	('SNHG15', 'Gene', '285958', (117, 123))	('binding', 'Interaction', (73, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('173', '182'))	('apoptosis', 'biological_process', 'GO:0006915', ('173', '182'))	('MYC', 'Gene', '4609', (18, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (287, 304))	('activated', 'PosReg', (159, 168))	('high expression', 'Var', (133, 148))	('SNHG15', 'Gene', (58, 64))	('SNHG15', 'Gene', '285958', (58, 64))	('proliferation', 'CPA', (232, 245))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('apoptosis', 'Gene', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
28578	32633324	reported that SNHG15 regulated the vascular endothelial growth factor A (VEGFA) and the expression of Cdc42 by sponging miR-153, contributing to the occurrence and development of glioma.	('vascular endothelial growth factor A', 'Gene', '7422', (35, 71))	('contributing to', 'Reg', (129, 144))	('vascular endothelial growth factor A', 'Gene', (35, 71))	('VEGFA', 'Gene', (73, 78))	('VEGFA', 'Gene', '7422', (73, 78))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('SNHG15', 'Gene', (14, 20))	('Cdc42', 'Gene', '998', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('35', '69'))	('sponging miR-153', 'Var', (111, 127))	('miR-153', 'Chemical', '-', (120, 127))	('miR-153', 'Var', (120, 127))	('expression', 'MPA', (88, 98))	('SNHG15', 'Gene', '285958', (14, 20))	('glioma', 'Disease', (179, 185))	('Cdc42', 'Gene', (102, 107))
28586	32633324	In addition, high expression level of SNHG15 was associated with shorter overall survival, progression-free survival and recurrence-free survival.	('recurrence-free survival', 'CPA', (121, 145))	('SNHG15', 'Gene', (38, 44))	('expression level', 'MPA', (18, 34))	('high', 'Var', (13, 17))	('overall', 'MPA', (73, 80))	('shorter', 'NegReg', (65, 72))	('SNHG15', 'Gene', '285958', (38, 44))	('progression-free survival', 'CPA', (91, 116))
28588	32633324	The results showed that high expression level of SNHG15 was associated with shorter overall survival in digestive, respiratory and female reproductive system cancers, and supported the positive association between high expression level of SNHG15 and poor prognosis in various cancer types.	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('SNHG15', 'Gene', (49, 55))	('high', 'Var', (24, 28))	('SNHG15', 'Gene', '285958', (49, 55))	('SNHG15', 'Gene', (239, 245))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('SNHG15', 'Gene', '285958', (239, 245))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', (158, 165))	('digestive', 'Disease', (104, 113))	('respiratory', 'Disease', (115, 126))	('shorter', 'NegReg', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('expression', 'MPA', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('overall', 'MPA', (84, 91))
28590	32633324	The present study is the first meta-analysis exploring the connection between the abnormal expression of SNHG15 and cancer prognosis.	('abnormal expression', 'Var', (82, 101))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('SNHG15', 'Gene', '285958', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('SNHG15', 'Gene', (105, 111))
28593	32633324	Detailed molecular biological mechanisms between the abnormal expression of SNHG15 and the development of cancers were also discussed and summarized.	('SNHG15', 'Gene', (76, 82))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('abnormal', 'Var', (53, 61))	('SNHG15', 'Gene', '285958', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
28597	32633324	SNHG15 could serve as the competitive endogenous RNA, interacting with miR-211-3p, miR-200a-3p, miR-153, miR-141-3p, miR-141 and so on, directly or indirectly acting on downstream signaling pathway, promoting the cell proliferation, migration, invasion or cycle arrest of most cancers, the high expression of SNHG15 manifested worse cancer prognosis, especially in the glioma.	('high expression', 'Var', (290, 305))	('glioma', 'Disease', (369, 375))	('signaling pathway', 'biological_process', 'GO:0007165', ('180', '197'))	('arrest', 'Disease', (262, 268))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('miR-141', 'Gene', '406933', (105, 112))	('glioma', 'Disease', 'MESH:D005910', (369, 375))	('cell proliferation', 'biological_process', 'GO:0008283', ('213', '231'))	('SNHG15', 'Gene', (0, 6))	('miR-141', 'Gene', (105, 112))	('cancer', 'Disease', (277, 283))	('SNHG15', 'Gene', (309, 315))	('cancer', 'Disease', (333, 339))	('glioma', 'Phenotype', 'HP:0009733', (369, 375))	('SNHG15', 'Gene', '285958', (0, 6))	('SNHG15', 'Gene', '285958', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('arrest', 'Disease', 'MESH:D006323', (262, 268))	('cell proliferation', 'CPA', (213, 231))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (277, 284))	('miR-211-3p', 'Gene', '100302164', (71, 81))	('worse', 'NegReg', (327, 332))	('miR-211-3p', 'Gene', (71, 81))	('migration', 'CPA', (233, 242))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))	('promoting', 'PosReg', (199, 208))	('miR-141', 'Gene', '406933', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('miR-153', 'Chemical', '-', (96, 103))	('invasion', 'CPA', (244, 252))	('miR-141', 'Gene', (117, 124))
28604	32562536	Aberrant SATB1 expression has been reported in various neoplasms.	('Aberrant', 'Var', (0, 8))	('reported', 'Reg', (35, 43))	('neoplasms', 'Disease', 'MESH:D009369', (55, 64))	('expression', 'MPA', (15, 25))	('neoplasms', 'Disease', (55, 64))	('SATB1', 'Gene', (9, 14))	('SATB1', 'Gene', '6304', (9, 14))	('neoplasms', 'Phenotype', 'HP:0002664', (55, 64))
28610	32562536	Decreased expression of SATB1 was associated with poor overall and progression-free survival of BRAC patients with positive estrogen receptor (ER) as well as mutated TP53.	('patients', 'Species', '9606', (101, 109))	('poor', 'NegReg', (50, 54))	('estrogen receptor', 'Gene', (124, 141))	('Decreased', 'NegReg', (0, 9))	('SATB1', 'Gene', (24, 29))	('SATB1', 'Gene', '6304', (24, 29))	('expression', 'MPA', (10, 20))	('TP53', 'Gene', '7157', (166, 170))	('estrogen receptor', 'Gene', '2099', (124, 141))	('TP53', 'Gene', (166, 170))	('mutated', 'Var', (158, 165))	('BRAC', 'Phenotype', 'HP:0003002', (96, 100))	('progression-free survival', 'CPA', (67, 92))	('ER', 'Gene', '2099', (143, 145))
28626	32562536	A recent study suggested that SATB1 regulates PDCD1 expression during T cell activation and prevents T cell exhaustion, and that dysregulation of this pathway results in anti-tumor immune dysfunction.	('SATB1', 'Gene', (30, 35))	('SATB1', 'Gene', '6304', (30, 35))	('dysregulation', 'Var', (129, 142))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('expression', 'MPA', (52, 62))	('T cell exhaustion', 'CPA', (101, 118))	('PDCD1', 'Gene', '5133', (46, 51))	('PDCD1', 'Gene', (46, 51))	('tumor immune dysfunction', 'Disease', 'MESH:D007154', (175, 199))	('T cell activation', 'biological_process', 'GO:0042110', ('70', '87'))	('tumor immune dysfunction', 'Disease', (175, 199))	('results in', 'Reg', (159, 169))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (101, 118))
28651	32562536	In particularly, the expression of SATB1 significantly affected prognosis in 7 types of cancers, including breast cancer (Figure 3A-3E), lung cancer (Figures 3F-3I), brain cancer (Figure 3J, 3K), prostate cancer (Figure 3L), skin cancer (Figure 3M), bladder cancer (Figure 3N), and eye cancer (Figure 3O).	('eye cancer', 'Disease', (282, 292))	('affected', 'Reg', (55, 63))	('SATB1', 'Gene', (35, 40))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('expression', 'Var', (21, 31))	('skin cancer', 'Disease', (225, 236))	('brain cancer', 'Disease', (166, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('eye cancer', 'Disease', 'MESH:D009369', (282, 292))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('SATB1', 'Gene', '6304', (35, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('skin cancer', 'Phenotype', 'HP:0008069', (225, 236))	('eye cancer', 'Phenotype', 'HP:0100012', (282, 292))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('brain cancer', 'Phenotype', 'HP:0030692', (166, 178))	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('skin cancer', 'Disease', 'MESH:D012878', (225, 236))	('lung cancer', 'Disease', (137, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (250, 264))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('prostate cancer', 'Disease', (196, 211))	('brain cancer', 'Disease', 'MESH:D001932', (166, 178))	('bladder cancer', 'Disease', (250, 264))	('prognosis', 'CPA', (64, 73))	('bladder cancer', 'Phenotype', 'HP:0009725', (250, 264))
28655	32562536	In addition, a low level of SATB1 was correlated with poor OS in LUAD (HR: 0.57, 95% CI: 0.49-0.68) (Figure 4C).	('LUAD', 'Disease', (65, 69))	('poor OS', 'MPA', (54, 61))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('SATB1', 'Gene', '6304', (28, 33))	('SATB1', 'Gene', (28, 33))	('low level', 'Var', (15, 24))
28659	32562536	Additionally, a high level of SATB1 was associated with worse DFS in STAD (P<0.05) (Table 2).	('SATB1', 'Gene', (30, 35))	('SATB1', 'Gene', '6304', (30, 35))	('DFS', 'Disease', (62, 65))	('STAD', 'Disease', (69, 73))	('high level', 'Var', (16, 26))
28662	32562536	As shown in Table 3, a low level of SATB1 was associated with poor OS and PFS in BRCA patients with positive estrogen receptor (ER) and mutated TP53.	('BRCA', 'Gene', (81, 85))	('SATB1', 'Gene', (36, 41))	('TP53', 'Gene', (144, 148))	('SATB1', 'Gene', '6304', (36, 41))	('TP53', 'Gene', '7157', (144, 148))	('poor OS', 'Disease', (62, 69))	('low', 'Var', (23, 26))	('ER', 'Gene', '2099', (128, 130))	('PFS', 'Disease', (74, 77))	('mutated', 'Var', (136, 143))	('BRCA', 'Phenotype', 'HP:0003002', (81, 85))	('BRCA', 'Gene', '672', (81, 85))	('estrogen receptor', 'Gene', (109, 126))	('estrogen receptor', 'Gene', '2099', (109, 126))	('patients', 'Species', '9606', (86, 94))
28666	32562536	Additionally, SATB1 expression was associated with infiltration of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in 11, 19, 25, 16, and 18 types of cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('SATB1', 'Gene', '6304', (14, 19))	('CD4', 'Gene', '920', (81, 84))	('expression', 'Var', (20, 30))	('SATB1', 'Gene', (14, 19))	('associated with', 'Reg', (35, 50))	('cancer', 'Disease', (164, 170))	('CD4', 'Gene', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('CD8', 'Gene', (67, 70))	('infiltration', 'CPA', (51, 63))	('CD8', 'Gene', '925', (67, 70))
28681	32562536	In our research, we found that aberrant SATB1 expression was related to prognosis in diverse cancers.	('cancers', 'Disease', (93, 100))	('SATB1', 'Gene', (40, 45))	('SATB1', 'Gene', '6304', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('aberrant', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('related', 'Reg', (61, 68))	('expression', 'MPA', (46, 56))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
28682	32562536	Lower SATB1 expression correlated with poor survival in BRCA patients with positive ER and mutated TP53.	('TP53', 'Gene', (99, 103))	('SATB1', 'Gene', (6, 11))	('SATB1', 'Gene', '6304', (6, 11))	('BRCA', 'Phenotype', 'HP:0003002', (56, 60))	('patients', 'Species', '9606', (61, 69))	('poor', 'NegReg', (39, 43))	('mutated', 'Var', (91, 98))	('BRCA', 'Gene', '672', (56, 60))	('ER', 'Gene', '2099', (84, 86))	('Lower', 'NegReg', (0, 5))	('BRCA', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (99, 103))	('expression', 'MPA', (12, 22))
28693	32562536	Moreover, depletion of SATB1 led to poor OS and PFS in BRAC patients with positive ER and mutated TP53.	('BRAC', 'Disease', (55, 59))	('mutated', 'Var', (90, 97))	('poor', 'NegReg', (36, 40))	('patients', 'Species', '9606', (60, 68))	('ER', 'Gene', '2099', (83, 85))	('depletion', 'Var', (10, 19))	('PFS', 'MPA', (48, 51))	('TP53', 'Gene', '7157', (98, 102))	('BRAC', 'Phenotype', 'HP:0003002', (55, 59))	('SATB1', 'Gene', (23, 28))	('SATB1', 'Gene', '6304', (23, 28))	('TP53', 'Gene', (98, 102))
28695	32562536	Another important finding in our research was that a low level of SATB1 was associated with different levels of immune infiltration in neoplasms, especially in BRAC, HNSC, and PRAD.	('neoplasms', 'Phenotype', 'HP:0002664', (135, 144))	('BRAC', 'Phenotype', 'HP:0003002', (160, 164))	('BRAC', 'Disease', (160, 164))	('HNSC', 'Disease', (166, 170))	('SATB1', 'Gene', '6304', (66, 71))	('neoplasms', 'Disease', 'MESH:D009369', (135, 144))	('associated', 'Reg', (76, 86))	('neoplasms', 'Disease', (135, 144))	('SATB1', 'Gene', (66, 71))	('PRAD', 'Disease', (176, 180))	('immune infiltration', 'MPA', (112, 131))	('low level', 'Var', (53, 62))
28705	32562536	reported that dynamic variations in SATB1 expression were required for the generation and immuno-stimulatory activity of conventional DCs; however, overexpressed SATB1 in differentiated DCs could convert them into pro-inflammatory or tolerogenic cells and prompt malignant transformation.	('SATB1', 'Gene', (36, 41))	('SATB1', 'Gene', '6304', (36, 41))	('overexpressed', 'Var', (148, 161))	('malignant transformation', 'CPA', (263, 287))	('SATB1', 'Gene', '6304', (162, 167))	('convert', 'Reg', (196, 203))	('SATB1', 'Gene', (162, 167))	('pro-inflammatory', 'MPA', (214, 230))
28706	32562536	In an in vivo experiment, SATB1 knockdown in DCs could reverse the inflammation and carcinogenic activity, and enhance protective immune responses.	('protective immune responses', 'CPA', (119, 146))	('SATB1', 'Gene', (26, 31))	('SATB1', 'Gene', '6304', (26, 31))	('reverse', 'NegReg', (55, 62))	('knockdown', 'Var', (32, 41))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('inflammation', 'biological_process', 'GO:0006954', ('67', '79'))	('inflammation', 'Disease', (67, 79))	('enhance', 'PosReg', (111, 118))	('carcinogenic', 'Disease', 'MESH:D063646', (84, 96))	('carcinogenic', 'Disease', (84, 96))
28707	32562536	SATB1 also participates in the pathogenesis of cutaneous T-cell lymphoma, and depletion of SATB1 upregulates IL-5 and IL-9.	('IL-5', 'Gene', (109, 113))	('SATB1', 'Gene', '6304', (91, 96))	('upregulates', 'PosReg', (97, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('SATB1', 'Gene', (0, 5))	('cell lymphoma', 'Phenotype', 'HP:0012191', (59, 72))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (47, 72))	('pathogenesis', 'biological_process', 'GO:0009405', ('31', '43'))	('IL-9', 'molecular_function', 'GO:0005140', ('118', '122'))	('SATB1', 'Gene', '6304', (0, 5))	('IL-9', 'Gene', '3578', (118, 122))	('IL-5', 'molecular_function', 'GO:0005137', ('109', '113'))	('IL-5', 'Gene', '3567', (109, 113))	('cutaneous T-cell lymphoma', 'Disease', (47, 72))	('participates', 'Reg', (11, 23))	('depletion', 'Var', (78, 87))	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (47, 72))	('IL-9', 'Gene', (118, 122))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (57, 72))	('SATB1', 'Gene', (91, 96))
28710	32562536	In summary, a low level of SATB1 expression was associated with poor survival rates and enhanced the immune infiltration level of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in various types of cancer, especially in BRAC, HNSC, and PRAD.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('SATB1', 'Gene', (27, 32))	('HNSC', 'Disease', (249, 253))	('enhanced', 'PosReg', (88, 96))	('CD8', 'Gene', (139, 142))	('BRAC', 'Phenotype', 'HP:0003002', (243, 247))	('SATB1', 'Gene', '6304', (27, 32))	('immune infiltration level of B', 'MPA', (101, 131))	('expression', 'Var', (33, 43))	('cancer', 'Disease', (221, 227))	('survival rates', 'CPA', (69, 83))	('poor', 'NegReg', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('BRAC', 'Disease', (243, 247))	('CD4', 'Gene', '920', (153, 156))	('CD8', 'Gene', '925', (139, 142))	('CD4', 'Gene', (153, 156))	('PRAD', 'Disease', (259, 263))	('low', 'Var', (14, 17))
28717	32548260	Pharmacological and macrophage-specific genetic ablation of beta-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth.	('lung tumor', 'Disease', (224, 234))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('lung tumor', 'Phenotype', 'HP:0100526', (224, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('beta-catenin', 'Protein', (60, 72))	('TAMs', 'Chemical', '-', (110, 114))	('TAMs', 'Chemical', '-', (94, 98))	('ablation', 'Var', (48, 56))	('lung tumor', 'Disease', 'MESH:D008175', (224, 234))
28723	32548260	Targeted therapies are beneficial to only 15 to 20% of patients with lung cancer harboring drug-sensitive mutations.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
28739	32548260	Activation of Wnt/beta-catenin signaling in lung cancer is a result of co-occurring genetic, epigenetic, and gene expression alterations in lung cancer cells as well as aberrant expressions of molecules related to Wnt signaling activity.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('lung cancer', 'Disease', (140, 151))	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('expressions', 'MPA', (178, 189))	('Wnt/beta-catenin signaling', 'Pathway', (14, 40))	('alterations', 'Var', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('Activation', 'PosReg', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('aberrant', 'Var', (169, 177))	('lung cancer', 'Disease', (44, 55))
28775	32548260	Both FACS analysis of cell surface phenotypic markers (CD80 and CD163) (fig.	('CD163', 'Gene', '9332', (64, 69))	('CD80', 'Var', (55, 59))	('CD163', 'Gene', (64, 69))	('cell surface', 'cellular_component', 'GO:0009986', ('22', '34'))	('S', 'Chemical', 'MESH:D013455', (8, 9))
28781	32548260	Notably, CM from human primary lung cancer cells and other lung tumor cells such as A427 and H1650, which were cocultured with macrophages, also displayed a significant increase in the proliferation and migration of tumor cells by CM of M2-like TAMs compared with their M1 counterparts (fig.	('lung tumor', 'Phenotype', 'HP:0100526', (59, 69))	('lung cancer', 'Disease', (31, 42))	('TAMs', 'Chemical', '-', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (216, 221))	('human', 'Species', '9606', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('lung tumor', 'Disease', 'MESH:D008175', (59, 69))	('migration', 'CPA', (203, 212))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('proliferation', 'CPA', (185, 198))	('tumor', 'Disease', (64, 69))	('increase', 'PosReg', (169, 177))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('M2-like', 'Var', (237, 244))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('lung tumor', 'Disease', (59, 69))
28795	32548260	Moreover, TAMs trained through coculture with A427, H1650, and primary lung tumor cells showed up-regulation of the Wnt/beta-catenin pathway in M2-like TAMs compared with that in M1-like TAMs (fig.	('TAMs', 'Chemical', '-', (10, 14))	('lung tumor', 'Disease', 'MESH:D008175', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('lung tumor', 'Disease', (71, 81))	('Wnt/beta-catenin pathway', 'Pathway', (116, 140))	('TAMs', 'Chemical', '-', (187, 191))	('TAMs', 'Chemical', '-', (152, 156))	('lung tumor', 'Phenotype', 'HP:0100526', (71, 81))	('up-regulation', 'PosReg', (95, 108))	('M2-like', 'Var', (144, 151))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))
28801	32548260	Decreased protein expression of Wnt/beta-catenin signaling (beta-catenin and TNKS1/2) and its target genes (CCND1, MYC, and MET) demonstrated the down-regulation of nuclear beta-catenin activity in M2-like TAMs transfected with sh_beta-catenin (Fig.	('down-regulation', 'NegReg', (146, 161))	('protein expression', 'MPA', (10, 28))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('sh_beta-catenin', 'Var', (228, 243))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('Decreased', 'NegReg', (0, 9))	('TAMs', 'Chemical', '-', (206, 210))	('MYC', 'Gene', (115, 118))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('nuclear beta-catenin activity', 'MPA', (165, 194))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('TNKS1/2', 'Gene', (77, 84))	('MYC', 'Gene', '4609', (115, 118))
28802	32548260	Notably, the mRNA expression of M1 macrophage markers was up-regulated, whereas that of M2 macrophage markers was down-regulated in M2-like TAMs transfected with sh_beta-catenin, demonstrating the phenotypic transition of M2-like TAMs to M1-like TAMs (Fig.	('up-regulated', 'PosReg', (58, 70))	('TAMs', 'Chemical', '-', (140, 144))	('TAMs', 'Chemical', '-', (230, 234))	('transfected', 'Var', (145, 156))	('mRNA expression', 'MPA', (13, 28))	('down-regulated', 'NegReg', (114, 128))	('TAMs', 'Chemical', '-', (246, 250))
28804	32548260	In addition, the treatment of A549 cells with CM from M2-like TAMs transfected with sh_beta-catenin showed increased apoptosis (Fig.	('increased', 'PosReg', (107, 116))	('TAMs', 'Chemical', '-', (62, 66))	('sh_beta-catenin', 'Var', (84, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('apoptosis', 'CPA', (117, 126))
28806	32548260	Moreover, small interfering RNA (siRNA)-mediated knockdown of beta-catenin in ex vivo TAMs isolated from human lung tumors for 24 hours down-regulated the mRNA expression of CCND1 (Fig.	('lung tumors', 'Phenotype', 'HP:0100526', (111, 122))	('knockdown', 'Var', (49, 58))	('down-regulated', 'NegReg', (136, 150))	('lung tumors', 'Disease', (111, 122))	('lung tumor', 'Phenotype', 'HP:0100526', (111, 121))	('TAMs', 'Chemical', '-', (86, 90))	('lung tumors', 'Disease', 'MESH:D008175', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('CCND1', 'Gene', (174, 179))	('human', 'Species', '9606', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('RNA', 'cellular_component', 'GO:0005562', ('28', '31'))	('mRNA expression', 'MPA', (155, 170))
28807	32548260	Similar to M2-like TAMs, ex vivo TAMs transfected with si_beta-catenin also showed increased expression of M1 and decreased expression of M2 macrophage markers (Fig.	('increased', 'PosReg', (83, 92))	('si_beta-catenin', 'Var', (55, 70))	('decreased', 'NegReg', (114, 123))	('expression', 'MPA', (93, 103))	('expression', 'MPA', (124, 134))	('TAMs', 'Chemical', '-', (33, 37))	('TAMs', 'Chemical', '-', (19, 23))	('S', 'Chemical', 'MESH:D013455', (0, 1))
28814	32548260	In addition, CM from XAV939-treated M2-like TAMs (trained in vitro by coculturing with A427 and H1650) decreased the survival and proliferation of A427 and H1650 cells compared with CM from untreated M2-like TAMs (fig.	('XAV939-treated', 'Gene', (21, 35))	('decreased', 'NegReg', (103, 112))	('XAV939', 'Chemical', 'MESH:C544261', (21, 27))	('survival', 'CPA', (117, 125))	('proliferation', 'CPA', (130, 143))	('TAMs', 'Chemical', '-', (208, 212))	('TAMs', 'Chemical', '-', (44, 48))	('H1650', 'Var', (156, 161))
28821	32548260	Collectively, these results strongly demonstrate that the genetic and pharmacological ablation of beta-catenin shifts tumor-promoting M2-like TAMs to tumor-inhibiting M1-like TAMs.	('TAMs', 'Chemical', '-', (175, 179))	('ablation', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('TAMs', 'Chemical', '-', (142, 146))	('beta-catenin', 'Protein', (98, 110))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
28827	32548260	In addition, to study whether targeting the Wnt/beta-catenin pathway in tumor cells is sufficient to prevent M2 polarization of TAMs, we assessed the expression of the polarization markers from macrophages that were subjected to CM from A549 cells transfected with si_beta-catenin (fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('si_beta-catenin', 'Var', (265, 280))	('tumor', 'Disease', (72, 77))	('TAMs', 'Chemical', '-', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
28837	32548260	Notably, TAMs isolated from the XAV939 group showed increased expression of M1 macrophage markers (Tnf, Nos2, and Il1b) and decreased expression of M2 macrophage markers (Il10, Arg1, and Chit1) (Fig.	('Chit1', 'Gene', (187, 192))	('Il10', 'Gene', (171, 175))	('Chit1', 'Gene', '1118', (187, 192))	('Tnf', 'Gene', (99, 102))	('Il1b', 'Gene', (114, 118))	('Arg1', 'Gene', (177, 181))	('XAV939', 'Chemical', 'MESH:C544261', (32, 38))	('increased', 'PosReg', (52, 61))	('Arg1', 'Gene', '383', (177, 181))	('Nos2', 'Gene', '4843', (104, 108))	('Il10', 'Gene', '3586', (171, 175))	('Il1b', 'Gene', '3553', (114, 118))	('expression', 'MPA', (134, 144))	('expression', 'MPA', (62, 72))	('XAV939', 'Var', (32, 38))	('Il1', 'molecular_function', 'GO:0005149', ('114', '117'))	('Nos2', 'Gene', (104, 108))	('Il10', 'molecular_function', 'GO:0005141', ('171', '175'))	('decreased', 'NegReg', (124, 133))	('TAMs', 'Chemical', '-', (9, 13))
28839	32548260	Moreover, treatment with XAV939 significantly reduced the number of CD206+ M2-like TAMs in TME (Fig.	('XAV939', 'Var', (25, 31))	('TAMs', 'Chemical', '-', (83, 87))	('CD206+ M2-like', 'Var', (68, 82))	('XAV939', 'Chemical', 'MESH:C544261', (25, 31))	('reduced', 'NegReg', (46, 53))
28840	32548260	Collectively, these results indicate that inhibiting beta-catenin restricts tumor growth in vivo.	('inhibiting', 'Var', (42, 52))	('beta-catenin', 'Protein', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('restricts', 'NegReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
28842	32548260	We hypothesized that inactivating beta-catenin in TAMs switches the phenotype to that of M1-like TAMs, thereby inducing functional antitumor immunity in lung TME.	('inducing', 'PosReg', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('TAMs', 'Chemical', '-', (97, 101))	('TAMs', 'Chemical', '-', (50, 54))	('beta-catenin', 'Protein', (34, 46))	('inactivating', 'Var', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
28857	32548260	Collectively, these results indicate that inhibiting macrophage-specific beta-catenin significantly reduced lung tumorigenesis by inducing an antitumor response in M2-like TAMs in TME.	('tumor', 'Disease', (113, 118))	('lung tumor', 'Disease', (108, 118))	('macrophage-specific beta-catenin', 'Protein', (53, 85))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibiting', 'Var', (42, 52))	('TAMs', 'Chemical', '-', (172, 176))	('reduced', 'NegReg', (100, 107))	('lung tumor', 'Phenotype', 'HP:0100526', (108, 118))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('inducing', 'PosReg', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lung tumor', 'Disease', 'MESH:D008175', (108, 118))
28865	32548260	Thus, to determine whether the switching of macrophage phenotype is entirely dependent on beta-catenin-modulated TNF, we performed siRNA-mediated down-regulation of TNF in beta-catenin_KO macrophages (M0_Catnbf/fLysmCre + si_TNF) and M2-like TAMs transfected with si_beta-catenin (M2-like TAMs_ si_beta-catenin + si_TNF) (Fig.	('down-regulation', 'NegReg', (146, 161))	('Lysm', 'Gene', '17105', (212, 216))	('si_beta-catenin', 'Var', (264, 279))	('TAMs', 'Chemical', '-', (289, 293))	('Catnb', 'Gene', '12387', (204, 209))	('Catnb', 'Gene', (204, 209))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('Lysm', 'Gene', (212, 216))	('TAMs', 'Chemical', '-', (242, 246))	('TNF', 'Gene', (165, 168))
28870	32548260	5A heatmap, most M1 macrophage markers were up-regulated, whereas M2 macrophage markers were down-regulated in M2-like TAMs transfected with sh_beta-catenin.	('down-regulated', 'NegReg', (93, 107))	('sh_beta-catenin', 'Var', (141, 156))	('TAMs', 'Chemical', '-', (119, 123))	('up-regulated', 'PosReg', (44, 56))
28871	32548260	Notably, RNA-seq data revealed the differential expression of transcription factors (TFs) between M2-like TAMs transfected with sh_beta-catenin and those transfected with sh_control (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('sh_beta-catenin', 'Var', (128, 143))	('TAMs', 'Chemical', '-', (106, 110))	('expression', 'MPA', (48, 58))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('TFs', 'Gene', (85, 88))
28883	32548260	XAV939 significantly impaired the binding of beta-catenin to the promoter regions of the aforementioned target genes (Fig.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('XAV939', 'Var', (0, 6))	('binding', 'Interaction', (34, 41))	('XAV939', 'Chemical', 'MESH:C544261', (0, 6))	('impaired', 'NegReg', (21, 29))	('beta-catenin', 'Protein', (45, 57))
28888	32548260	In contrast, FOSL2 expression was down-regulated in M2-like TAMs transfected with si_beta-catenin.	('expression', 'MPA', (19, 29))	('down-regulated', 'NegReg', (34, 48))	('FOSL2', 'Gene', (13, 18))	('TAMs', 'Chemical', '-', (60, 64))	('si_beta-catenin', 'Var', (82, 97))
28893	32548260	6D), whereas that of certain M2 (IL10 and ALOX15) and M1 macrophage markers (IL1B, IL8, and CCR7) remained unchanged in M2-like TAMs transfected with si_FOSL2 (fig.	('IL8', 'Gene', '3576', (83, 86))	('CCR7', 'Gene', '1236', (92, 96))	('ALOX15', 'Gene', (42, 48))	('IL10', 'molecular_function', 'GO:0005141', ('33', '37'))	('TAMs', 'Chemical', '-', (128, 132))	('IL10', 'Gene', (33, 37))	('IL10', 'Gene', '3586', (33, 37))	('ALOX15', 'Gene', '246', (42, 48))	('IL8', 'molecular_function', 'GO:0005153', ('83', '86'))	('si_FOSL2', 'Var', (150, 158))	('IL1B', 'Gene', '3553', (77, 81))	('IL1B', 'Gene', (77, 81))	('CCR7', 'Gene', (92, 96))	('IL8', 'Gene', (83, 86))	('CCR', 'molecular_function', 'GO:0043880', ('92', '95'))	('IL1', 'molecular_function', 'GO:0005149', ('77', '80'))
28903	32548260	CM from M2-like TAMs transfected with OE_ARID5A led to decreased survival and proliferation of A549 cells (fig.	('transfected', 'Var', (21, 32))	('OE_ARID5A', 'Var', (38, 47))	('decreased', 'NegReg', (55, 64))	('survival', 'CPA', (65, 73))	('proliferation', 'CPA', (78, 91))	('TAMs', 'Chemical', '-', (16, 20))
28907	32548260	The LysmCre M0 macrophage treatment with XAV939 led to a significant up-regulation of M1 macrophage-associated TF (Arid5a) and genes (Tnf, Nos2, and Il1b) and down-regulation of M2 macrophage-associated TF (Fosl2) and genes (Il10, Arg1, and Chit1).	('down-regulation', 'NegReg', (159, 174))	('Lysm', 'Gene', '17105', (4, 8))	('regulation', 'biological_process', 'GO:0065007', ('164', '174'))	('XAV939', 'Chemical', 'MESH:C544261', (41, 47))	('Il10', 'Gene', (225, 229))	('Chit1', 'Gene', (241, 246))	('Nos2', 'Gene', '4843', (139, 143))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))	('Chit1', 'Gene', '1118', (241, 246))	('Arg1', 'Gene', '383', (231, 235))	('Arg1', 'Gene', (231, 235))	('Il10', 'Gene', '3586', (225, 229))	('Il1', 'molecular_function', 'GO:0005149', ('149', '152'))	('up-regulation', 'PosReg', (69, 82))	('XAV939', 'Var', (41, 47))	('Nos2', 'Gene', (139, 143))	('Lysm', 'Gene', (4, 8))	('Il1b', 'Gene', (149, 153))	('Il10', 'molecular_function', 'GO:0005141', ('225', '229'))	('Fosl2', 'Gene', (207, 212))	('Tnf', 'Gene', (134, 137))	('Il1b', 'Gene', '3553', (149, 153))
28917	32548260	Second, genetic or pharmacological ablation of nuclear beta-catenin activity in primary TAMs isolated from human and mouse lung tumors, as well as in in vitro trained M2-like TAMs, phenotypically and functionally "reprograms" M2-like TAMs to M1-like TAMs.	('lung tumor', 'Phenotype', 'HP:0100526', (123, 133))	('TAMs', 'Chemical', '-', (175, 179))	('lung tumors', 'Disease', 'MESH:D008175', (123, 134))	('TAMs', 'Chemical', '-', (234, 238))	('mouse', 'Species', '10090', (117, 122))	('human', 'Species', '9606', (107, 112))	('TAMs', 'Chemical', '-', (250, 254))	('lung tumors', 'Phenotype', 'HP:0100526', (123, 134))	('lung tumors', 'Disease', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('activity', 'MPA', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('TAMs', 'Chemical', '-', (88, 92))	('ablation', 'Var', (35, 43))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('nuclear beta-catenin', 'Protein', (47, 67))
28918	32548260	Third, pharmacological and macrophage-specific genetic ablation of beta-catenin in five different in vivo lung tumor models reduce primary and metastatic lung tumor growth, together with reactivation of the antitumor response of M1-like TAMs in lung TME.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (211, 216))	('lung tumor', 'Disease', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('genetic ablation', 'Var', (47, 63))	('lung tumor', 'Phenotype', 'HP:0100526', (106, 116))	('TAMs', 'Chemical', '-', (237, 241))	('lung tumor', 'Disease', 'MESH:D008175', (154, 164))	('reduce', 'NegReg', (124, 130))	('reactivation', 'PosReg', (187, 199))	('tumor', 'Disease', (111, 116))	('beta-catenin', 'Protein', (67, 79))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('lung tumor', 'Disease', 'MESH:D008175', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('ablation', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('lung tumor', 'Disease', (154, 164))	('lung tumor', 'Phenotype', 'HP:0100526', (154, 164))
28930	32548260	These investigations clearly demonstrated that Wnt/beta-catenin signaling is strongly activated in M2-like TAMs, unlike in M1-like TAMs, as well as in human TAMs in lung cancer tissues.	('TAMs', 'Chemical', '-', (157, 161))	('lung cancer', 'Disease', (165, 176))	('human', 'Species', '9606', (151, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('TAMs', 'Chemical', '-', (107, 111))	('Wnt/beta-catenin signaling', 'MPA', (47, 73))	('TAMs', 'Chemical', '-', (131, 135))	('M2-like TAMs', 'Var', (99, 111))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('activated', 'PosReg', (86, 95))
28945	32548260	(i) The genetic and pharmacological inhibition of beta-catenin phenotypically and functionally reprograms M2-like TAMs to M1-like TAMs, and inhibition in M1-like TAMs augments its antitumor effects.	('TAMs', 'Chemical', '-', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('inhibition', 'Var', (36, 46))	('beta-catenin', 'Protein', (50, 62))	('inhibition', 'Var', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('augments', 'PosReg', (167, 175))	('tumor', 'Disease', (184, 189))	('TAMs', 'Chemical', '-', (162, 166))	('TAMs', 'Chemical', '-', (114, 118))
28946	32548260	(ii) In vitro dose-comparison study suggests that reactivation of antitumor response in M2-like TAMs requires less amount of pharmacological inhibitor of beta-catenin when compared to direct treatment to tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('TAMs', 'Chemical', '-', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (70, 75))	('M2-like', 'Var', (88, 95))	('reactivation', 'PosReg', (50, 62))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
28947	32548260	(iii) Further comparison of tumor cell functions and the TAM polarization status upon genetic and pharmacological ablation of beta-catenin in tumor cells versus macrophages suggested that beta-catenin ablation in tumor cells influences only tumor cell functions with no subsequent influence on the TAM polarization status, whereas beta-catenin ablation in TAMs influences both tumor cell function and the TAM polarization status.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (28, 33))	('TAM', 'Gene', (356, 359))	('TAM', 'Gene', '8205', (356, 359))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('TAM', 'Gene', (298, 301))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('ablation', 'Var', (201, 209))	('TAMs', 'Chemical', '-', (356, 360))	('tumor', 'Disease', (377, 382))	('tumor', 'Disease', (241, 246))	('TAM', 'Gene', '8205', (298, 301))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (142, 147))	('influences', 'Reg', (361, 371))	('TAM', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Disease', (213, 218))	('TAM', 'Gene', (405, 408))	('TAM', 'Gene', '8205', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('TAM', 'Gene', '8205', (405, 408))	('influences', 'Reg', (225, 235))
28993	32548260	Following serum starvation, we treated the cells with different CM for 24 hours, such as CM from M0, M1, M2 macrophages, in vitro trained M1-like TAMs, M2-like TAMs, M2-like TAMs and M2-like TAMs treated with DMSO, 5 muM XAV939, M2-like TAMs transfected with sh_EG5; sh_NS; sh_beta-catenin; and M2-like TAMs transfected with si_NS, si_FOSL2, OE_Ctrl, OE_ARID5A, and OE_beta-catenin.	('sh_NS', 'Gene', (267, 272))	('muM', 'Gene', '56925', (217, 220))	('TAMs', 'Chemical', '-', (174, 178))	('si_NS', 'Chemical', '-', (325, 330))	('EG5', 'Gene', (262, 265))	('TAMs', 'Chemical', '-', (237, 241))	('TAMs', 'Chemical', '-', (146, 150))	('TAMs', 'Chemical', '-', (303, 307))	('muM', 'Gene', (217, 220))	('EG5', 'Gene', '3832', (262, 265))	('si_FOSL2', 'Var', (332, 340))	('DMSO', 'Chemical', 'MESH:D004121', (209, 213))	('TAMs', 'Chemical', '-', (191, 195))	('TAMs', 'Chemical', '-', (160, 164))	('sh_NS', 'Gene', '57511', (267, 272))	('XAV939', 'Chemical', 'MESH:C544261', (221, 227))	('si_NS', 'Var', (325, 330))
29038	32548260	C57BL/6, Catnbf/f (B6.129-Ctnnb1tm2Kem/KnwJ), and LysmCre (B6.129P2-Lyz2tm1(cre)Ifo/J) mice were purchased from the Jackson laboratory (Bar Harbor, ME, USA).	('Lysm', 'Gene', (50, 54))	('Catnb', 'Gene', (9, 14))	('mice', 'Species', '10090', (87, 91))	('Catnb', 'Gene', '12387', (9, 14))	('S', 'Chemical', 'MESH:D013455', (153, 154))	('P', 'Chemical', 'MESH:D010758', (65, 66))	('Lysm', 'Gene', '17105', (50, 54))	('B6.129P2-Lyz2tm1', 'Var', (59, 75))
29066	32548260	For characterization and sorting of immune cell subsets in mouse tumors, we used the following antibodies: anti-CD3-PE-CF594, anti-CD4-BV510, anti-CD8-BV650, anti-CD11b-BV605, anti-CD11c-AlexaFluor700, anti-CD19-APC-H7, anti-CD326-BV711, anti-Ly6C-Per-CP-Cy5.5 (BD Biosciences), anti-CD45-Vio-Blu, anti-MHC-II-APC (Miltenyi Biotec), anti-CD80-PE, anti-F4/80-PE-Cy7, anti-CD206-FITC, and anti-Ly6G-APC-Cy7 (BioLegend).	('AlexaFluor700', 'Chemical', '-', (187, 200))	('anti-CD206-FITC', 'Var', (366, 381))	('tumors', 'Disease', (65, 71))	('CD4', 'Gene', (284, 287))	('Ly6C', 'Gene', (243, 247))	('CD3', 'Gene', (225, 228))	('CD19', 'Gene', (207, 211))	('CD3', 'Gene', '28134', (225, 228))	('APC', 'cellular_component', 'GO:0005680', ('212', '215'))	('APC', 'cellular_component', 'GO:0005680', ('310', '313'))	('Ly6G', 'Gene', '546644', (392, 396))	('P', 'Chemical', 'MESH:D010758', (248, 249))	('CD11c', 'Gene', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('F4/80', 'Gene', '13733', (352, 357))	('anti-CD80-PE', 'Var', (333, 345))	('CD4', 'Gene', '12504', (284, 287))	('CD3', 'Gene', (112, 115))	('Ly6G', 'Gene', (392, 396))	('P', 'Chemical', 'MESH:D010758', (311, 312))	('mouse', 'Species', '10090', (59, 64))	('P', 'Chemical', 'MESH:D010758', (343, 344))	('CD3', 'Gene', '28134', (112, 115))	('P', 'Chemical', 'MESH:D010758', (398, 399))	('CD11c', 'Gene', '16411', (181, 186))	('MHC-II-APC', 'Disease', 'MESH:D011125', (303, 313))	('F4/80', 'Gene', (352, 357))	('CD4', 'Gene', (131, 134))	('CD326', 'Gene', (225, 230))	('CD11b', 'Gene', '16409', (163, 168))	('P', 'Chemical', 'MESH:D010758', (358, 359))	('FITC', 'Chemical', 'MESH:D016650', (377, 381))	('CD326', 'Gene', '17075', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('P', 'Chemical', 'MESH:D010758', (253, 254))	('P', 'Chemical', 'MESH:D010758', (213, 214))	('CD19', 'Gene', '12478', (207, 211))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('CD11b', 'Gene', (163, 168))	('MHC-II-APC', 'Disease', (303, 313))	('CD4', 'Gene', '12504', (131, 134))	('APC', 'cellular_component', 'GO:0005680', ('397', '400'))	('Ly6C', 'Gene', '17067', (243, 247))	('P', 'Chemical', 'MESH:D010758', (116, 117))
29067	32548260	For the characterization and sorting of human macrophages, single-cell suspensions were stained with the following antibodies: anti-CD33-BV510, anti-CD45-AlexaFluor700, anti-CD64-BV605, anti-CD83-BV711 (BD Biosciences), anti-CD163-PE, anti-CD206-PE-Cy7, and anti-CD326-FITC (BioLegend).	('CD326', 'Gene', '17075', (263, 268))	('FITC', 'Chemical', 'MESH:D016650', (269, 273))	('AlexaFluor700', 'Chemical', '-', (154, 167))	('CD33', 'Gene', '945', (132, 136))	('CD83', 'Gene', (191, 195))	('CD33', 'Gene', (132, 136))	('P', 'Chemical', 'MESH:D010758', (231, 232))	('anti-CD45-AlexaFluor700', 'Var', (144, 167))	('CD163', 'Gene', '9332', (225, 230))	('CD64', 'Gene', (174, 178))	('anti-CD206-PE-Cy7', 'Var', (235, 252))	('CD83', 'Gene', '9308', (191, 195))	('CD326', 'Gene', (263, 268))	('CD163', 'Gene', (225, 230))	('P', 'Chemical', 'MESH:D010758', (246, 247))	('human', 'Species', '9606', (40, 45))	('CD64', 'Gene', '2209', (174, 178))
29083	32548260	We aligned trimmed and filtered reads versus the Ensembl human genome version hg38 (GRCh38.27) using STAR 2.5.4b with the parameter "--outFilterMismatchNoverLmax 0.1" to increase the maximum ratio of mismatches to mapped length of up to 10%.	('mum', 'Gene', (187, 190))	('mismatches', 'Var', (200, 210))	('S', 'Chemical', 'MESH:D013455', (101, 102))	('hg38', 'Gene', (78, 82))	('hg38', 'Gene', '8549', (78, 82))	('mum', 'Gene', '56925', (187, 190))	('human', 'Species', '9606', (57, 62))
29173	31791014	Knock down of linc00174 increased BTB permeability and reduced the expression of the tight junction-related proteins ZO-1, occludin, and claudin-5.	('ZO-1', 'Gene', '7082', (117, 121))	('Knock down', 'Var', (0, 10))	('reduced', 'NegReg', (55, 62))	('linc00174', 'Gene', (14, 23))	('claudin-5', 'Gene', (137, 146))	('linc00174', 'Gene', '285908', (14, 23))	('occludin', 'Gene', '100506658', (123, 131))	('claudin-5', 'Gene', '7122', (137, 146))	('BTB permeability', 'MPA', (34, 50))	('BTB', 'Chemical', '-', (34, 37))	('expression', 'MPA', (67, 77))	('occludin', 'Gene', (123, 131))	('tight junction', 'cellular_component', 'GO:0070160', ('85', '99'))	('ZO-1', 'Gene', (117, 121))	('increased', 'PosReg', (24, 33))
29174	31791014	Both bioinformatics data and results of luciferase reporter assays demonstrated that linc00174 regulated BTB permeability by binding to miR-138-5p and miR-150-5p.	('miR-150-5p', 'Var', (151, 161))	('BTB', 'Chemical', '-', (105, 108))	('linc00174', 'Gene', '285908', (85, 94))	('miR-150-5p', 'Chemical', '-', (151, 161))	('regulated', 'Reg', (95, 104))	('rat', 'Species', '10116', (74, 77))	('miR-138-5p', 'Chemical', '-', (136, 146))	('binding', 'Interaction', (125, 132))	('BTB permeability', 'MPA', (105, 121))	('binding', 'molecular_function', 'GO:0005488', ('125', '132'))	('miR-138-5p', 'Var', (136, 146))	('linc00174', 'Gene', (85, 94))
29175	31791014	Furthermore, knock down of linc00174 inhibited FOSL2 expression via upregulating miR-138-5p and miR-150-5p.	('miR-150-5p', 'Chemical', '-', (96, 106))	('upregulating', 'PosReg', (68, 80))	('inhibited', 'NegReg', (37, 46))	('FOSL2', 'Gene', (47, 52))	('miR-138-5p', 'Chemical', '-', (81, 91))	('linc00174', 'Gene', (27, 36))	('miR-150-5p', 'MPA', (96, 106))	('linc00174', 'Gene', '285908', (27, 36))	('knock down', 'Var', (13, 23))	('miR-138-5p', 'MPA', (81, 91))	('expression', 'MPA', (53, 63))
29182	31791014	Therefore, selective opening of the BTB, as well as increasing transporting drugs into glioma tissues, is one of the most important parts in improving the chemotherapeutic effect of glioma.	('glioma', 'Disease', (87, 93))	('increasing', 'PosReg', (52, 62))	('BTB', 'Chemical', '-', (36, 39))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('BTB', 'Gene', (36, 39))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Disease', (182, 188))	('selective', 'Var', (11, 20))	('transporting drugs into', 'MPA', (63, 86))
29186	31791014	Abundant and functionally important types of non-coding RNAs include long non-coding RNAs (lncRNAs), as well as short non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and others.	('small interfering', 'Var', (163, 180))	('PIWI', 'Gene', '9271', (196, 200))	('PIWI', 'Gene', (196, 200))
29191	31791014	miR-138-5p is a member of the miR-138 family, which contains a 23-bp sequence locus on chromosome 16, and is involved in modulating biological behaviors of multiple tumor cells.	('tumor', 'Disease', (165, 170))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('biological', 'CPA', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('modulating', 'Reg', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('miR-138-5p', 'Chemical', '-', (0, 10))	('involved', 'Reg', (109, 117))	('miR-138-5p', 'Var', (0, 10))
29192	31791014	miR-138-5p was reported to be downregulated in the tissues and cells of melanoma and renal cell carcinoma, and it participated in the regulation of cancer development and progression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('downregulated', 'NegReg', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('participated in', 'Reg', (114, 129))	('progression', 'CPA', (171, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 105))	('miR-138-5p', 'Chemical', '-', (0, 10))	('miR-138-5p', 'Var', (0, 10))
29193	31791014	miR-150-5p, located on chromosome 19 with a length of 22 bp, showed a low expression level in colorectal cancer, non-small cell lung cancer, and other tumors, while inhibiting the proliferation, migration, and invasion of the above tumor cells.	('miR-150-5p', 'Chemical', '-', (0, 10))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (113, 139))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('invasion', 'CPA', (210, 218))	('inhibiting', 'NegReg', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('proliferation', 'CPA', (180, 193))	('tumors', 'Disease', (151, 157))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('non-small cell lung cancer', 'Disease', (113, 139))	('rat', 'Species', '10116', (198, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('tumor', 'Disease', (232, 237))	('migration', 'CPA', (195, 204))	('miR-150-5p', 'Var', (0, 10))	('rat', 'Species', '10116', (187, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('colorectal cancer', 'Disease', (94, 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))	('low', 'NegReg', (70, 73))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('expression level', 'MPA', (74, 90))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
29194	31791014	At present, no studies on the regulation of BTB function by miR-138-5p and miR-150-5p have been reported.	('regulation', 'biological_process', 'GO:0065007', ('30', '40'))	('BTB', 'Chemical', '-', (44, 47))	('miR-138-5p', 'Chemical', '-', (60, 70))	('miR-150-5p', 'Chemical', '-', (75, 85))	('miR-150-5p', 'Var', (75, 85))	('miR-138-5p', 'Var', (60, 70))
29203	31791014	In the present study, we first verified the endogenous expression of linc00174, miR-138-5p, miR-150-5p, and FOSL2 in glioma microvascular endothelium and the effect of these molecules on the permeability of BTB.	('BTB', 'Chemical', '-', (207, 210))	('FOSL2', 'Gene', (108, 113))	('miR-138-5p', 'Chemical', '-', (80, 90))	('linc00174', 'Gene', (69, 78))	('miR-138-5p', 'Var', (80, 90))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('miR-150-5p', 'Var', (92, 102))	('linc00174', 'Gene', '285908', (69, 78))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('miR-150-5p', 'Chemical', '-', (92, 102))	('glioma', 'Disease', (117, 123))
29208	31791014	To explore the possible functional role of linc00174 on BTB permeability, GECs with stable knock down of linc00174 were established.	('linc00174', 'Gene', (105, 114))	('BTB', 'Chemical', '-', (56, 59))	('knock down', 'Var', (91, 101))	('linc00174', 'Gene', (43, 52))	('linc00174', 'Gene', '285908', (43, 52))	('linc00174', 'Gene', '285908', (105, 114))
29210	31791014	TEER values were significantly decreased in the linc00174(-) group compared with that in the linc00174(-)NC group, which suggested that linc00174 knockdown impaired the BTB integrity (Figure 1D).	('knockdown', 'Var', (146, 155))	('linc00174', 'Gene', (136, 145))	('linc00174', 'Gene', '285908', (136, 145))	('impaired', 'NegReg', (156, 164))	('BTB integrity', 'CPA', (169, 182))	('linc00174', 'Gene', (48, 57))	('linc00174', 'Gene', (93, 102))	('decreased', 'NegReg', (31, 40))	('linc00174', 'Gene', '285908', (48, 57))	('TEER values', 'MPA', (0, 11))	('linc00174', 'Gene', '285908', (93, 102))	('BTB', 'Chemical', '-', (169, 172))
29216	31791014	Quantitative real-time PCR were performed to detect the expression levels of miR-138-5p and miR-150-5p in GECs.	('miR-138-5p', 'Var', (77, 87))	('miR-150-5p', 'Chemical', '-', (92, 102))	('miR-150-5p', 'Var', (92, 102))	('miR-138-5p', 'Chemical', '-', (77, 87))
29217	31791014	Figures 2A and 2F showed that the expressions of miR-138-5p and miR-150-5p were significantly decreased in the GECs group compared with that in the AECs group.	('miR-138-5p', 'Var', (49, 59))	('expressions', 'MPA', (34, 45))	('miR-138-5p', 'Chemical', '-', (49, 59))	('decreased', 'NegReg', (94, 103))	('miR-150-5p', 'Chemical', '-', (64, 74))	('miR-150-5p', 'Var', (64, 74))	('GECs', 'Disease', (111, 115))
29218	31791014	To further clarify the effect of miR-138-5p and miR-150-5p on BTB permeability, overexpression and inhibition of miR-138-5p or miR-150-5p, respectively, were transiently transfected in GECs.	('miR-150-5p', 'Chemical', '-', (48, 58))	('miR-138-5p', 'Chemical', '-', (33, 43))	('miR-138-5p', 'Chemical', '-', (113, 123))	('BTB', 'Chemical', '-', (62, 65))	('miR-138-5p', 'Var', (113, 123))	('miR-150-5p', 'Chemical', '-', (127, 137))	('miR-150-5p', 'Var', (127, 137))
29220	31791014	However, the HRP flux in the miR-138-5p(+) or miR-150-5p(+) group was significantly higher than that in the miR-138-5p(+)NC or miR-150-5p(+)NC group.	('miR-138-5p', 'Chemical', '-', (108, 118))	('miR-138-5p', 'Chemical', '-', (29, 39))	('miR-150-5p(+', 'Var', (46, 58))	('miR-150-5p', 'Chemical', '-', (46, 56))	('HRP flux', 'MPA', (13, 21))	('miR-150-5p', 'Chemical', '-', (127, 137))	('higher', 'PosReg', (84, 90))
29221	31791014	The HRP flux in the miR-138-5p(-) or miR-150-5p(-) group was significantly lower than that in miR-138-5p(-) or miR-150-5p(-) group (Figures 2C and 2H).	('HRP flux', 'MPA', (4, 12))	('lower', 'NegReg', (75, 80))	('miR-138-5p', 'Chemical', '-', (94, 104))	('miR-150-5p', 'Chemical', '-', (111, 121))	('miR-150-5p', 'Chemical', '-', (37, 47))	('miR-138-5p', 'Chemical', '-', (20, 30))	('miR-150-5p(-', 'Var', (37, 49))
29222	31791014	These results demonstrated that overexpression of miR-138-5p or miR-150-5p increased the BTB permeability in GECs.	('miR-138-5p', 'Chemical', '-', (50, 60))	('BTB', 'Chemical', '-', (89, 92))	('miR-138-5p', 'Var', (50, 60))	('BTB permeability in', 'MPA', (89, 108))	('rat', 'Species', '10116', (21, 24))	('miR-150-5p', 'Chemical', '-', (64, 74))	('increased', 'PosReg', (75, 84))	('miR-150-5p', 'Var', (64, 74))
29224	31791014	As shown in Figures 2D and 2I, the expression of ZO-1, occludin, and claudin-5 were significantly decreased in the miR-138-5p(+) or miR-150-5p(+) group compared with the miR-138-5p(+)NC or miR-150-5p(+)NC group.	('ZO-1', 'Gene', '7082', (49, 53))	('miR-138-5p', 'Chemical', '-', (115, 125))	('occludin', 'Gene', (55, 63))	('miR-150-5p', 'Chemical', '-', (189, 199))	('miR-138-5p', 'Chemical', '-', (170, 180))	('miR-138-5p(+', 'Var', (115, 127))	('miR-150-5p(+', 'Var', (132, 144))	('expression', 'MPA', (35, 45))	('miR-150-5p', 'Chemical', '-', (132, 142))	('claudin-5', 'Gene', (69, 78))	('ZO-1', 'Gene', (49, 53))	('decreased', 'NegReg', (98, 107))	('occludin', 'Gene', '100506658', (55, 63))	('claudin-5', 'Gene', '7122', (69, 78))
29225	31791014	Those proteins were significantly increased in the miR-138-5p(-) or miR-150-5p(-) group.	('miR-138-5p', 'Chemical', '-', (51, 61))	('miR-138-5p', 'Var', (51, 61))	('increased', 'PosReg', (34, 43))	('miR-150-5p', 'Chemical', '-', (68, 78))	('miR-150-5p', 'Var', (68, 78))
29226	31791014	As shown in Figures 2E and 2J, the effects of miR-138-5p or miR-150-5p overexpression on ZO-1, occludin, and claudin-5 protein levels and distribution were determined via immunofluorescence staining.	('miR-138-5p', 'Chemical', '-', (46, 56))	('claudin-5', 'Gene', (109, 118))	('occludin', 'Gene', '100506658', (95, 103))	('miR-138-5p', 'Var', (46, 56))	('occludin', 'Gene', (95, 103))	('claudin-5', 'Gene', '7122', (109, 118))	('ZO-1', 'Gene', (89, 93))	('miR-150-5p', 'Chemical', '-', (60, 70))	('miR-150-5p', 'Var', (60, 70))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('ZO-1', 'Gene', '7082', (89, 93))
29227	31791014	The opposite results were observed in the miR-138-5p(-) or miR-150-5p(-) group.	('miR-138-5p', 'Var', (42, 52))	('miR-150-5p', 'Var', (59, 69))	('miR-150-5p', 'Chemical', '-', (59, 69))	('miR-138-5p', 'Chemical', '-', (42, 52))
29228	31791014	Database: starBase v2.0 was used to detect whether linc00174 has a potential binding site on miR-138-5p and miR-150-5p.	('miR-138-5p', 'Chemical', '-', (93, 103))	('binding', 'molecular_function', 'GO:0005488', ('77', '84'))	('miR-150-5p', 'Var', (108, 118))	('miR-138-5p', 'Var', (93, 103))	('linc00174', 'Gene', (51, 60))	('miR-150-5p', 'Chemical', '-', (108, 118))	('linc00174', 'Gene', '285908', (51, 60))	('binding', 'Interaction', (77, 84))
29230	31791014	Meanwhile, Figures 3A and 3H showed that the expressions of miR-138-5p and miR-150-5p were significantly increased after stable knock down of linc00174.	('knock down', 'Var', (128, 138))	('expressions', 'MPA', (45, 56))	('miR-138-5p', 'Chemical', '-', (60, 70))	('linc00174', 'Gene', (142, 151))	('linc00174', 'Gene', '285908', (142, 151))	('miR-150-5p', 'Chemical', '-', (75, 85))	('miR-150-5p', 'Var', (75, 85))	('miR-138-5p', 'Var', (60, 70))	('increased', 'PosReg', (105, 114))	('3H', 'Chemical', 'MESH:D014316', (26, 28))
29231	31791014	However, linc00174 expression was decreased in the miR-138-5p(+) or miR-150-5p(+) group and increased in the miR-138-5p(-) or miR-150-5p(-) group (Figures 3B and 3I).	('miR-138-5p', 'Chemical', '-', (51, 61))	('expression', 'MPA', (19, 29))	('decreased', 'NegReg', (34, 43))	('miR-138-5p', 'Chemical', '-', (109, 119))	('increased', 'PosReg', (92, 101))	('miR-138-5p', 'Var', (109, 119))	('miR-150-5p', 'Chemical', '-', (68, 78))	('linc00174', 'Gene', '285908', (9, 18))	('linc00174', 'Gene', (9, 18))	('miR-150-5p', 'Chemical', '-', (126, 136))	('miR-150-5p(+', 'Var', (68, 80))
29232	31791014	The above results indicated that linc00174 and miR-138-5p or miR-150-5p were reciprocally repressed.	('miR-138-5p', 'Chemical', '-', (47, 57))	('miR-138-5p', 'Var', (47, 57))	('miR-150-5p', 'Var', (61, 71))	('linc00174', 'Gene', (33, 42))	('miR-150-5p', 'Chemical', '-', (61, 71))	('linc00174', 'Gene', '285908', (33, 42))
29233	31791014	Luciferase activity was not significantly different in cells co-transfected with miR-138-5p(+) or miR-150-5p(+) and linc00174-Mut.	('linc00174', 'Gene', (116, 125))	('Luciferase activity', 'molecular_function', 'GO:0050397', ('0', '19'))	('activity', 'MPA', (11, 19))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('0', '19'))	('miR-138-5p', 'Chemical', '-', (81, 91))	('Luciferase activity', 'molecular_function', 'GO:0047712', ('0', '19'))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('0', '19'))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('0', '19'))	('miR-150-5p', 'Chemical', '-', (98, 108))	('Luciferase', 'Enzyme', (0, 10))	('miR-150-5p(+', 'Var', (98, 110))	('linc00174', 'Gene', '285908', (116, 125))
29234	31791014	However, luciferase activity was significantly decreased in cells co-transfected in miR-138-5p(+) or miR-150-5p(+) and linc00174-wild-type (Wt) (Figures 3C and 3J).	('luciferase', 'Enzyme', (9, 19))	('activity', 'MPA', (20, 28))	('luciferase activity', 'molecular_function', 'GO:0050397', ('9', '28'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('9', '28'))	('miR-138-5p', 'Chemical', '-', (84, 94))	('linc00174', 'Gene', '285908', (119, 128))	('linc00174', 'Gene', (119, 128))	('luciferase activity', 'molecular_function', 'GO:0047077', ('9', '28'))	('miR-150-5p', 'Var', (101, 111))	('miR-150-5p', 'Chemical', '-', (101, 111))	('luciferase activity', 'molecular_function', 'GO:0045289', ('9', '28'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('9', '28'))	('decreased', 'NegReg', (47, 56))
29235	31791014	An RNA immunoprecipitation (RIP) assay was performed and showed that the enrichment of linc00174 and miR-138-5p or miR-150-5p was higher in the anti-Ago2 group than that in the anti-normal immunoglobulin G (IgG) group.	('Ago2', 'Gene', '27161', (149, 153))	('miR-138-5p', 'Chemical', '-', (101, 111))	('miR-150-5p', 'Chemical', '-', (115, 125))	('higher', 'PosReg', (130, 136))	('miR-150-5p', 'Var', (115, 125))	('linc00174', 'Gene', (87, 96))	('RNA', 'cellular_component', 'GO:0005562', ('3', '6'))	('miR-138-5p', 'Var', (101, 111))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('189', '203'))	('linc00174', 'Gene', '285908', (87, 96))	('Ago2', 'Gene', (149, 153))	('enrichment', 'MPA', (73, 83))
29236	31791014	However, knock down of miR-138-5p or miR-150-5p reduced the enrichment of linc00174 and miR-138-5p or miR-150-5p in Ago2 precipitates (Figures 3D and 3K).	('enrichment', 'MPA', (60, 70))	('knock down', 'Var', (9, 19))	('miR-138-5p', 'Var', (88, 98))	('miR-138-5p', 'Chemical', '-', (88, 98))	('reduced', 'NegReg', (48, 55))	('miR-138-5p', 'Chemical', '-', (23, 33))	('miR-150-5p', 'Chemical', '-', (37, 47))	('miR-150-5p', 'Var', (37, 47))	('Ago2', 'Gene', '27161', (116, 120))	('miR-138-5p', 'Var', (23, 33))	('miR-150-5p', 'Var', (102, 112))	('linc00174', 'Gene', (74, 83))	('miR-150-5p', 'Chemical', '-', (102, 112))	('Ago2', 'Gene', (116, 120))	('linc00174', 'Gene', '285908', (74, 83))
29237	31791014	Having confirmed that miR-138-5p and miR-150-5p were negatively regulated by linc00174, we further speculated that miR-138-5p and miR-150-5p might be involved in the effects of linc00174 knockdown on BTB permeability.	('miR-138-5p', 'Chemical', '-', (115, 125))	('BTB', 'Chemical', '-', (200, 203))	('involved', 'Reg', (150, 158))	('miR-138-5p', 'Var', (115, 125))	('miR-138-5p', 'Chemical', '-', (22, 32))	('miR-150-5p', 'Chemical', '-', (37, 47))	('miR-138-5p', 'Gene', (22, 32))	('negatively', 'NegReg', (53, 63))	('linc00174', 'Gene', '285908', (77, 86))	('miR-150-5p', 'Chemical', '-', (130, 140))	('miR-150-5p', 'Var', (130, 140))	('linc00174', 'Gene', (77, 86))	('linc00174', 'Gene', (177, 186))	('linc00174', 'Gene', '285908', (177, 186))
29238	31791014	Overexpression or knockdown of miR-138-5p or miR-150-5p was co-transfected in GECs with linc00174 inhibition.	('miR-150-5p', 'Var', (45, 55))	('miR-150-5p', 'Chemical', '-', (45, 55))	('miR-138-5p', 'Var', (31, 41))	('miR-138-5p', 'Chemical', '-', (31, 41))	('linc00174', 'Gene', (88, 97))	('linc00174', 'Gene', '285908', (88, 97))
29239	31791014	As shown in Figures 3E and 3L, TEER values were significant decreased in the GECs with miR-138-5p or miR-150-5p overexpression, which stably knocked down linc00174.	('decreased', 'NegReg', (60, 69))	('linc00174', 'Gene', (154, 163))	('miR-138-5p', 'Var', (87, 97))	('overexpression', 'PosReg', (112, 126))	('linc00174', 'Gene', '285908', (154, 163))	('miR-150-5p', 'Var', (101, 111))	('miR-150-5p', 'Chemical', '-', (101, 111))	('miR-138-5p', 'Chemical', '-', (87, 97))
29240	31791014	However, miR-138-5p or miR-150-5p inhibition, which stably knocked down linc00174, largely rescued the inhibition effect of linc00174(-) on TEER values.	('rescued', 'PosReg', (91, 98))	('miR-138-5p', 'Var', (9, 19))	('inhibition', 'MPA', (103, 113))	('linc00174', 'Gene', '285908', (72, 81))	('linc00174', 'Gene', (72, 81))	('linc00174', 'Gene', '285908', (124, 133))	('linc00174', 'Gene', (124, 133))	('knocked', 'NegReg', (59, 66))	('miR-150-5p', 'Var', (23, 33))	('miR-150-5p', 'Chemical', '-', (23, 33))	('miR-138-5p', 'Chemical', '-', (9, 19))
29241	31791014	Similarly, miR-138-5p or miR-150-5p inhibition, which stably knocked down linc00174, largely rescued the promotion effect of linc00174(-) on HRP flux (Figures 3F and 3M).	('miR-150-5p', 'Var', (25, 35))	('HRP flux', 'MPA', (141, 149))	('linc00174', 'Gene', (125, 134))	('linc00174', 'Gene', '285908', (74, 83))	('miR-138-5p', 'Var', (11, 21))	('promotion', 'PosReg', (105, 114))	('linc00174', 'Gene', '285908', (125, 134))	('miR-138-5p', 'Chemical', '-', (11, 21))	('linc00174', 'Gene', (74, 83))	('miR-150-5p', 'Chemical', '-', (25, 35))	('rescued', 'NegReg', (93, 100))
29243	31791014	The expressions of ZO-1, occludin, and claudin-5 were decreased after overexpression of miR-138-5p or miR-150-5p, which stably knocked down linc00174.	('claudin-5', 'Gene', (39, 48))	('linc00174', 'Gene', (140, 149))	('ZO-1', 'Gene', (19, 23))	('miR-138-5p', 'Chemical', '-', (88, 98))	('miR-138-5p', 'Var', (88, 98))	('linc00174', 'Gene', '285908', (140, 149))	('claudin-5', 'Gene', '7122', (39, 48))	('expressions', 'MPA', (4, 15))	('ZO-1', 'Gene', '7082', (19, 23))	('decreased', 'NegReg', (54, 63))	('miR-150-5p', 'Var', (102, 112))	('occludin', 'Gene', '100506658', (25, 33))	('miR-150-5p', 'Chemical', '-', (102, 112))	('occludin', 'Gene', (25, 33))
29244	31791014	However, miR-138-5p or miR-150-5p inhibition, which stably knocked down linc00174, largely rescued the inhibition effect of linc00174(-) on ZO-1, occludin, and claudin-5 expression (Figures 3G and 3N).	('rescued', 'PosReg', (91, 98))	('claudin-5', 'Gene', '7122', (160, 169))	('occludin', 'Gene', '100506658', (146, 154))	('claudin-5', 'Gene', (160, 169))	('miR-138-5p', 'Var', (9, 19))	('occludin', 'Gene', (146, 154))	('linc00174', 'Gene', (72, 81))	('ZO-1', 'Gene', (140, 144))	('linc00174', 'Gene', '285908', (72, 81))	('miR-138-5p', 'Chemical', '-', (9, 19))	('linc00174', 'Gene', (124, 133))	('linc00174', 'Gene', '285908', (124, 133))	('ZO-1', 'Gene', '7082', (140, 144))	('miR-150-5p', 'Var', (23, 33))	('miR-150-5p', 'Chemical', '-', (23, 33))	('expression', 'MPA', (170, 180))	('inhibition', 'NegReg', (103, 113))
29247	31791014	Similar to western blot, immunofluorescence staining revealed that ZO-1, occludin, and claudin-5 exhibited a discontinuous distribution and decrease in the FOSL2(-) group compared with the FOSL2(-)NC group.	('occludin', 'Gene', '100506658', (73, 81))	('ZO-1', 'Gene', (67, 71))	('occludin', 'Gene', (73, 81))	('decrease', 'NegReg', (140, 148))	('ZO-1', 'Gene', '7082', (67, 71))	('claudin-5', 'Gene', (87, 96))	('claudin-5', 'Gene', '7122', (87, 96))	('FOSL2(-', 'Var', (156, 163))
29250	31791014	Furthermore, we assessed the effects of miR-138-5p or miR-150-5p overexpression and inhibition on the expression of FOSL2.	('inhibition', 'NegReg', (84, 94))	('miR-138-5p', 'Chemical', '-', (40, 50))	('FOSL2', 'Gene', (116, 121))	('miR-150-5p', 'Chemical', '-', (54, 64))	('miR-138-5p', 'Var', (40, 50))	('miR-150-5p', 'Var', (54, 64))
29251	31791014	Figures 5C-5F show that miR-138-5p or miR-150-5p overexpression decreased the mRNA and protein expression of FOSL2, whereas miR-138-5p or miR-150-5p inhibition exerted the opposite effects.	('miR-138-5p', 'Chemical', '-', (124, 134))	('miR-150-5p', 'Gene', (38, 48))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('miR-150-5p', 'Chemical', '-', (138, 148))	('FOSL2', 'Gene', (109, 114))	('miR-138-5p', 'Chemical', '-', (24, 34))	('miR-150-5p', 'Chemical', '-', (38, 48))	('miR-138-5p', 'Var', (24, 34))	('decreased', 'NegReg', (64, 73))
29253	31791014	However, miR-138-5p(+) and miR-150-5p(+) rescued the effects on FOSL2 expression decreased by linc00174(-).	('decreased', 'NegReg', (81, 90))	('miR-150-5p', 'Chemical', '-', (27, 37))	('linc00174', 'Gene', (94, 103))	('FOSL2', 'Gene', (64, 69))	('linc00174', 'Gene', '285908', (94, 103))	('miR-150-5p', 'Var', (27, 37))	('miR-138-5p', 'Chemical', '-', (9, 19))
29254	31791014	Furthermore, a luciferase assay was performed to detect whether FOSL2 was a direct target of miR-138-5p and miR-150-5p in GECs.	('miR-138-5p', 'Var', (93, 103))	('miR-150-5p', 'Chemical', '-', (108, 118))	('miR-138-5p', 'Chemical', '-', (93, 103))	('miR-150-5p', 'Var', (108, 118))
29256	31791014	However, luciferase activity was significantly decreased in cells co-transfected with miR-138-5p(+) or miR-150-5p(+) and FOSL2-3' UTR-Wt, compared with miR-138-5p(+)NC or miR-150-5p(+)NC and FOSL2-3' UTR-Wt.	('luciferase', 'Enzyme', (9, 19))	('activity', 'MPA', (20, 28))	('luciferase activity', 'molecular_function', 'GO:0050397', ('9', '28'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('9', '28'))	('miR-150-5p', 'Chemical', '-', (103, 113))	('miR-138-5p', 'Chemical', '-', (152, 162))	('miR-138-5p(+', 'Var', (86, 98))	('miR-150-5p(+', 'Var', (103, 115))	("FOSL2-3' UTR-Wt", 'Var', (121, 136))	('luciferase activity', 'molecular_function', 'GO:0047077', ('9', '28'))	('miR-150-5p', 'Chemical', '-', (171, 181))	('luciferase activity', 'molecular_function', 'GO:0045289', ('9', '28'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('9', '28'))	('miR-138-5p', 'Chemical', '-', (86, 96))	('decreased', 'NegReg', (47, 56))
29257	31791014	The results suggested that FOSL2 was a directed target of both miR-138-5p and miR-150-5p.	('miR-138-5p', 'Var', (63, 73))	('miR-150-5p', 'Chemical', '-', (78, 88))	('miR-150-5p', 'Var', (78, 88))	('miR-138-5p', 'Chemical', '-', (63, 73))	('FOSL2', 'Gene', (27, 32))
29258	31791014	To clarify whether FOSL2 was involved in miR-138-5p or miR-150-5p overexpression in regulating BTB permeability, co-transfections between miR-138-5p or miR-150-5p and FOSL2 were conducted.	('miR-138-5p', 'Chemical', '-', (138, 148))	('regulating BTB permeability', 'MPA', (84, 111))	('BTB', 'Chemical', '-', (95, 98))	('miR-138-5p', 'Var', (138, 148))	('miR-150-5p', 'Chemical', '-', (55, 65))	('miR-150-5p', 'Chemical', '-', (152, 162))	('miR-138-5p', 'Chemical', '-', (41, 51))
29259	31791014	Results showed that overexpression of FOSL2 with overexpression of miR-138-5p or miR-150-5p rescued the promotion effects on miR-138-5p or miR-150-5p overexpression on BTB permeability (Figures 6A, 6B, 6E, and 6F).	('miR-138-5p', 'Chemical', '-', (67, 77))	('miR-138-5p', 'Var', (125, 135))	('BTB permeability', 'MPA', (168, 184))	('promotion', 'PosReg', (104, 113))	('miR-150-5p', 'Chemical', '-', (139, 149))	('miR-150-5p', 'Var', (139, 149))	('BTB', 'Chemical', '-', (168, 171))	('miR-150-5p', 'Chemical', '-', (81, 91))	('miR-150-5p', 'Var', (81, 91))	('miR-138-5p', 'Chemical', '-', (125, 135))
29260	31791014	Furthermore, FOSL2 overexpression largely rescued the effects on ZO-1, occludin, and claudin-5 downregulated by miR-138-5p or miR-150-5p overexpression (Figures 6C, 6D, 6G, and 6H).	('downregulated', 'NegReg', (95, 108))	('miR-150-5p', 'Chemical', '-', (126, 136))	('claudin-5', 'Gene', (85, 94))	('miR-138-5p', 'Chemical', '-', (112, 122))	('occludin', 'Gene', '100506658', (71, 79))	('overexpression', 'PosReg', (137, 151))	('claudin-5', 'Gene', '7122', (85, 94))	('miR-138-5p', 'Var', (112, 122))	('miR-150-5p', 'Var', (126, 136))	('ZO-1', 'Gene', (65, 69))	('occludin', 'Gene', (71, 79))	('ZO-1', 'Gene', '7082', (65, 69))
29261	31791014	These results suggested that FOSL2 was involved in the effects of miR-138-5p or miR-150-5p overexpression on BTB permeability.	('involved', 'Reg', (39, 47))	('miR-138-5p', 'Var', (66, 76))	('miR-150-5p', 'Var', (80, 90))	('BTB', 'Chemical', '-', (109, 112))	('miR-150-5p', 'Chemical', '-', (80, 90))	('BTB permeability', 'MPA', (109, 125))	('miR-138-5p', 'Chemical', '-', (66, 76))
29262	31791014	Knock down of FOSL2 reduced the expression of mRNA and protein of ZO-1, occludin, and claudin-5.	('ZO-1', 'Gene', '7082', (66, 70))	('Knock down', 'Var', (0, 10))	('reduced', 'NegReg', (20, 27))	('occludin', 'Gene', '100506658', (72, 80))	('occludin', 'Gene', (72, 80))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('ZO-1', 'Gene', (66, 70))	('FOSL2', 'Gene', (14, 19))	('claudin-5', 'Gene', (86, 95))	('claudin-5', 'Gene', '7122', (86, 95))
29273	31791014	Figure 7G shows that linc00174 expression was significantly increased in the FOSL2(+) group, compared with the FOSL2(+)NC group.	('linc00174', 'Gene', (21, 30))	('linc00174', 'Gene', '285908', (21, 30))	('expression', 'MPA', (31, 41))	('FOSL2(+', 'Var', (77, 84))	('increased', 'PosReg', (60, 69))
29274	31791014	However, linc00174 expression was decreased in the FOSL2(-) group, compared with the FOSL2(-)NC group.	('expression', 'MPA', (19, 29))	('decreased', 'NegReg', (34, 43))	('FOSL2(-', 'Var', (51, 58))	('linc00174', 'Gene', '285908', (9, 18))	('linc00174', 'Gene', (9, 18))
29277	31791014	Figure 7H shows that deletion of the region surrounding the -1886 site significantly increased linc00174 promoter activity.	('linc00174', 'Gene', '285908', (95, 104))	('linc00174', 'Gene', (95, 104))	('increased', 'PosReg', (85, 94))	('deletion', 'Var', (21, 29))
29278	31791014	However, deletion of the region surrounding the -1716 site significantly reduced linc00174 promoter activity.	('reduced', 'NegReg', (73, 80))	('linc00174', 'Gene', '285908', (81, 90))	('linc00174', 'Gene', (81, 90))	('deletion', 'Var', (9, 17))
29281	31791014	In this study, we co-transfected knock down of linc00174 and overexpression of miR-138-5p or miR-150-5p and co-transfected miR-138-5p or miR-150-5p overexpression separately.	('miR-150-5p', 'Chemical', '-', (137, 147))	('linc00174', 'Gene', (47, 56))	('linc00174', 'Gene', '285908', (47, 56))	('overexpression', 'PosReg', (61, 75))	('miR-150-5p', 'Var', (93, 103))	('knock down', 'Var', (33, 43))	('miR-150-5p', 'Chemical', '-', (93, 103))	('miR-138-5p', 'Chemical', '-', (123, 133))	('miR-138-5p', 'Chemical', '-', (79, 89))	('rat', 'Species', '10116', (167, 170))	('miR-138-5p', 'Var', (79, 89))
29283	31791014	As shown in Figure 8A, the apoptosis rate of U87 in the Dox group is significantly higher than that in the control group.	('U87', 'Var', (45, 48))	('Dox', 'Chemical', 'MESH:D004317', (56, 59))	('U87', 'CellLine', 'CVCL:0022', (45, 48))	('rat', 'Species', '10116', (37, 40))	('apoptosis rate', 'CPA', (27, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('higher', 'PosReg', (83, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))
29286	31791014	However, the apoptosis rate in the miR-138-5p(+)+miR-150-5p(+)+Dox group was higher than in the miR-138-5p(+)+miR-150-5p(+) group.	('miR-138-5p(+', 'Var', (35, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('higher', 'PosReg', (77, 83))	('miR-150-5p', 'Chemical', '-', (110, 120))	('miR-150-5p', 'Chemical', '-', (49, 59))	('rat', 'Species', '10116', (23, 26))	('apoptosis rate', 'CPA', (13, 27))	('miR-138-5p', 'Chemical', '-', (96, 106))	('miR-138-5p', 'Chemical', '-', (35, 45))	('Dox', 'Chemical', 'MESH:D004317', (63, 66))
29290	31791014	Knock down of linc00174 increased the BTB permeability and decreased the expression of tight junction proteins ZO-1, occludin, and claudin-5 by binding to miR-138-5p and miR-150-5p, which were downregulated in GECs.	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('miR-150-5p', 'Var', (170, 180))	('BTB', 'Chemical', '-', (38, 41))	('BTB permeability', 'MPA', (38, 54))	('ZO-1', 'Gene', '7082', (111, 115))	('occludin', 'Gene', (117, 125))	('tight junction', 'cellular_component', 'GO:0070160', ('87', '101'))	('expression', 'MPA', (73, 83))	('ZO-1', 'Gene', (111, 115))	('Knock down', 'Var', (0, 10))	('claudin-5', 'Gene', (131, 140))	('miR-138-5p', 'Chemical', '-', (155, 165))	('miR-138-5p', 'Var', (155, 165))	('linc00174', 'Gene', '285908', (14, 23))	('linc00174', 'Gene', (14, 23))	('miR-150-5p', 'Chemical', '-', (170, 180))	('increased', 'PosReg', (24, 33))	('decreased', 'NegReg', (59, 68))	('binding', 'Interaction', (144, 151))	('occludin', 'Gene', '100506658', (117, 125))	('claudin-5', 'Gene', '7122', (131, 140))
29294	31791014	In addition, combination of linc00174 knockdown and miR-138-5p overexpression or miR-150-5p overexpression and treated with Dox enhanced the anti-tumor effects of Dox.	('miR-138-5p', 'Var', (52, 62))	('Dox', 'Chemical', 'MESH:D004317', (163, 166))	('Dox', 'Chemical', 'MESH:D004317', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('linc00174', 'Gene', '285908', (28, 37))	('linc00174', 'Gene', (28, 37))	('tumor', 'Disease', (146, 151))	('enhanced', 'PosReg', (128, 136))	('miR-150-5p', 'Chemical', '-', (81, 91))	('miR-150-5p', 'Var', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('knockdown', 'Var', (38, 47))	('miR-138-5p', 'Chemical', '-', (52, 62))	('overexpression', 'PosReg', (63, 77))
29299	31791014	Emerging evidence shows that non-coding RNAs are not only involved in regulating tumor development, but they regulate BTB permeability as well.	('BTB', 'Chemical', '-', (118, 121))	('regulate', 'Reg', (109, 117))	('BTB permeability', 'MPA', (118, 134))	('non-coding RNAs', 'Var', (29, 44))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
29306	31791014	Knock down of linc00174 increased the permeability of the BTB by downregulating the expression of tight junction proteins ZO-1, occludin, and claudin-5, indicating that linc00174 inhibition increased the permeability of the BTB through the paracellular pathway.	('tight junction', 'cellular_component', 'GO:0070160', ('98', '112'))	('ZO-1', 'Gene', (122, 126))	('linc00174', 'Gene', (169, 178))	('permeability', 'MPA', (38, 50))	('linc00174', 'Gene', '285908', (169, 178))	('permeability', 'MPA', (204, 216))	('BTB', 'Chemical', '-', (58, 61))	('inhibition', 'NegReg', (179, 189))	('Knock down', 'Var', (0, 10))	('occludin', 'Gene', '100506658', (128, 136))	('claudin-5', 'Gene', '7122', (142, 151))	('linc00174', 'Gene', '285908', (14, 23))	('linc00174', 'Gene', (14, 23))	('BTB', 'Chemical', '-', (224, 227))	('expression', 'MPA', (84, 94))	('increased', 'PosReg', (24, 33))	('paracellular pathway', 'Pathway', (240, 260))	('downregulating', 'NegReg', (65, 79))	('occludin', 'Gene', (128, 136))	('increased', 'PosReg', (190, 199))	('claudin-5', 'Gene', (142, 151))	('ZO-1', 'Gene', '7082', (122, 126))
29309	31791014	miR-138-5p is involved in the regulation of the pathological process of many diseases.	('involved', 'Reg', (14, 22))	('miR-138-5p', 'Chemical', '-', (0, 10))	('regulation', 'biological_process', 'GO:0065007', ('30', '40'))	('miR-138-5p', 'Var', (0, 10))
29310	31791014	miR-138-5p shows low expression in osteoarthritis, and it acts as a tumor suppressor in bladder cancer.	('tumor', 'Disease', (68, 73))	('osteoarthritis', 'Disease', (35, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('osteoarthritis', 'Disease', 'MESH:D010003', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('expression', 'MPA', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('miR-138-5p', 'Chemical', '-', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('osteoarthritis', 'Phenotype', 'HP:0002758', (35, 49))	('miR-138-5p', 'Var', (0, 10))
29311	31791014	Moreover, in retinoblastoma, overexpression of miR-138-5p decreased the expression of pyruvate dehydrogenase kinase 1 (PDK1), repressed retinoblastoma cell viability, migration, and invasion, and induced apoptosis of retinoblastoma cells.	('overexpression', 'PosReg', (29, 43))	('PDK1', 'molecular_function', 'GO:0004740', ('119', '123'))	('miR-138-5p', 'Chemical', '-', (47, 57))	('decreased', 'NegReg', (58, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('miR-138-5p', 'Var', (47, 57))	('retinoblastoma', 'Disease', 'MESH:D012175', (217, 231))	('apoptosis', 'CPA', (204, 213))	('PDK1', 'Gene', '5163', (119, 123))	('retinoblastoma', 'Phenotype', 'HP:0009919', (13, 27))	('expression', 'MPA', (72, 82))	('retinoblastoma', 'Disease', 'MESH:D012175', (136, 150))	('retinoblastoma', 'Disease', (13, 27))	('retinoblastoma', 'Phenotype', 'HP:0009919', (217, 231))	('induced', 'Reg', (196, 203))	('retinoblastoma', 'Disease', (217, 231))	('retinoblastoma', 'Phenotype', 'HP:0009919', (136, 150))	('PDK1', 'Gene', (119, 123))	('rat', 'Species', '10116', (170, 173))	('pyruvate dehydrogenase kinase 1', 'Gene', (86, 117))	('migration', 'CPA', (167, 176))	('repressed', 'PosReg', (126, 135))	('retinoblastoma', 'Disease', (136, 150))	('invasion', 'CPA', (182, 190))	('pyruvate dehydrogenase kinase 1', 'Gene', '5163', (86, 117))	('retinoblastoma', 'Disease', 'MESH:D012175', (13, 27))
29312	31791014	In addition, miR-150-5p is downregulated in circulating blood of patients with delayed myasthenia gravis and acts as a biomarker.	('myasthenia gravis', 'Disease', (87, 104))	('myasthenia gravis', 'Disease', 'MESH:D009157', (87, 104))	('downregulated', 'NegReg', (27, 40))	('patients', 'Species', '9606', (65, 73))	('miR-150-5p', 'Var', (13, 23))	('myasthenia', 'Phenotype', 'HP:0003473', (87, 97))	('miR-150-5p', 'Chemical', '-', (13, 23))
29313	31791014	miR-150-5p is downregulated in head and neck squamous carcinoma cells.	('miR-150-5p', 'Var', (0, 10))	('neck squamous carcinoma', 'Disease', (40, 63))	('miR-150-5p', 'Chemical', '-', (0, 10))	('head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (31, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('downregulated', 'NegReg', (14, 27))	('neck', 'cellular_component', 'GO:0044326', ('40', '44'))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (45, 63))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (40, 63))
29314	31791014	Overexpression of miR-150-5p inhibits the proliferation, migration, invasion, and epithelial interstitial transformation of non-small cell lung cancer cells.	('miR-150-5p', 'Var', (18, 28))	('non-small cell lung cancer', 'Disease', (124, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('miR-150-5p', 'Chemical', '-', (18, 28))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('invasion', 'CPA', (68, 76))	('rat', 'Species', '10116', (60, 63))	('migration', 'CPA', (57, 66))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('epithelial interstitial transformation', 'CPA', (82, 120))	('inhibits', 'NegReg', (29, 37))	('rat', 'Species', '10116', (49, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (124, 150))
29315	31791014	In this study, we found that miR-138-5p and miR-150-5p were downregulated in GECs.	('GECs', 'Disease', (77, 81))	('miR-138-5p', 'Chemical', '-', (29, 39))	('miR-138-5p', 'Var', (29, 39))	('miR-150-5p', 'Var', (44, 54))	('miR-150-5p', 'Chemical', '-', (44, 54))	('downregulated', 'NegReg', (60, 73))
29316	31791014	Overexpressing miR-138-5p or miR-150-5p, respectively, increased BTB permeability and decreased the expression and distribution of ZO-1, occludin, and claudin-5.	('miR-138-5p', 'Chemical', '-', (15, 25))	('ZO-1', 'Gene', (131, 135))	('BTB permeability', 'MPA', (65, 81))	('miR-138-5p', 'Var', (15, 25))	('miR-150-5p', 'Var', (29, 39))	('ZO-1', 'Gene', '7082', (131, 135))	('increased', 'PosReg', (55, 64))	('occludin', 'Gene', '100506658', (137, 145))	('miR-150-5p', 'Chemical', '-', (29, 39))	('expression', 'MPA', (100, 110))	('distribution', 'MPA', (115, 127))	('decreased', 'NegReg', (86, 95))	('claudin-5', 'Gene', (151, 160))	('BTB', 'Chemical', '-', (65, 68))	('occludin', 'Gene', (137, 145))	('claudin-5', 'Gene', '7122', (151, 160))
29319	31791014	In our study, knock down of linc00174 increased the expression of miR-138-5p and miR-150-5p.	('miR-138-5p', 'Var', (66, 76))	('knock down', 'Var', (14, 24))	('linc00174', 'Gene', '285908', (28, 37))	('linc00174', 'Gene', (28, 37))	('expression', 'MPA', (52, 62))	('miR-150-5p', 'Chemical', '-', (81, 91))	('miR-150-5p', 'Var', (81, 91))	('miR-138-5p', 'Chemical', '-', (66, 76))	('increased', 'PosReg', (38, 47))
29320	31791014	Furthermore, bioinformatics analysis (starBase v2.0) and a luciferase reporter assay were used to find miR-138-5p and miR-150-5p direct binding, respectively, to linc00174.	('miR-150-5p', 'Chemical', '-', (118, 128))	('linc00174', 'Gene', '285908', (162, 171))	('miR-150-5p', 'Var', (118, 128))	('linc00174', 'Gene', (162, 171))	('miR-138-5p', 'Var', (103, 113))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('miR-138-5p', 'Chemical', '-', (103, 113))	('binding', 'Interaction', (136, 143))
29321	31791014	Moreover, upregulation of miR-138-5p or miR-150-5p suppressed the linc00174 expression; however, downregulating miR-138-5p or miR-150-5p showed the opposite results, which indicated that there was a reciprocal repression between linc00174 and miR-138-5p or miR-150-5p.	('miR-150-5p', 'Chemical', '-', (257, 267))	('miR-138-5p', 'Chemical', '-', (112, 122))	('linc00174', 'Gene', (66, 75))	('linc00174', 'Gene', '285908', (66, 75))	('miR-138-5p', 'Chemical', '-', (26, 36))	('suppressed', 'NegReg', (51, 61))	('expression', 'MPA', (76, 86))	('downregulating', 'NegReg', (97, 111))	('miR-138-5p', 'Var', (26, 36))	('miR-150-5p', 'Var', (40, 50))	('linc00174', 'Gene', (229, 238))	('miR-150-5p', 'Chemical', '-', (40, 50))	('linc00174', 'Gene', '285908', (229, 238))	('miR-150-5p', 'Chemical', '-', (126, 136))	('upregulation', 'PosReg', (10, 22))	('miR-138-5p', 'Chemical', '-', (243, 253))
29326	31791014	Moreover, FOSL2 is abundantly detected in ECs and vascular smooth muscle cells of SSc lesional skin, and silencing FOSL2 promotes angiogenesis in human microvascular ECs.	('FOSL2', 'Gene', (115, 120))	('angiogenesis', 'CPA', (130, 142))	('human', 'Species', '9606', (146, 151))	('promotes', 'PosReg', (121, 129))	('angiogenesis', 'biological_process', 'GO:0001525', ('130', '142'))	('silencing', 'Var', (105, 114))
29327	31791014	Knock down of FOSL2 increased BTB permeability and decreased the expression of ZO-1, occludin, and claudin-5.	('increased', 'PosReg', (20, 29))	('occludin', 'Gene', (85, 93))	('claudin-5', 'Gene', (99, 108))	('BTB', 'Chemical', '-', (30, 33))	('decreased', 'NegReg', (51, 60))	('claudin-5', 'Gene', '7122', (99, 108))	('expression', 'MPA', (65, 75))	('occludin', 'Gene', '100506658', (85, 93))	('ZO-1', 'Gene', (79, 83))	('FOSL2', 'Gene', (14, 19))	('Knock down', 'Var', (0, 10))	('BTB permeability', 'MPA', (30, 46))	('ZO-1', 'Gene', '7082', (79, 83))
29330	31791014	The results of bioinformatics analysis and luciferase assays indicated that FOSL2 was one of the direct targets of miR-138-5p and miR-150-5p in regulating the permeability of the BTB.	('miR-138-5p', 'Chemical', '-', (115, 125))	('FOSL2', 'Gene', (76, 81))	('miR-138-5p', 'Var', (115, 125))	('permeability of the BTB', 'MPA', (159, 182))	('BTB', 'Chemical', '-', (179, 182))	('miR-150-5p', 'Chemical', '-', (130, 140))	('miR-150-5p', 'Var', (130, 140))
29331	31791014	Furthermore, overexpression of FOSL2, which stably overexpresses miR-138-5p or miR-150-5p, largely rescued the regulation of miR-138-5p and miR-150-5p on BTB permeability through downregulating the expression of ZO-1, occludin, and claudin-5.	('miR-138-5p', 'Chemical', '-', (65, 75))	('miR-150-5p', 'Chemical', '-', (140, 150))	('miR-138-5p', 'Chemical', '-', (125, 135))	('downregulating', 'NegReg', (179, 193))	('miR-138-5p', 'Var', (125, 135))	('rescued', 'PosReg', (99, 106))	('BTB', 'Chemical', '-', (154, 157))	('occludin', 'Gene', '100506658', (218, 226))	('claudin-5', 'Gene', '7122', (232, 241))	('ZO-1', 'Gene', '7082', (212, 216))	('expression', 'MPA', (198, 208))	('regulation', 'MPA', (111, 121))	('ZO-1', 'Gene', (212, 216))	('regulation', 'biological_process', 'GO:0065007', ('111', '121'))	('miR-150-5p', 'Var', (140, 150))	('occludin', 'Gene', (218, 226))	('BTB permeability', 'MPA', (154, 170))	('miR-150-5p', 'Chemical', '-', (79, 89))	('claudin-5', 'Gene', (232, 241))
29339	31791014	Knock down of FOSL2 in human adipocytes decreased leptin (LEP) expression at the transcriptional level, reducing adiposity.	('LEP', 'Gene', (58, 61))	('leptin', 'Gene', '3952', (50, 56))	('adipocytes decreased', 'Phenotype', 'HP:0040063', (29, 49))	('adiposity', 'MPA', (113, 122))	('leptin', 'Gene', (50, 56))	('LEP', 'Gene', '3952', (58, 61))	('expression', 'MPA', (63, 73))	('reducing', 'NegReg', (104, 112))	('reducing adiposity', 'Phenotype', 'HP:0040063', (104, 122))	('human', 'Species', '9606', (23, 28))	('decreased leptin', 'Phenotype', 'HP:0003292', (40, 56))	('FOSL2', 'Gene', (14, 19))	('Knock down', 'Var', (0, 10))	('decreased', 'NegReg', (40, 49))
29345	31791014	However, inhibition of FOSL2 decreased linc00174 expression.	('linc00174', 'Gene', '285908', (39, 48))	('FOSL2', 'Gene', (23, 28))	('decreased', 'NegReg', (29, 38))	('inhibition', 'Var', (9, 19))	('linc00174', 'Gene', (39, 48))
29352	31791014	Remarkably, we finally demonstrated that knock down of linc00174 combined with overexpression of miR-138-5p or miR-150-5p, which when treated with Dox significantly increased glioma cell apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('187', '196'))	('miR-150-5p', 'Var', (111, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('187', '196'))	('miR-138-5p', 'Chemical', '-', (97, 107))	('miR-138-5p', 'Var', (97, 107))	('miR-150-5p', 'Chemical', '-', (111, 121))	('rat', 'Species', '10116', (30, 33))	('linc00174', 'Gene', '285908', (55, 64))	('glioma', 'Disease', (175, 181))	('linc00174', 'Gene', (55, 64))	('Dox', 'Chemical', 'MESH:D004317', (147, 150))	('increased', 'PosReg', (165, 174))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('knock down', 'Var', (41, 51))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
29353	31791014	This study demonstrated that the combination of silencing linc00174 and overexpression of miR-138-5p or miR-150-5p could enhance the anti-tumor effects of Dox in the in vitro BTB model.	('rat', 'Species', '10116', (18, 21))	('miR-138-5p', 'Chemical', '-', (90, 100))	('silencing', 'Var', (48, 57))	('Dox', 'Chemical', 'MESH:D004317', (155, 158))	('linc00174', 'Gene', (58, 67))	('tumor', 'Disease', (138, 143))	('miR-150-5p', 'Var', (104, 114))	('miR-138-5p', 'Var', (90, 100))	('miR-150-5p', 'Chemical', '-', (104, 114))	('linc00174', 'Gene', '285908', (58, 67))	('enhance', 'PosReg', (121, 128))	('BTB', 'Chemical', '-', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
29354	31791014	In conclusion, this study demonstrated that the expression of linc00174 and FOSL2 were upregulated while the expression of miR-138-5p and miR-150-5p were downregulated in GECs for the first time.	('FOSL2', 'Gene', (76, 81))	('downregulated', 'NegReg', (154, 167))	('miR-150-5p', 'Chemical', '-', (138, 148))	('miR-150-5p', 'Var', (138, 148))	('linc00174', 'Gene', (62, 71))	('expression', 'MPA', (48, 58))	('rat', 'Species', '10116', (33, 36))	('linc00174', 'Gene', '285908', (62, 71))	('miR-138-5p', 'Chemical', '-', (123, 133))	('upregulated', 'PosReg', (87, 98))	('miR-138-5p', 'Var', (123, 133))
29355	31791014	Knock down of linc00174 increased BTB permeability by upregulating miR-138-5p and miR-150-5p through FOSL2 inhibition.	('miR-138-5p', 'Chemical', '-', (67, 77))	('linc00174', 'Gene', '285908', (14, 23))	('linc00174', 'Gene', (14, 23))	('miR-150-5p', 'MPA', (82, 92))	('miR-150-5p', 'Chemical', '-', (82, 92))	('BTB permeability', 'MPA', (34, 50))	('miR-138-5p', 'MPA', (67, 77))	('BTB', 'Chemical', '-', (34, 37))	('Knock down', 'Var', (0, 10))	('upregulating', 'PosReg', (54, 66))	('increased', 'PosReg', (24, 33))
29368	31791014	The expression levels of linc00174, miR-138-5p, miR-150-5p, and FOSL2 were determined by quantitative real-time PCR.	('miR-150-5p', 'Chemical', '-', (48, 58))	('linc00174', 'Gene', (25, 34))	('miR-138-5p', 'Chemical', '-', (36, 46))	('linc00174', 'Gene', '285908', (25, 34))	('miR-138-5p', 'Var', (36, 46))
29372	31791014	For quantification of miR-138-5p and miR-150-5p expression, reverse transcription was first carried out with TaqMan Micro RNA reverse transcription kits (Applied Biosystems, Foster City, CA, USA), according to the manufacturer's protocol.	('Fos', 'Gene', (174, 177))	('reverse transcription', 'biological_process', 'GO:0001171', ('126', '147'))	('miR-138-5p', 'Chemical', '-', (22, 32))	('RNA', 'cellular_component', 'GO:0005562', ('122', '125'))	('reverse transcription', 'biological_process', 'GO:0001171', ('60', '81'))	('miR-150-5p', 'Chemical', '-', (37, 47))	('miR-150-5p', 'Var', (37, 47))	('miR-138-5p', 'Var', (22, 32))	('Fos', 'Gene', '2353', (174, 177))
29373	31791014	Then, TaqMan Universal Master Mix II (Applied Biosystems) was used to detect the probes for miR-138-5p (2452336), miR-150-5p (2824926), and endogenous control U6 (2819045).	('U6', 'CellLine', 'CVCL:D316', (159, 161))	('miR-150-5p (2824926', 'Var', (114, 133))	('miR-150-5p', 'Chemical', '-', (114, 124))	('miR-138-5p', 'Chemical', '-', (92, 102))	('2819045', 'Var', (163, 170))	('2452336', 'Var', (104, 111))	('miR-138-5p (2452336', 'Var', (92, 111))	('2824926', 'Var', (126, 133))
29381	31791014	The transfection efficiency of linc00174, FOSL2, and miR-138-5p or miR-150-5p are shown in Figure S1.	('transfection', 'MPA', (4, 16))	('miR-138-5p', 'Chemical', '-', (53, 63))	('linc00174', 'Gene', (31, 40))	('miR-138-5p', 'Var', (53, 63))	('miR-150-5p', 'Var', (67, 77))	('linc00174', 'Gene', '285908', (31, 40))	('miR-150-5p', 'Chemical', '-', (67, 77))
29390	31791014	After fulfilling with the blocking buffer (5% nonfat-dried Milk) for 2 h at room temperature, the membranes were incubated with primary antibodies against FOSL2 (1:500; Abcam, USA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH; 1:10,000; Proteintech, Chicago, IL, USA), ZO-1 (1:300; Life Technologies, Frederick, MD, USA), occludin (1:600; Proteintech, Chicago, IL, USA), and claudin-5 (1:250; Proteintech, Chicago, IL, USA) at 4 C overnight.	('FOSL2', 'Gene', (155, 160))	('GAPDH', 'Gene', '2597', (224, 229))	('claudin-5', 'Gene', '7122', (379, 388))	('ZO-1', 'Gene', (273, 277))	('occludin', 'Gene', '100506658', (326, 334))	('1:600; Proteintech', 'Var', (336, 354))	('GAPDH', 'Gene', (224, 229))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (182, 222))	('1:500;', 'Var', (162, 168))	('1:250; Proteintech', 'Var', (390, 408))	('occludin', 'Gene', (326, 334))	('ZO-1', 'Gene', '7082', (273, 277))	('claudin-5', 'Gene', (379, 388))	('rat', 'Species', '10116', (86, 89))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (182, 222))
29395	31791014	The potential binding sequence of miR-138-5p and miR-150-5p in the linc00174 gene and its mutant sequence was amplified by PCR, synthesized, and cloned into the pmirGLO Dual-Luciferase vector (Promega, Madison, WI, USA).	('miR-150-5p', 'Var', (49, 59))	('miR-150-5p', 'Chemical', '-', (49, 59))	('mutant', 'Var', (90, 96))	('binding', 'Interaction', (14, 21))	('miR-138-5p', 'Chemical', '-', (34, 44))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('linc00174', 'Gene', '285908', (67, 76))	('linc00174', 'Gene', (67, 76))
29396	31791014	Wild-type pmirGLO-linc00174 (or linc00174 mutant) reporter plasmid and agomir-138-5p or agomir-138-5p-NC/agomir-150-5p or agomir-150-5p-NC were co-transfected into HEK293T cells.	('mutant', 'Var', (42, 48))	('-150-5p', 'Chemical', '-', (128, 135))	('-138-5p', 'Chemical', '-', (77, 84))	('-150-5p', 'Chemical', '-', (111, 118))	('linc00174', 'Gene', (18, 27))	('HEK293T', 'CellLine', 'CVCL:0063', (164, 171))	('linc00174', 'Gene', '285908', (18, 27))	('linc00174', 'Gene', (32, 41))	('-138-5p', 'Chemical', '-', (94, 101))	('linc00174', 'Gene', '285908', (32, 41))
29429	31615563	Various reports have convincingly shown that abnormal expression of key genes in the process of NER are highly correlated with platinum drug resistance in a variety of tumor types, particularly testicular, ovarian and NSCLC.	('expression', 'MPA', (54, 64))	('abnormal', 'Var', (45, 53))	('ovarian', 'Disease', 'MESH:D010049', (206, 213))	('ovarian', 'Disease', (206, 213))	('tumor', 'Disease', (168, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (218, 223))	('testicular', 'Disease', (194, 204))	('drug resistance', 'biological_process', 'GO:0042493', ('136', '151'))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('NSCLC', 'Disease', (218, 223))	('platinum', 'Chemical', 'MESH:D010984', (127, 135))	('correlated with', 'Reg', (111, 126))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('drug resistance', 'biological_process', 'GO:0009315', ('136', '151'))	('platinum drug', 'CPA', (127, 140))	('drug resistance', 'Phenotype', 'HP:0020174', (136, 151))	('NER', 'biological_process', 'GO:0006289', ('96', '99'))	('NSCLC', 'Disease', 'MESH:D002289', (218, 223))
29436	31615563	The miR-29 family is also down-regulated in lung cancer tissue and the re-expression of miR-29 in lung cancer cells can inhibit tumorigenesis.	('miR', 'Gene', (88, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('re-expression', 'Var', (71, 84))	('lung cancer', 'Disease', (44, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('miR', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inhibit', 'NegReg', (120, 127))	('miR', 'Gene', '220972', (4, 7))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('tumor', 'Disease', (128, 133))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('miR', 'Gene', '220972', (88, 91))	('down-regulated', 'NegReg', (26, 40))
29440	31615563	Furthermore, our data showed that inactivation of CSB could induce apoptosis and increase the sensitivity of lung cancer cells to cisplatin and carboplatin.	('induce', 'PosReg', (60, 66))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('apoptosis', 'CPA', (67, 76))	('CSB', 'Gene', '2074', (50, 53))	('carboplatin', 'Chemical', 'MESH:D016190', (144, 155))	('inactivation', 'Var', (34, 46))	('sensitivity', 'MPA', (94, 105))	('CSB', 'Gene', (50, 53))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('increase', 'PosReg', (81, 89))
29452	31615563	The let-7 or miR-29 binding site in the 3'UTR of CSB on WT construct were mutated by PCR based enzyme synthesis commercially (Synbio Technologies, China) to create MT-let-7 and MT-miR-29 constructs, respectively.	('CSB', 'Gene', (49, 52))	('synthesis', 'biological_process', 'GO:0009058', ('102', '111'))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('let-7', 'Gene', (4, 9))	('mutated', 'Var', (74, 81))	('CSB', 'Gene', '2074', (49, 52))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))
29453	31615563	The CMV-d2eGFP-cxcr4 vector (Addgene plasmid 21,967) was digested with XhoI and PmeI and ligated a sponge insert (synthesized commercially, Synbio Technologies) containing 10x let-7, miR-29 and CXCR4 bulged binding sites (let-7: AAC TAT ACA AAA CCT ACC TCA, miR-29: TAA CCG ATT TTC TTG GTG CTA, CXCR4: AAG TTT TCA GAA AGC TAA CA, 4 nt-spacer: CCGG) together to generate let-7, miR-29 and CXCR4 sponge.	('TCA', 'Chemical', 'MESH:C000589078', (253, 256))	('AAG', 'Gene', '4350', (302, 305))	('miR', 'Gene', '220972', (377, 380))	('CXCR4', 'Gene', '7852', (388, 393))	('cxcr4', 'Gene', (15, 20))	('miR', 'Gene', '220972', (258, 261))	('cxcr4', 'molecular_function', 'GO:0038147', ('15', '20'))	('CXCR4', 'Gene', (388, 393))	('cxcr4', 'Gene', '7852', (15, 20))	('CXCR4', 'molecular_function', 'GO:0038147', ('388', '393'))	('miR', 'Gene', (377, 380))	('CCT', 'Gene', '907', (245, 248))	('miR', 'Gene', (258, 261))	('miR', 'Gene', '220972', (183, 186))	('AAG', 'Gene', (302, 305))	('CXCR4', 'Gene', '7852', (194, 199))	('CXCR4', 'Gene', (194, 199))	('CXCR4', 'molecular_function', 'GO:0038147', ('295', '300'))	('TAA', 'Chemical', 'MESH:C052697', (266, 269))	('miR', 'Gene', (183, 186))	('CXCR4', 'molecular_function', 'GO:0038147', ('194', '199'))	('TAA', 'Chemical', 'MESH:C052697', (322, 325))	('CXCR4', 'Gene', '7852', (295, 300))	('let-7', 'Var', (370, 375))	('CXCR4', 'Gene', (295, 300))	('TCA', 'Chemical', 'MESH:C000589078', (310, 313))	('binding', 'molecular_function', 'GO:0005488', ('207', '214'))	('CCT', 'Gene', (245, 248))
29462	31615563	The qPCR primers for targeting distinct polyadenylation sites on CSB 3'UTR and apoptosis analysis were list in Additional file 1.	('CSB', 'Gene', (65, 68))	('polyadenylation', 'Var', (40, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('poly', 'Chemical', 'MESH:C017937', (40, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('CSB', 'Gene', '2074', (65, 68))
29479	31615563	Based upon the online miRNA target prediction tools, TargetScan and miRnada, two 8mer sites of let-7 (position 125-132) and miR-29 (position 367-374) are highlighted in the 3'UTR transcript of CSB (4337 nt, NM_000124), both residing in more proximal 3'UTR contexts (Fig.	('4337 nt', 'Var', (198, 205))	('miR', 'Gene', '220972', (22, 25))	('CSB', 'Gene', '2074', (193, 196))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('miRnada', 'Disease', 'None', (68, 75))	('miRnada', 'Disease', (68, 75))	('CSB', 'Gene', (193, 196))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))	('miR', 'Gene', (22, 25))
29483	31615563	Recently, longer tandem 3'UTR isoforms were found by sequencing (2370 nt, CR749388; 3449 nt, ENST00000355832; 4337 nt, NM_000124) (Fig.	('4337 nt', 'Var', (110, 117))	('CR749388; 3449 nt', 'Var', (74, 91))	('CR749388', 'Chemical', 'MESH:C120400', (74, 82))	('2370 nt', 'Var', (65, 72))
29488	31615563	This result indicates that the longest known 4337 nt 3'UTR isoform might be prevalent in lung cancer cells and is also affected by the potential let-7 or miR-29 mediated regulation.	('regulation', 'biological_process', 'GO:0065007', ('170', '180'))	('prevalent', 'Reg', (76, 85))	('affected', 'Reg', (119, 127))	('miR', 'Gene', '220972', (154, 157))	('miR', 'Gene', (154, 157))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('4337 nt', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))
29489	31615563	To determine whether let-7 family and miR-29 family directly interact with the putative target sites in the 3'UTR of CSB, we generated three psiCHECK2-CSB-3'UTR luciferase reporter constructs with WT, MT-let-7 or MT-miR-29.	('CSB', 'Gene', (117, 120))	('MT-let-7', 'Var', (201, 209))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('CSB', 'Gene', '2074', (151, 154))	('CSB', 'Gene', (151, 154))	('CSB', 'Gene', '2074', (117, 120))
29492	31615563	Luciferase reporter gene analysis revealed that the relative Renilla luciferase activity of WT was reduced about 55% in response to additional let-7a or let-7f (P < 0.001) and 40% in response to additional miR-29a, 19% to miR-29b, 28% to miR-29c (P < 0.01), whereas both MT-let-7 and MT-miR-29 showed no change of luciferase activity (Fig.	('miR-29c', 'Gene', (238, 245))	('miR', 'Gene', (222, 225))	('activity', 'MPA', (325, 333))	('let-7f', 'Var', (153, 159))	('luciferase activity', 'molecular_function', 'GO:0047077', ('314', '333'))	('miR-29b', 'Gene', '407024', (222, 229))	('luciferase activity', 'molecular_function', 'GO:0045289', ('314', '333'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('314', '333'))	('activity', 'MPA', (80, 88))	('Renilla luciferase', 'Enzyme', (61, 79))	('miR', 'Gene', '220972', (238, 241))	('luciferase', 'Enzyme', (314, 324))	('miR-29a', 'Gene', (206, 213))	('miR', 'Gene', '220972', (287, 290))	('miR-29a', 'Gene', '407021', (206, 213))	('luciferase activity', 'molecular_function', 'GO:0050248', ('314', '333'))	('miR-29b', 'Gene', (222, 229))	('luciferase activity', 'molecular_function', 'GO:0050397', ('314', '333'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('69', '88'))	('miR', 'Gene', '220972', (206, 209))	('luciferase activity', 'molecular_function', 'GO:0045289', ('69', '88'))	('miR', 'Gene', (238, 241))	('luciferase activity', 'molecular_function', 'GO:0047712', ('69', '88'))	('miR-29c', 'Gene', '407026', (238, 245))	('miR', 'Gene', '220972', (222, 225))	('miR', 'Gene', (287, 290))	('miR', 'Gene', (206, 209))	('luciferase activity', 'molecular_function', 'GO:0050397', ('69', '88'))	('reduced', 'NegReg', (99, 106))	('luciferase activity', 'molecular_function', 'GO:0050248', ('69', '88'))	('let-7a', 'Var', (143, 149))
29501	31615563	5c, CSB protein level was dramatically decreased with expression of either let-7f or miR-29a construct, suggesting the endogenous CSB expression can be suppressed by let-7 and miR-29.	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('miR', 'Gene', '220972', (85, 88))	('miR-29a', 'Gene', '407021', (85, 92))	('miR', 'Gene', (85, 88))	('CSB', 'Gene', '2074', (130, 133))	('miR-29a', 'Gene', (85, 92))	('CSB', 'Gene', '2074', (4, 7))	('decreased', 'NegReg', (39, 48))	('let-7f', 'Var', (75, 81))	('CSB', 'Gene', (4, 7))	('miR', 'Gene', '220972', (176, 179))	('CSB', 'Gene', (130, 133))	('miR', 'Gene', (176, 179))
29502	31615563	To assess the effect of CSB on the development of NSCLC treated by cisplatin or carboplatin, we transfected lentiviral short hairpin RNA (shRNA) construct to H2030 cells to knockdown CSB and observed a striking reduced CSB protein levels (P < 0.001) (Fig.	('reduced CSB protein', 'Phenotype', 'HP:0025457', (211, 230))	('CSB', 'Gene', (24, 27))	('CSB', 'Gene', (219, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('CSB', 'Gene', (183, 186))	('knockdown', 'Var', (173, 182))	('reduced', 'NegReg', (211, 218))	('RNA', 'cellular_component', 'GO:0005562', ('133', '136'))	('carboplatin', 'Chemical', 'MESH:D016190', (80, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('NSCLC', 'Disease', (50, 55))	('CSB', 'Gene', '2074', (219, 222))	('CSB', 'Gene', '2074', (183, 186))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('CSB', 'Gene', '2074', (24, 27))
29503	31615563	We then tested the cell viability after CSB knockdown in response to cisplatin and carboplatin.	('tested', 'Reg', (8, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('CSB', 'Gene', '2074', (40, 43))	('carboplatin', 'Chemical', 'MESH:D016190', (83, 94))	('CSB', 'Gene', (40, 43))	('knockdown', 'Var', (44, 53))	('response to cisplatin', 'biological_process', 'GO:0072718', ('57', '78'))
29508	31615563	7, the overexpression of CSB in lung cancer cells treated with cisplatin and carboplatin could induce apoptosis and the knockdown of CSB by siRNA significantly increased apoptosis.	('apoptosis', 'CPA', (102, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('CSB', 'Gene', '2074', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('CSB', 'Gene', (133, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('apoptosis', 'CPA', (170, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('increased', 'PosReg', (160, 169))	('CSB', 'Gene', '2074', (133, 136))	('knockdown', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('carboplatin', 'Chemical', 'MESH:D016190', (77, 88))	('overexpression', 'PosReg', (7, 21))	('lung cancer', 'Disease', (32, 43))	('CSB', 'Gene', (25, 28))
29516	31615563	We also found that the transcriptional activity of CSB could be suppressed by global decreased let-7 and miR-29 and promoted by additional let-7 or miRNA-29 in lung cancer cells.	('CSB', 'Gene', (51, 54))	('miR', 'Gene', (105, 108))	('decreased', 'NegReg', (85, 94))	('let-7', 'Var', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('promoted', 'PosReg', (116, 124))	('suppressed', 'NegReg', (64, 74))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('let-7', 'Gene', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('miR', 'Gene', (148, 151))	('CSB', 'Gene', '2074', (51, 54))	('miR', 'Gene', '220972', (148, 151))	('lung cancer', 'Disease', (160, 171))	('transcriptional activity', 'MPA', (23, 47))	('miR', 'Gene', '220972', (105, 108))
29527	31615563	Our findings also suggested that CSB knockdown could sensitize H2030 cells to platinum-based drugs and induce a potent antiproliferative effect.	('CSB', 'Gene', '2074', (33, 36))	('knockdown', 'Var', (37, 46))	('antiproliferative effect', 'CPA', (119, 143))	('sensitize', 'Reg', (53, 62))	('CSB', 'Gene', (33, 36))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))
29529	31615563	Recently, two reports have shown that genetic polymorphisms of ERCC6 could affect sensitivity of NSCLC patients to platinum-based chemotherapy, which confirming the important role of CSB in predicting chemotherapy sensitivity and toxicity.	('sensitivity', 'MPA', (82, 93))	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('platinum', 'Chemical', 'MESH:D010984', (115, 123))	('toxicity', 'Disease', (230, 238))	('NSCLC', 'Disease', (97, 102))	('CSB', 'Gene', (183, 186))	('ERCC6', 'Gene', '2074', (63, 68))	('poly', 'Chemical', 'MESH:C017937', (46, 50))	('ERCC6', 'Gene', (63, 68))	('affect', 'Reg', (75, 81))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('genetic polymorphisms', 'Var', (38, 59))	('patients', 'Species', '9606', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('CSB', 'Gene', '2074', (183, 186))
29530	31615563	Although interstrand crosslinks (ICLs) account for the minority of all types of cisplatin-damages, they are considered extremely toxic by blocking fundamental cellular processes such as replication and transcription and further leading to cell death or genome instability.	('genome instability', 'CPA', (253, 271))	('leading to', 'Reg', (228, 238))	('replication', 'CPA', (186, 197))	('blocking', 'NegReg', (138, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('transcription', 'biological_process', 'GO:0006351', ('202', '215'))	('death', 'Disease', 'MESH:D003643', (244, 249))	('death', 'Disease', (244, 249))	('transcription', 'CPA', (202, 215))	('cell death', 'biological_process', 'GO:0008219', ('239', '249'))	('interstrand', 'Var', (9, 20))
29534	31615563	The deregulation of non-coding RNAs, especially miRNA, has emerged as an important mechanism of cisplatin resistance implicated in numerous cancers including lung cancer.	('deregulation', 'Var', (4, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('cisplatin resistance', 'MPA', (96, 116))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancers', 'Disease', (140, 147))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))	('implicated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-coding', 'Protein', (20, 30))
29554	31616560	The programmed death-1 (PD-1) receptor, which is expressed on activated T cells, is engaged by the ligands PD-1 ligand 1 (PD-L1) and PD-L2, which are expressed by tumor cells and infiltrating immune cells.	('PD-L2', 'Var', (133, 138))	('ligand', 'molecular_function', 'GO:0005488', ('112', '118'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('PD-1', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('PD-1', 'Gene', '5133', (24, 28))	('programmed death-1', 'Gene', (4, 22))	('PD-1', 'Gene', (107, 111))	('PD-1 ligand 1', 'Gene', (107, 120))	('PD-1', 'Gene', '5133', (107, 111))	('tumor', 'Disease', (163, 168))	('programmed death-1', 'Gene', '5133', (4, 22))	('PD-1 ligand 1', 'Gene', '29126', (107, 120))
29590	31616560	Driver gene alterations were detected in three patients [KRAS mutation: Cases 2 and 3; MET exon 14 skipping: Case 4; gene alterations were not investigated in the patient with squamous cell carcinoma (case 1)].	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('patient', 'Species', '9606', (47, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('MET exon 14 skipping', 'Var', (87, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 199))	('patients', 'Species', '9606', (47, 55))	('squamous cell carcinoma', 'Disease', (176, 199))	('KRAS', 'Gene', (57, 61))	('patient', 'Species', '9606', (163, 170))	('KRAS', 'Gene', '3845', (57, 61))
29701	31216461	C. albicans yeasts interacts poorly with epithelial cells, while C. albicans hyphae invade epithelial cells and induce pro-inflammatory cytokines and host defense peptides.	('yeasts', 'Species', '4932', (12, 18))	('pro-inflammatory cytokines', 'MPA', (119, 145))	('C. albicans', 'Var', (65, 76))	('C. albicans', 'Species', '5476', (0, 11))	('C. albicans', 'Species', '5476', (65, 76))	('induce', 'PosReg', (112, 118))
29705	31216461	Upon epithelial cells damage, candidalysin induces the activation of MAPK/cFos/MPK1 pathway, which further lead to the production of pro-inflammatory cytokines, including IL-1alpha/beta, IL-6, IL-8, G-CSF and GM-CSF in both oral and vaginal squamous epithelial cell lines in vitro.	('lead to', 'Reg', (107, 114))	('MAPK/cFos/MPK1 pathway', 'Pathway', (69, 91))	('IL-6', 'Gene', (187, 191))	('IL-6', 'Gene', '16193', (187, 191))	('production', 'MPA', (119, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('IL-6', 'molecular_function', 'GO:0005138', ('187', '191'))	('IL-8', 'molecular_function', 'GO:0005153', ('193', '197'))	('candidalysin', 'Var', (30, 42))	('IL-1', 'molecular_function', 'GO:0005149', ('171', '175'))
29708	31216461	However, in response to specific intestinal bacteria, such as Salmonella typhimurium and segmented filamentous bacteria (SFB), CX3CR1+ MNPs activate Th17 adaptive immune responses.	('SFB', 'Species', '49118', (121, 124))	('Salmonella typhimurium', 'Species', '90371', (62, 84))	('Th17', 'Chemical', '-', (149, 153))	('activate', 'PosReg', (140, 148))	('CX3CR1+ MNPs', 'Var', (127, 139))	('segmented filamentous bacteria', 'Species', '49118', (89, 119))	('Th17 adaptive immune responses', 'CPA', (149, 179))
29710	31216461	In the gut, CX3CR1+ MNPs induce fungal antigens specific Th17 responses to C. albicans via the activation of Syk signaling (Figure 1).	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('CX3CR1+ MNPs', 'Var', (12, 24))	('Syk', 'MPA', (109, 112))	('induce', 'PosReg', (25, 31))	('C. albicans', 'Species', '5476', (75, 86))	('Th17', 'Chemical', '-', (57, 61))	('activation', 'PosReg', (95, 105))	('Th17 responses to C. albicans', 'MPA', (57, 86))	('gut', 'Gene', (7, 10))	('gut', 'Gene', '110006', (7, 10))
29724	31216461	Follow up experiments in murine model of colitis suggested a role of S. cerevisiae in UA induction and aggravated intestinal inflammation.	('aggravated', 'PosReg', (103, 113))	('S. cerevisiae', 'Var', (69, 82))	('colitis', 'Disease', 'MESH:D003092', (41, 48))	('S. cerevisiae', 'Species', '4932', (69, 82))	('colitis', 'Disease', (41, 48))	('inflammation', 'biological_process', 'GO:0006954', ('125', '137'))	('colitis', 'Phenotype', 'HP:0002583', (41, 48))	('UA', 'Chemical', 'MESH:D014527', (86, 88))	('intestinal inflammation', 'Disease', 'MESH:D007249', (114, 137))	('murine', 'Species', '10090', (25, 31))	('intestinal inflammation', 'Disease', (114, 137))
29757	31216461	Evidence for the immunoprotective role of the gut mycobiota comes from recent studies showing that targeted perturbation of gut fungi by anti-fungal drugs has persistent effects on host immunity and health through mechanisms discussed later in this review.	('gut', 'Gene', '110006', (46, 49))	('effects', 'Reg', (170, 177))	('health', 'CPA', (199, 205))	('host immunity', 'CPA', (181, 194))	('perturbation', 'Var', (108, 120))	('gut', 'Gene', (124, 127))	('gut', 'Gene', '110006', (124, 127))	('gut', 'Gene', (46, 49))
29762	31216461	In conditions promoting fungal intestinal domination triggered by antibiotics, multiple microscale genetic changes increase the in vivo fitness of C. albicans within the host, leading to the acquisition of commensal-like traits.	('acquisition', 'PosReg', (191, 202))	('increase', 'PosReg', (115, 123))	('fitness', 'Disease', (136, 143))	('fitness', 'Disease', 'MESH:D012640', (136, 143))	('C. albicans', 'Species', '5476', (147, 158))	('commensal-like', 'CPA', (206, 220))	('changes', 'Var', (107, 114))
29773	31216461	In additional studies, daily administration with C. albicans exacerbated the outcome of DSS-induced colitis in SPF mice but had no effect following antibiotic administration.	('colitis', 'Disease', 'MESH:D003092', (100, 107))	('colitis', 'Disease', (100, 107))	('colitis', 'Phenotype', 'HP:0002583', (100, 107))	('C. albicans', 'Var', (49, 60))	('exacerbated', 'PosReg', (61, 72))	('mice', 'Species', '10090', (115, 119))	('C. albicans', 'Species', '5476', (49, 60))
29793	31216461	M. restricta gastrointestinal delivery in mice aggravates the outcome of DSS-induced colitis in a CARD9-dependent manner.	('colitis', 'Phenotype', 'HP:0002583', (85, 92))	('M. restricta', 'Species', '76775', (0, 12))	('CARD9', 'Gene', (98, 103))	('mice', 'Species', '10090', (42, 46))	('M. restricta', 'Var', (0, 12))	('colitis', 'Disease', 'MESH:D003092', (85, 92))	('CARD9', 'Gene', '332579', (98, 103))	('aggravates', 'PosReg', (47, 57))	('colitis', 'Disease', (85, 92))
29798	31216461	In particular, C. albicans and C. parapsilosis appear consistently increased in various cohorts, including CD patients with different ethnicity (Table 1).	('C. albicans', 'Species', '5476', (15, 26))	('CD', 'Phenotype', 'HP:0100280', (107, 109))	('increased', 'PosReg', (67, 76))	('C. parapsilosis', 'Species', '5480', (31, 46))	('C. parapsilosis', 'Var', (31, 46))	('patients', 'Species', '9606', (110, 118))	('C. albicans', 'Var', (15, 26))
29806	31216461	In addition to the direct impact on gut innate immune pathways and on the induction of humoral immunity, the recognition of C. albicans by CX3CR1+ MNPs, also triggers antifungal Th17 responses (Figure 1) and CX3CR1+ MNPs might be involved in the induction of these cross-reactive Th17 cells.	('recognition', 'Var', (109, 120))	('gut', 'Gene', (36, 39))	('C. albicans', 'Species', '5476', (124, 135))	('gut', 'Gene', '110006', (36, 39))	('antifungal Th17 responses', 'CPA', (167, 192))	('Th17', 'Chemical', '-', (280, 284))	('CX3CR1+ MNPs', 'Var', (139, 151))	('triggers', 'PosReg', (158, 166))	('C. albicans', 'Var', (124, 135))	('Th17', 'Chemical', '-', (178, 182))
29807	31216461	A missense mutation of the CX3CR1 gene, termed T280M, impairs the fractalkine-mediated survival of circulating blood monocytes in humans.	('impairs', 'NegReg', (54, 61))	('T280M', 'Var', (47, 52))	('CX3CR1', 'Gene', (27, 33))	('humans', 'Species', '9606', (130, 136))	('T280M', 'Mutation', 'rs3732378', (47, 52))
29810	31216461	Furthermore, this mutation is associated with the development of intestinal stenosis and ileocolonic involvement in CD patients.	('ileocolonic involvement', 'Disease', (89, 112))	('intestinal stenosis', 'Disease', 'MESH:D007410', (65, 84))	('CD', 'Phenotype', 'HP:0100280', (116, 118))	('patients', 'Species', '9606', (119, 127))	('mutation', 'Var', (18, 26))	('intestinal stenosis', 'Disease', (65, 84))	('associated with', 'Reg', (30, 45))
29811	31216461	Importantly, the T280M mutation is also associated with impaired anti-fungal humoral responses in CD patients.	('T280M', 'Mutation', 'rs3732378', (17, 22))	('patients', 'Species', '9606', (101, 109))	('CD', 'Phenotype', 'HP:0100280', (98, 100))	('T280M', 'Var', (17, 22))	('impaired', 'NegReg', (56, 64))	('anti-fungal humoral responses', 'CPA', (65, 94))
29812	31216461	In particular, T280M patients have decreased titers of serum IgG against various gut mycobiota members including species such as C. albicans and C. parapsilosis that are associated with intestinal inflammation.	('serum IgG against', 'MPA', (55, 72))	('gut', 'Gene', (81, 84))	('decreased titers of serum IgG', 'Phenotype', 'HP:0004315', (35, 64))	('gut', 'Gene', '110006', (81, 84))	('C. albicans', 'Species', '5476', (129, 140))	('T280M', 'Mutation', 'rs3732378', (15, 20))	('decreased', 'NegReg', (35, 44))	('patients', 'Species', '9606', (21, 29))	('titers', 'MPA', (45, 51))	('inflammation', 'biological_process', 'GO:0006954', ('197', '209'))	('intestinal inflammation', 'Disease', 'MESH:D007249', (186, 209))	('T280M', 'Var', (15, 20))	('decreased titers of serum', 'Phenotype', 'HP:0004313', (35, 60))	('intestinal inflammation', 'Disease', (186, 209))	('C. parapsilosis', 'Species', '5480', (145, 160))
29813	31216461	These finding are corroborated by studies in mice where the depletion of CX3CR1+ MNPs causes a reduction in serum anti-fungal IgG despite a concomitant increase of the fungal burden (Figure 1).	('mice', 'Species', '10090', (45, 49))	('increase', 'PosReg', (152, 160))	('reduction', 'NegReg', (95, 104))	('serum anti-fungal IgG', 'MPA', (108, 129))	('CX3CR1+ MNPs', 'Var', (73, 85))	('fungal burden', 'CPA', (168, 181))
29878	31216461	Antibiotic perturbation modestly enhances probiotic colonization in the healthy human mucosa, delays the post-antibiotic recovery to the original microbiota composition and is associated with a different transcriptomal profile in host cells as compared to controls.	('probiotic colonization', 'CPA', (42, 64))	('enhances', 'PosReg', (33, 41))	('human', 'Species', '9606', (80, 85))	('delays', 'NegReg', (94, 100))	('different', 'Reg', (194, 203))	('transcriptomal profile', 'MPA', (204, 226))	('post-antibiotic recovery', 'MPA', (105, 129))	('perturbation', 'Var', (11, 23))
29939	30988808	TMA slides for IHC were deparaffinized by bathing in xylene solution for 10 min, and rehydrated through decreasing ethanol gradient (100, 90, 75 and 50%) for 5 min.	('xylene', 'Chemical', 'MESH:D014992', (53, 59))	('ethanol', 'Chemical', 'MESH:D000431', (115, 122))	('ethanol gradient', 'MPA', (115, 131))	('100', 'Var', (133, 136))	('paraffin', 'Chemical', 'MESH:D010232', (26, 34))
29951	30988808	P0013B; Beyotime Institute of Biotechnology) and the protein concentration was measured using a bicinchoninic acid assay.	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('bicinchoninic acid', 'Chemical', 'MESH:C047117', (96, 114))	('protein concentration', 'MPA', (53, 74))	('P0013B', 'Var', (0, 6))
29966	30988808	According to these results, AMPK alpha1 may serve an aggressive role in NSCLC, and high levels of AMPK alpha1 may act as an indicator of poor prognosis in patients with NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('NSCLC', 'Disease', (72, 77))	('AMPK', 'molecular_function', 'GO:0050405', ('28', '32'))	('AMPK', 'molecular_function', 'GO:0050405', ('98', '102'))	('patients', 'Species', '9606', (155, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('AMPK alpha1', 'Gene', '5562', (28, 39))	('SCLC', 'Phenotype', 'HP:0030357', (170, 174))	('AMPK', 'molecular_function', 'GO:0004691', ('98', '102'))	('AMPK', 'molecular_function', 'GO:0004691', ('28', '32'))	('AMPK alpha1', 'Gene', '5562', (98, 109))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('AMPK', 'molecular_function', 'GO:0047322', ('28', '32'))	('AMPK', 'molecular_function', 'GO:0047322', ('98', '102'))	('high levels', 'Var', (83, 94))	('AMPK alpha1', 'Gene', (28, 39))	('NSCLC', 'Disease', (169, 174))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('AMPK alpha1', 'Gene', (98, 109))
29973	30988808	Patients that expressed high levels of AMPK alpha1 and VEGF had a significantly shorter OS compared with those that expressed low levels of AMPK alpha1 and VEGF, and those with all other expression level combinations (AMPK alpha1 low, VEGF low; AMPK alpha1 high, VEGF low; and AMPK alpha1 low, VEGF high; Fig.	('AMPK alpha1', 'Gene', '5562', (39, 50))	('AMPK alpha1', 'Gene', '5562', (140, 151))	('AMPK alpha1', 'Gene', '5562', (277, 288))	('VEGF', 'Gene', (156, 160))	('VEGF', 'Gene', (235, 239))	('AMPK', 'molecular_function', 'GO:0004691', ('245', '249'))	('AMPK', 'molecular_function', 'GO:0047322', ('218', '222'))	('high', 'Var', (24, 28))	('AMPK', 'molecular_function', 'GO:0047322', ('39', '43'))	('AMPK', 'molecular_function', 'GO:0050405', ('277', '281'))	('AMPK', 'molecular_function', 'GO:0050405', ('140', '144'))	('Patients', 'Species', '9606', (0, 8))	('AMPK', 'molecular_function', 'GO:0047322', ('245', '249'))	('AMPK alpha1', 'Gene', (245, 256))	('OS', 'Chemical', '-', (88, 90))	('AMPK alpha1', 'Gene', (39, 50))	('AMPK alpha1', 'Gene', (140, 151))	('AMPK alpha1', 'Gene', (277, 288))	('VEGF', 'Gene', '7422', (263, 267))	('VEGF', 'Gene', '7422', (294, 298))	('AMPK', 'molecular_function', 'GO:0004691', ('277', '281'))	('AMPK alpha1', 'Gene', '5562', (218, 229))	('AMPK', 'molecular_function', 'GO:0050405', ('218', '222'))	('AMPK', 'molecular_function', 'GO:0050405', ('39', '43'))	('AMPK', 'molecular_function', 'GO:0004691', ('140', '144'))	('VEGF', 'Gene', '7422', (55, 59))	('VEGF', 'Gene', (263, 267))	('VEGF', 'Gene', (294, 298))	('VEGF', 'Gene', (55, 59))	('AMPK', 'molecular_function', 'GO:0050405', ('245', '249'))	('AMPK', 'molecular_function', 'GO:0004691', ('218', '222'))	('AMPK', 'molecular_function', 'GO:0047322', ('277', '281'))	('AMPK', 'molecular_function', 'GO:0004691', ('39', '43'))	('AMPK', 'molecular_function', 'GO:0047322', ('140', '144'))	('shorter', 'NegReg', (80, 87))	('VEGF', 'Gene', '7422', (156, 160))	('VEGF', 'Gene', '7422', (235, 239))	('AMPK alpha1', 'Gene', '5562', (245, 256))	('AMPK alpha1', 'Gene', (218, 229))
29985	30988808	However, AMPK alpha1 has also been indicated as a tumor suppressor, and its deletion reportedly promotes cell proliferation and angiogenesis.	('deletion', 'Var', (76, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('AMPK', 'molecular_function', 'GO:0047322', ('9', '13'))	('AMPK', 'molecular_function', 'GO:0050405', ('9', '13'))	('AMPK alpha1', 'Gene', '5562', (9, 20))	('promotes', 'PosReg', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('angiogenesis', 'biological_process', 'GO:0001525', ('128', '140'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('AMPK alpha1', 'Gene', (9, 20))	('cell proliferation', 'CPA', (105, 123))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('AMPK', 'molecular_function', 'GO:0004691', ('9', '13'))	('angiogenesis', 'CPA', (128, 140))	('tumor', 'Disease', (50, 55))
29994	30988808	In conclusion, the present study identified an aggressive pro-cancerous effect of high levels of AMPK alpha1 in patients with NSCLC.	('high levels', 'Var', (82, 93))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancerous', 'Disease', 'MESH:D009369', (62, 71))	('AMPK alpha1', 'Gene', (97, 108))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('AMPK', 'molecular_function', 'GO:0050405', ('97', '101'))	('AMPK alpha1', 'Gene', '5562', (97, 108))	('AMPK', 'molecular_function', 'GO:0047322', ('97', '101'))	('SCLC', 'Phenotype', 'HP:0030357', (127, 131))	('AMPK', 'molecular_function', 'GO:0004691', ('97', '101'))	('NSCLC', 'Disease', (126, 131))	('cancerous', 'Disease', (62, 71))
30045	30353639	EA elevated autophagy-associated cell death by down-regulating the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), and CIP2A overexpression attenuated EA-induced autophagy of lung cancer cells.	('autophagy of lung cancer', 'Disease', 'MESH:D008175', (183, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CIP2A', 'Gene', (128, 133))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('expression', 'MPA', (67, 77))	('cancerous inhibitor of protein phosphatase 2A', 'Gene', (81, 126))	('attenuated', 'NegReg', (161, 171))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('104', '126'))	('elevated', 'PosReg', (3, 11))	('overexpression', 'PosReg', (146, 160))	('autophagy', 'biological_process', 'GO:0016236', ('12', '21'))	('autophagy', 'biological_process', 'GO:0016236', ('183', '192'))	('EA', 'Chemical', 'MESH:D004610', (0, 2))	('cell death', 'biological_process', 'GO:0008219', ('33', '43'))	('autophagy-associated cell death', 'CPA', (12, 43))	('CIP2A', 'Var', (140, 145))	('autophagy of lung cancer', 'Disease', (183, 207))	('EA', 'Chemical', 'MESH:D004610', (172, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('autophagy', 'biological_process', 'GO:0006914', ('12', '21'))	('autophagy', 'biological_process', 'GO:0006914', ('183', '192'))	('cancerous inhibitor of protein phosphatase 2A', 'Gene', '57650', (81, 126))	('down-regulating', 'NegReg', (47, 62))
30062	30353639	The lung adenocarcinoma cell lines HOP62 and H1975 (harbouring L858R/T790M EGFR mutation) were purchased from Cell Bank of Chinese Academy of Sciences (Shanghai, China) and American Type Culture Collection (Manassas, VA, USA) respectively.	('lung adenocarcinoma', 'Disease', (4, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('L858R', 'Var', (63, 68))	('H1975', 'CellLine', 'CVCL:1511', (45, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('T790M', 'SUBSTITUTION', 'None', (69, 74))	('L858R', 'SUBSTITUTION', 'None', (63, 68))	('EGFR', 'Gene', '1956', (75, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('HOP62', 'CellLine', 'CVCL:1285', (35, 40))	('EGFR', 'Gene', (75, 79))	('T790M', 'Var', (69, 74))
30104	30353639	In addition, we showed that knockdown of ATG5 by siRNA blocked the formation of LC3-II in EA-treated HOP62 cells (Figure 3F).	('HOP62', 'CellLine', 'CVCL:1285', (101, 106))	('ATG5', 'Gene', (41, 45))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('LC3-II', 'Protein', (80, 86))	('formation of', 'MPA', (67, 79))	('EA', 'Chemical', 'MESH:D004610', (90, 92))	('knockdown', 'Var', (28, 37))	('ATG5', 'Gene', '9474', (41, 45))	('blocked', 'NegReg', (55, 62))
30156	30510430	The tumor remission rate in the MLT group was significantly higher than that in the control group (relative risk [RR] =2.25; 95% CI, 1.86-2.71; P<0.00001; I2=9%).	('tumor', 'Disease', (4, 9))	('higher', 'PosReg', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MLT', 'Var', (32, 35))
30157	30510430	And, MLT could significantly enhance the overall survival rate in non-small-cell lung cancer patients (RR =2.13; 95% CI, 1.41-3.24; P=0.0004; I2=0%) and various solid tumor patients (RR =2.31; 95% CI, 1.78-2.99; P<0.00001; I2=0%).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('MLT', 'Var', (5, 8))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('solid tumor', 'Disease', (161, 172))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('solid tumor', 'Disease', 'MESH:D009369', (161, 172))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('enhance', 'PosReg', (29, 36))	('overall survival', 'CPA', (41, 57))
30158	30510430	It was further proved that MLT could effectively reduce the incidence of neurotoxicity (RR =0.30, 95% CI, 0.19-0.45; P<0.00001), thrombocytopenia (RR =0.23; 95% CI, 0.16-0.33; P<0.00001), and asthenia (RR =0.43, 95% CI, 0.38-0.49; P<0.00001) during chemotherapy.	('thrombocytopenia', 'Disease', (129, 145))	('neurotoxicity', 'Disease', (73, 86))	('asthenia', 'Disease', 'MESH:D001247', (192, 200))	('thrombocytopenia', 'Disease', 'MESH:D013921', (129, 145))	('asthenia', 'Disease', (192, 200))	('MLT', 'Var', (27, 30))	('asthenia', 'Phenotype', 'HP:0025406', (192, 200))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (129, 145))	('reduce', 'NegReg', (49, 55))	('neurotoxicity', 'Disease', 'MESH:D020258', (73, 86))
30167	30510430	Further studies evidence that exogenous MLT exerted a certain degree of inhibition on the growth of tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('MLT', 'Protein', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('exogenous', 'Var', (30, 39))	('inhibition', 'NegReg', (72, 82))
30168	30510430	Preclinical studies reveals that MLT functions in anticancer effects mainly through the following ways: 1) by binding to MLT membrane receptors, MLT could exert antiangiogenic effects in tumor (such as neuroblastoma and ovarian carcinoma) by the downregulation of vascular endothelial growth factor (VEGF); 2) MLT has the ability to inhibit the growth of breast cancer through interference with estrogen sulfatase enzyme; 3) MLT could function as immunomodulatory effect by regulating mononuclear cells to induce tumor cell apoptosis and arrest tumor cell cycle in G0/G1; 4) MLT could suppress the metastasis of triple-negative breast cancer by inducing KISS1 expression; 5) MLT would decrease epithelial-mesenchymal transition (EMT) and matrix metalloproteinase 9 (MMP9) activity to control the invasion and metastasis of cancer stem cells; 6) MLT is able to reduce prostate cancer cell growth and promote neuroendocrine differentiation via binding MLT membrane receptors; 7) MLT could potentiate the antitumor effect and overcome the resistance of chemotherapy, radiotherapy and other therapy.	('tumor', 'Disease', (545, 550))	('neuroblastoma', 'Phenotype', 'HP:0003006', (202, 215))	('promote', 'PosReg', (899, 906))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('694', '727'))	('VEGF', 'Gene', (300, 304))	('breast cancer', 'Disease', 'MESH:D001943', (628, 641))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('arrest tumor', 'Disease', 'MESH:D006323', (538, 550))	('cancer', 'Phenotype', 'HP:0002664', (876, 882))	('metastasis of cancer', 'Disease', (809, 829))	('cancer', 'Disease', (635, 641))	('breast cancer', 'Disease', (628, 641))	('arrest tumor', 'Disease', (538, 550))	('binding', 'Interaction', (942, 949))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (513, 518))	('KISS1', 'Gene', '3814', (654, 659))	('prostate cancer', 'Disease', 'MESH:D011471', (867, 882))	('tumor', 'Disease', 'MESH:D009369', (545, 550))	('cancer', 'Disease', 'MESH:D009369', (823, 829))	('breast cancer', 'Phenotype', 'HP:0003002', (355, 368))	('prostate cancer', 'Phenotype', 'HP:0012125', (867, 882))	('cancer', 'Phenotype', 'HP:0002664', (635, 641))	('tumor', 'Phenotype', 'HP:0002664', (1006, 1011))	('potentiate', 'PosReg', (987, 997))	('apoptosis', 'biological_process', 'GO:0006915', ('524', '533'))	('apoptosis', 'biological_process', 'GO:0097194', ('524', '533'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('264', '298'))	('neuroendocrine differentiation', 'CPA', (907, 937))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('reduce prostate', 'Phenotype', 'HP:0008687', (860, 875))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (513, 518))	('binding', 'molecular_function', 'GO:0005488', ('110', '117'))	('cell growth', 'biological_process', 'GO:0016049', ('883', '894'))	('prostate cancer', 'Disease', (867, 882))	('KISS1', 'Gene', (654, 659))	('metastasis of cancer', 'Disease', 'MESH:D009362', (809, 829))	('membrane', 'cellular_component', 'GO:0016020', ('954', '962'))	('breast cancer', 'Disease', 'MESH:D001943', (355, 368))	('neuroblastoma and ovarian carcinoma', 'Disease', 'MESH:D009447', (202, 237))	('cancer', 'Disease', 'MESH:D009369', (876, 882))	('tumor', 'Phenotype', 'HP:0002664', (545, 550))	('breast cancer', 'Disease', (355, 368))	('membrane', 'cellular_component', 'GO:0016020', ('125', '133'))	('MLT', 'Protein', (950, 953))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (513, 518))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cell cycle', 'biological_process', 'GO:0007049', ('551', '561'))	('MMP9', 'Gene', '4318', (766, 770))	('cancer', 'Disease', 'MESH:D009369', (635, 641))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (823, 829))	('MMP9', 'Gene', (766, 770))	('matrix metalloproteinase 9', 'Gene', (738, 764))	('vascular endothelial growth factor', 'Gene', '7422', (264, 298))	('cancer', 'Phenotype', 'HP:0002664', (823, 829))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('EMT', 'biological_process', 'GO:0001837', ('729', '732'))	('MMP9', 'molecular_function', 'GO:0004229', ('766', '770'))	('tumor', 'Disease', (1006, 1011))	('matrix metalloproteinase 9', 'Gene', '4318', (738, 764))	('reduce', 'NegReg', (860, 866))	('cancer', 'Disease', (362, 368))	('MLT', 'Var', (977, 980))	('vascular endothelial growth factor', 'Gene', (264, 298))	('tumor', 'Disease', 'MESH:D009369', (1006, 1011))	('breast cancer', 'Phenotype', 'HP:0003002', (628, 641))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (220, 237))	('VEGF', 'Gene', '7422', (300, 304))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancer', 'Disease', (876, 882))	('binding', 'molecular_function', 'GO:0005488', ('942', '949'))
30172	30510430	In most randomized clinical trials (RCTs), it is believed that supplement of MLT could enhance tumor remission response and survival rates, while reducing the incidence of side effects in chemotherapy or radiotherapy.	('MLT', 'Gene', (77, 80))	('supplement', 'Var', (63, 73))	('survival rates', 'CPA', (124, 138))	('enhance', 'PosReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('reducing', 'NegReg', (146, 154))	('tumor', 'Disease', (95, 100))
30188	30510430	A number of systematic studies have concluded that supplementation of MLT could increase the survival rate and disease remission rate in cancer patients, while reducing the incidence of side effects of radiotherapy and chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('side', 'MPA', (186, 190))	('increase', 'PosReg', (80, 88))	('disease remission rate', 'CPA', (111, 133))	('survival rate', 'CPA', (93, 106))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Disease', (137, 143))	('reducing', 'NegReg', (160, 168))	('MLT', 'Gene', (70, 73))	('supplementation', 'Var', (51, 66))
30195	30510430	MLT significantly increased the tumor remission rate compared to the control group (RR =2.25; 95% CI, 1.86-2.71; P<0.00001).	('increased', 'PosReg', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MLT', 'Var', (0, 3))	('tumor', 'Disease', (32, 37))
30196	30510430	Compared to the control group, MLT significantly increased the overall survival rate of cancer patients (RR =2.07; 95% CI, 1.55-2.76; P<0.00001).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('overall', 'MPA', (63, 70))	('patients', 'Species', '9606', (95, 103))	('increased', 'PosReg', (49, 58))	('MLT', 'Var', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
30199	30510430	A total of 384 patients were involved in lung cancer; the survival rate of MLT group was 27.98% (n=61/218), which was significantly higher than that of 14.46% (n=24/166) in the control group.	('higher', 'PosReg', (132, 138))	('patients', 'Species', '9606', (15, 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))	('MLT', 'Var', (75, 78))
30207	30510430	The neurotoxicity rate in the MLT group was 13.12% (n=87/663), which was significantly lower than that of 20.16% (n=123/610) in the control group (RR =0.31; 95% CI, 0.14-0.66; P=0.003).	('lower', 'NegReg', (87, 92))	('MLT', 'Var', (30, 33))	('neurotoxicity', 'Disease', 'MESH:D020258', (4, 17))	('neurotoxicity', 'Disease', (4, 17))
30208	30510430	The MLT group had a 4.43% (n=25/564) neurotoxicity rate, which was significantly lower than that of 16.31% (n=92/564) in the control group, with combined RR 0.30 (95% CI, 0.19-0.45; P<0.00001).	('lower', 'NegReg', (81, 86))	('neurotoxicity', 'Disease', (37, 50))	('MLT', 'Var', (4, 7))	('neurotoxicity', 'Disease', 'MESH:D020258', (37, 50))
30214	30510430	The incidence of asthenia was 18.91% (n=251/1,327) in the MLT group and 43.50% (n=579/1,331) in the control group.	('asthenia', 'Phenotype', 'HP:0025406', (17, 25))	('MLT', 'Var', (58, 61))	('asthenia', 'Disease', 'MESH:D001247', (17, 25))	('asthenia', 'Disease', (17, 25))
30228	30510430	Through the combination of the results of the study, it was demonstrated that MLT significantly decreased the tumor remission rate compared to the control group (RR =2.25; 95% CI, 1.86-2.71; P<0.00001).	('MLT', 'Var', (78, 81))	('decreased', 'NegReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
30235	30510430	In the study of reducing side effects of chemotherapy, it was confirmed that MLT can effectively reduce the incidence rate of neurotoxicity (RR =0.30, 95% CI, 0.19-0.45; P<0.00001), thrombocytopenia (RR =0.23; 95% CI, 0.16-0.33; P<0.00001), and asthenia (RR =0.43, 95% CI, 0.38-0.49; P<0.00001).	('thrombocytopenia', 'Disease', 'MESH:D013921', (182, 198))	('MLT', 'Var', (77, 80))	('asthenia', 'Disease', 'MESH:D001247', (245, 253))	('asthenia', 'Phenotype', 'HP:0025406', (245, 253))	('asthenia', 'Disease', (245, 253))	('thrombocytopenia', 'Disease', (182, 198))	('neurotoxicity', 'Disease', 'MESH:D020258', (126, 139))	('neurotoxicity', 'Disease', (126, 139))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (182, 198))	('reduce', 'NegReg', (97, 103))
30236	30510430	Based on the above meta-analysis results, it was concluded that MLT, as an adjuvant for the treatment of tumors, can effectively improve the remission rate and overall survival rate of tumor patients, while reducing the incidence rate of neurotoxicity, thrombocytopenia, and asthenia during chemotherapy.	('tumors', 'Disease', (105, 111))	('reducing', 'NegReg', (207, 215))	('tumor', 'Disease', (185, 190))	('thrombocytopenia', 'Disease', (253, 269))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('neurotoxicity', 'Disease', (238, 251))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('asthenia', 'Phenotype', 'HP:0025406', (275, 283))	('asthenia', 'Disease', 'MESH:D001247', (275, 283))	('tumor', 'Disease', (105, 110))	('neurotoxicity', 'Disease', 'MESH:D020258', (238, 251))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('thrombocytopenia', 'Disease', 'MESH:D013921', (253, 269))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (253, 269))	('improve', 'PosReg', (129, 136))	('MLT', 'Var', (64, 67))	('patients', 'Species', '9606', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('remission', 'MPA', (141, 150))	('asthenia', 'Disease', (275, 283))
30287	29552286	CCK-8 assay indicated that repression of SOCS4 promoted cell proliferation, while miR-1290 downregulation inhibited cell proliferation (Figure 4E).	('cell proliferation', 'biological_process', 'GO:0008283', ('116', '134'))	('miR-1290', 'Gene', (82, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('promoted', 'PosReg', (47, 55))	('miR-1290', 'Gene', '100302276', (82, 90))	('cell proliferation', 'CPA', (56, 74))	('downregulation inhibited', 'NegReg', (91, 115))	('SOCS4', 'Gene', (41, 46))	('cell proliferation', 'CPA', (116, 134))	('repression', 'Var', (27, 37))
30293	29552286	Consistently, transfection of miR-1290 mimic increased expression of pSTAT3 and pAKT but not of total STAT3 or AKT (Figure 5B).	('AKT', 'Gene', '207', (111, 114))	('miR-1290', 'Gene', (30, 38))	('increased', 'PosReg', (45, 54))	('AKT', 'Gene', '207', (81, 84))	('expression', 'MPA', (55, 65))	('transfection', 'Var', (14, 26))	('AKT', 'Gene', (111, 114))	('AKT', 'Gene', (81, 84))	('miR-1290', 'Gene', '100302276', (30, 38))	('pSTAT3', 'Gene', (69, 75))
30326	29552286	Indeed, SOCS4 was previously shown to be inversely associated with tumor node metastasis in breast cancer, and another research found that SOCS4 was attenuated in gastric cancer tissues and SOCS4 hypermethylation was related to poor prognosis.	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('tumor', 'Disease', (67, 72))	('SOCS4', 'Gene', (139, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('related', 'Reg', (217, 224))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('gastric cancer', 'Disease', (163, 177))	('hypermethylation', 'Var', (196, 212))	('breast cancer', 'Disease', (92, 105))	('attenuated', 'NegReg', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('inversely', 'NegReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('SOCS4', 'Gene', (190, 195))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('SOCS4', 'Gene', (8, 13))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
30328	29552286	demonstrated that inhibition of miR-1290 suppressed cell proliferation and invasion of NSCLC in vitro.	('NSCLC', 'Disease', (87, 92))	('miR-1290', 'Gene', '100302276', (32, 40))	('cell proliferation', 'CPA', (52, 70))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('suppressed', 'NegReg', (41, 51))	('miR-1290', 'Gene', (32, 40))	('inhibition', 'Var', (18, 28))	('invasion of', 'CPA', (75, 86))
30336	29552286	We showed for the first time via functional assays that SOCS4 regulated the JAK/STAT3 and PI3K/AKT signaling pathways in LADC, as indicated by the fact that reducing SOCS4 level increased pSTAT3 and pAKT expression.	('JAK', 'molecular_function', 'GO:0004713', ('76', '79'))	('AKT signaling', 'biological_process', 'GO:0043491', ('95', '108'))	('AKT', 'Gene', '207', (200, 203))	('reducing', 'Var', (157, 165))	('AKT', 'Gene', '207', (95, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('90', '94'))	('AKT', 'Gene', (200, 203))	('LADC', 'Phenotype', 'HP:0030078', (121, 125))	('AKT', 'Gene', (95, 98))	('regulated', 'Reg', (62, 71))	('SOCS4 level', 'MPA', (166, 177))	('pSTAT3', 'MPA', (188, 194))	('increased', 'PosReg', (178, 187))
30430	29435134	Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively.	('MLKL', 'Gene', (151, 155))	('autophagy-related', 'CPA', (109, 126))	('RIP-1', 'Gene', '8737', (137, 142))	('tumor', 'Disease', (52, 57))	('elevated', 'PosReg', (30, 38))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RIP-3', 'Gene', '11035', (144, 149))	('level', 'MPA', (43, 48))	('MLKL', 'Gene', '197259', (151, 155))	('RIP-1', 'Gene', (137, 142))	('AgNPs', 'Var', (10, 15))	('LC3', 'Gene', '84557', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('autophagy', 'biological_process', 'GO:0016236', ('109', '118'))	('necroptosis', 'biological_process', 'GO:0070266', ('92', '103'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('necroptosis', 'biological_process', 'GO:0097528', ('92', '103'))	('RIP-3', 'Gene', (144, 149))	('autophagy', 'biological_process', 'GO:0006914', ('109', '118'))	('necroptosis-', 'CPA', (92, 104))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('LC3', 'Gene', (160, 163))
30468	29435134	2.6 nm AgNPs exerted about 16-fold higher cytotoxicity than 18 nm AgNPs.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('AgNPs', 'Var', (7, 12))	('cytotoxicity', 'Disease', (42, 54))	('higher', 'PosReg', (35, 41))
30506	29435134	Statistically significant increase of RIP3 and MLKL protein level was found after treatment with 2.5 mug/mL 2.6 nm AgNPs and after exposure to 25 mug/mL and 50 mug/mL 18 nm AgNPs.	('MLKL', 'Gene', (47, 51))	('mug', 'molecular_function', 'GO:0043739', ('101', '104'))	('mug', 'molecular_function', 'GO:0043739', ('146', '149'))	('RIP3', 'Gene', '11035', (38, 42))	('mug', 'molecular_function', 'GO:0043739', ('160', '163'))	('2.6 nm AgNPs', 'Var', (108, 120))	('MLKL', 'Gene', '197259', (47, 51))	('AgNPs', 'Var', (115, 120))	('RIP3', 'Gene', (38, 42))	('increase', 'PosReg', (26, 34))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
30521	29435134	In our previous study, we demonstrated that AgNO3 exerted more cytotoxic effect against human gingival fibroblast cells in comparison to 10 nm AgNPs.	('AgNO3', 'Chemical', 'MESH:D012835', (44, 49))	('cytotoxic effect', 'CPA', (63, 79))	('rat', 'Species', '10116', (33, 36))	('AgNO3', 'Var', (44, 49))	('human', 'Species', '9606', (88, 93))
30533	29435134	found that AgNPs may be approximately 2-fold more cytotoxic to acute myeloid leukemia compared to healthy human bone marrow cells.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (63, 85))	('human', 'Species', '9606', (106, 111))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (63, 85))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (69, 85))	('AgNPs', 'Var', (11, 16))	('acute myeloid leukemia', 'Disease', (63, 85))
30540	29435134	show that among three sizes of AgNPs, the smallest ones (20.6 +- 2.7 nm) had significant effect on enhancing apoptosis rate and thermo-induced killing of glioma cells in vitro.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('enhancing', 'PosReg', (99, 108))	('thermo-induced killing', 'CPA', (128, 150))	('rat', 'Species', '10116', (119, 122))	('20.6 +-', 'Var', (57, 64))	('glioma', 'Disease', (154, 160))	('apoptosis rate', 'CPA', (109, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))
30543	29435134	What is more, AgNPs showed more than a hundred thousand-fold higher efficiency compared with gemcitabine to decrease pancreatic cancer cell viability and induced pancreatic cancer cells death.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('induced', 'Reg', (154, 161))	('higher', 'PosReg', (61, 67))	('pancreatic cancer', 'Disease', (162, 179))	('AgNPs', 'Var', (14, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('decrease', 'NegReg', (108, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))
30565	29435134	found that human squamous carcinoma cells exposed to 10 nm AgNPs resulted in an increase of pro-apoptotic proteins (Bax).	('Bax', 'Gene', '581', (116, 119))	('human', 'Species', '9606', (11, 16))	('squamous carcinoma', 'Disease', 'MESH:D002294', (17, 35))	('increase', 'PosReg', (80, 88))	('squamous carcinoma', 'Disease', (17, 35))	('AgNPs', 'Var', (59, 64))	('Bax', 'Gene', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (17, 35))
30569	29435134	We noticed that both 2.6 and 18 nm AgNPs caused an elevation of p53 protein level in PANC-1 cells.	('PANC-1', 'CellLine', 'CVCL:0480', (85, 91))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('AgNPs', 'Var', (35, 40))	('elevation', 'PosReg', (51, 60))	('p53 protein level', 'MPA', (64, 81))
30572	29435134	Also, AgNPs are known to induce p53-mediated apoptosis in human breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('human', 'Species', '9606', (58, 63))	('AgNPs', 'Var', (6, 11))	('induce', 'PosReg', (25, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('p53-mediated apoptosis', 'CPA', (32, 54))	('breast cancer', 'Disease', (64, 77))
30576	29435134	indicated that activation of p53 enhanced autophagy levels in cells, which might contribute to the tumor suppressor functions of p53.	('tumor', 'Disease', (99, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('autophagy levels in cells', 'CPA', (42, 67))	('autophagy', 'biological_process', 'GO:0006914', ('42', '51'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))	('p53', 'Gene', (29, 32))	('activation', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('autophagy', 'biological_process', 'GO:0016236', ('42', '51'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('enhanced', 'PosReg', (33, 41))
30582	29435134	It has been found that inhibition of autophagy may be a new therapeutic approach in the treatment of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('inhibition', 'Var', (23, 33))	('pancreatic cancer', 'Disease', (101, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (101, 118))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('autophagy', 'CPA', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))
30588	29435134	Indeed, in our study we have observed that 2.6 and 18 nm AgNPs-induced apoptotic as well necroptotic PANC-1 cell death was associated with increased level of autophagy markers (LC-3) and formation of autophagosomes.	('autophagy', 'biological_process', 'GO:0016236', ('158', '167'))	('cell death', 'biological_process', 'GO:0008219', ('108', '118'))	('formation of autophagosomes', 'CPA', (187, 214))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('LC-3', 'Gene', '84557', (177, 181))	('increased', 'PosReg', (139, 148))	('PANC-1', 'CellLine', 'CVCL:0480', (101, 107))	('AgNPs-induced', 'Gene', (57, 70))	('autophagy', 'biological_process', 'GO:0006914', ('158', '167'))	('2.6', 'Var', (43, 46))	('level', 'MPA', (149, 154))	('LC-3', 'Gene', (177, 181))	('apoptotic', 'CPA', (71, 80))
30633	29435134	M300F- 500) (3:1 ratio) with 2 mM L-glutamine adjusted to 1.5 g/L sodium bicarbonate and supplemented with 5% FBS, 10 ng/ml human recombinant EGF, 5.5 mM D-glucose (1g/L) and 750 ng/mL puromycin, at 37 C in a humidified atmosphere of 5% CO2.	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (66, 84))	('M300F- 500', 'Var', (0, 10))	('FBS', 'Disease', (110, 113))	('rat', 'Species', '10116', (17, 20))	('glutamine', 'Chemical', 'MESH:D005973', (36, 45))	('EGF', 'molecular_function', 'GO:0005154', ('142', '145'))	('human', 'Species', '9606', (124, 129))	('CO2', 'Chemical', '-', (237, 240))	('D-glucose', 'Chemical', 'MESH:D005947', (154, 163))	('FBS', 'Disease', 'MESH:D005198', (110, 113))	('puromycin', 'Chemical', 'MESH:D011691', (185, 194))	('M300F', 'Mutation', 'p.M300F', (0, 5))
30673	29435134	The samples (40 mug protein per lane) were boiled for 5 minutes and separated by SDS-PAGE on polyacrylamide gel and transferred onto nitrocellulose membrane, which was blocked with 5% non-fat dry milk-PBST buffer (phosphate-buffered saline (PBS) containing 0.1% Tween-20) for 1 hour at room temperature and incubated at 4 C overnight with rabbit polyclonal antibody: anti-Bax, anti-Bcl-2, anti-RIP-1, anti-RIP-3, anti-LC3, anti-p53, and goat polyclonal anti-MLKL (diluted 1:500).	('RIP-3', 'Gene', '11035', (406, 411))	('goat', 'Species', '9925', (437, 441))	('antibody', 'cellular_component', 'GO:0019814', ('357', '365'))	('rat', 'Species', '10116', (72, 75))	('LC3', 'Gene', (418, 421))	('SDS', 'Chemical', 'MESH:D012967', (81, 84))	('PBS', 'Chemical', '-', (241, 244))	('MLKL', 'Gene', (458, 462))	('PBS', 'Chemical', '-', (201, 204))	('RIP-1', 'Gene', '8737', (394, 399))	('Bax', 'Gene', (372, 375))	('membrane', 'cellular_component', 'GO:0016020', ('148', '156'))	('Bcl-2', 'Gene', (382, 387))	('antibody', 'molecular_function', 'GO:0003823', ('357', '365'))	('Bax', 'Gene', '581', (372, 375))	('antibody', 'cellular_component', 'GO:0042571', ('357', '365'))	('RIP-3', 'Gene', (406, 411))	('MLKL', 'Gene', '197259', (458, 462))	('rat', 'Species', '10116', (296, 299))	('LC3', 'Gene', '84557', (418, 421))	('mug', 'molecular_function', 'GO:0043739', ('16', '19'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('382', '387'))	('RIP-1', 'Gene', (394, 399))	('boiled', 'Phenotype', 'HP:0020083', (43, 49))	('Bcl-2', 'Gene', '596', (382, 387))	('Tween', 'Chemical', 'MESH:D011136', (262, 267))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('rabbit', 'Species', '9986', (339, 345))	('antibody', 'cellular_component', 'GO:0019815', ('357', '365'))	('anti-p53', 'Var', (423, 431))
30687	29435134	Our results lead us to assume that AgNPs could bypass drug resistance by inducing mixed type of cell death in pancreatic ductal adenocarcinoma cells.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (110, 142))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('inducing', 'Reg', (73, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('drug resistance', 'biological_process', 'GO:0042493', ('54', '69'))	('AgNPs', 'Var', (35, 40))	('mixed type of cell death', 'CPA', (82, 106))	('drug resistance', 'biological_process', 'GO:0009315', ('54', '69'))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))	('pancreatic ductal adenocarcinoma', 'Disease', (110, 142))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (110, 142))
30697	28784178	Osimertinib, a third-generation EGFR TKI, received accelerated approval by the US FDA in November 2015 as it was demonstrated to display superiority in terms of the progression-free survival (PFS) and durability of response over platinum plus pemetrexed in EGFR T790M-positive patients after EGFR TKI treatment in a large phase III trial (AURA3, NCT02151981, principal investigator (PI) in China: Yi-long Wu, Guangdong General Hospital).	('EGFR', 'Gene', '1956', (292, 296))	('EGFR', 'molecular_function', 'GO:0005006', ('292', '296'))	('pemetrexed', 'Chemical', 'MESH:D000068437', (243, 253))	('EGFR', 'Gene', (257, 261))	('EGFR', 'Gene', (292, 296))	('EGFR', 'molecular_function', 'GO:0005006', ('257', '261'))	('EGFR', 'Gene', '1956', (32, 36))	('platinum', 'Chemical', 'MESH:D010984', (229, 237))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('patients', 'Species', '9606', (277, 285))	('T790M-positive', 'Var', (262, 276))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('T790M', 'Mutation', 'rs121434569', (262, 267))	('EGFR', 'Gene', '1956', (257, 261))
30700	28784178	Moreover, the fourth-generation EGFR inhibitor EAI045.3, which appears to overcome T790M and C797S resistance, is under preclinical development.	('EGFR', 'Gene', '1956', (32, 36))	('T790M', 'Mutation', 'rs121434569', (83, 88))	('C797S', 'Mutation', 'rs1057519861', (93, 98))	('EGFR', 'Gene', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('C797S', 'Var', (93, 98))	('T790M', 'Var', (83, 88))
30710	28784178	The purpose of this clinical trial is to determine the safety, antitumor activity, and recommended phase II dose (RP2D) of avitinib in T790M-positive NSCLC patients.	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('RP2', 'Gene', '6102', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('avitinib', 'Chemical', '-', (123, 131))	('T790M-positive', 'Var', (135, 149))	('NSCLC', 'Disease', (150, 155))	('T790M', 'Mutation', 'rs121434569', (135, 140))	('RP2', 'Gene', (114, 117))
30718	28784178	These preclinical agents include osimertinib, which is already on the market and is being tested in patients with the EGFR mutations who have CNS metastases, and another novel agent (AZD3759), which was primarily designed for favorable CNS penetration.	('CNS', 'Disease', (142, 145))	('metastases', 'Disease', (146, 156))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('EGFR', 'Gene', '1956', (118, 122))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', (118, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('AZD3759', 'Chemical', 'MESH:C000604577', (183, 190))	('mutations', 'Var', (123, 132))	('osimertinib', 'Chemical', 'MESH:C000603933', (33, 44))
30738	28784178	In phase III trials (ASCEND-4, NCT01828099; J-ALEX, NCT02075840) on first-line treatment with ceritinib or alectinib, both groups of patients showed a significant PFS benefit compared with patients receiving chemotherapy or crizotinib.	('benefit', 'PosReg', (167, 174))	('ceritinib', 'Chemical', 'MESH:C586847', (94, 103))	('crizotinib', 'Chemical', 'MESH:D000077547', (224, 234))	('patients', 'Species', '9606', (133, 141))	('alectinib', 'Chemical', 'MESH:C582670', (107, 116))	('NCT02075840', 'Var', (52, 63))	('patients', 'Species', '9606', (189, 197))	('PFS', 'CPA', (163, 166))
30750	28784178	It is currently being tested in a phase I/II study (CTR20160340 PI: Yi-long Wu, Guangdong General Hospital, China) to determine its safety, tolerability, and RP2D.	('RP2', 'Gene', (158, 161))	('CTR20160340', 'Var', (52, 63))	('RP2', 'Gene', '6102', (158, 161))
30754	28784178	NCT02838420 is a randomized phase III study (PI: Cai-cun Zhou, Shanghai Pulmonary Hospital, China) that aims to confirm the PFS benefit for patients treated with alectinib in the J-ALEX study (NCT02075840 PI in China: Cai-cun Zhou, Shanghai Pulmonary Hospital, China).	('alectinib', 'Chemical', 'MESH:C582670', (162, 171))	('patients', 'Species', '9606', (140, 148))	('NCT02075840', 'Var', (193, 204))	('NCT02838420', 'Var', (0, 11))
30760	28784178	In an expansion cohort phase I study (PROFILE 1001, NCT00585195), crizotinib, a multi-kinase inhibitor, showed encouraging ORRs of 44% (8/18) in patients with MET exon 14-altered NSCLC and 50% (3/6) in patients with MET amplification (MET/CEP7 ratio >=5) NSCLC.	('patients', 'Species', '9606', (145, 153))	('MET exon', 'Var', (159, 167))	('MET', 'Var', (216, 219))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('86', '102'))	('NSCLC', 'Disease', (255, 260))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('patients', 'Species', '9606', (202, 210))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('CEP', 'molecular_function', 'GO:0047849', ('239', '242'))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('crizotinib', 'Chemical', 'MESH:D000077547', (66, 76))	('NSCLC', 'Disease', (179, 184))
30767	28784178	Eligible patients were centrally assessed as being c-MET-positive (IHC 3+ or 2+ and gene copy number >5).	('c-MET', 'Gene', (51, 56))	('patients', 'Species', '9606', (9, 17))	('gene copy number >5', 'Var', (84, 103))	('c-MET', 'Gene', '4233', (51, 56))
30786	28784178	Four hundred thirty-seven patients with sensitive EGFR or ALK mutations, who must have received and have had intolerance to previous targeted therapies, were enrolled in this study.	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('ALK', 'Gene', (58, 61))	('EGFR', 'Gene', '1956', (50, 54))	('patients', 'Species', '9606', (26, 34))	('EGFR', 'Gene', (50, 54))	('mutations', 'Var', (62, 71))	('ALK', 'Gene', '238', (58, 61))
30801	28784178	Clinical trials of second-generation selective FGFR inhibitors (such as AZD4547, BGJ398, LY2874455, JNJ-42756493, and FP-1039) have started; most are still in phase I/II.	('FGFR', 'Gene', (47, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('AZD4547', 'Chemical', 'MESH:C572463', (72, 79))	('LY2874455', 'Var', (89, 98))	('BGJ398', 'Chemical', 'MESH:C568950', (81, 87))	('LY2874455', 'Chemical', 'MESH:C570663', (89, 98))	('BGJ398', 'Gene', (81, 87))
30804	28784178	Moreover, AL3810, a novel agent developed in China, is being tested in advanced solid tumors in a phase I study.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('AL3810', 'Var', (10, 16))	('solid tumors', 'Disease', 'MESH:D009369', (80, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('AL3810', 'Chemical', 'MESH:C000595232', (10, 16))	('solid tumors', 'Disease', (80, 92))
30806	28784178	This study is being conducted in Japan and China recruiting patients with advanced solid tumors harboring FGFR alterations.	('FGFR', 'Gene', (106, 110))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('patients', 'Species', '9606', (60, 68))	('alterations', 'Var', (111, 122))	('solid tumors', 'Disease', (83, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
30812	28784178	In this single-arm study, participants must meet the molecular eligibility criteria of FGFR alteration and will receive erdafitinib 8 mg once daily with the option to titrate up to 9 mg in 28-day cycles.	('alteration', 'Var', (92, 102))	('erdafitinib', 'Chemical', 'MESH:C000604580', (120, 131))	('participants', 'Species', '9606', (26, 38))	('FGFR', 'Gene', (87, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('to 9', 'Species', '1214577', (178, 182))
30817	28784178	NCT02597946 (PI: Cai-cun Zhou, Shanghai Pulmonary Hospital, China) is a single-arm phase II study designed to investigate the efficacy and safety of afatinib in patients with advanced NSCLC with HER2 mutations who were previously treated with one or two chemotherapy regimens.	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('mutations', 'Var', (200, 209))	('NSCLC', 'Disease', (184, 189))	('afatinib', 'Chemical', 'MESH:D000077716', (149, 157))	('patients', 'Species', '9606', (161, 169))	('HER2', 'Gene', (195, 199))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('HER2', 'Gene', '2064', (195, 199))
30827	28784178	Confirmatory phase II studies of these inhibitors are underway globally (NCT02183870, NCT01945021, NCT01964157, NCT02927340, NCT01970865); however, only crizotinib is being tested in Chinese patients with ROS1-positive NSCLC.	('NSCLC', 'Disease', (219, 224))	('crizotinib', 'Chemical', 'MESH:D000077547', (153, 163))	('patients', 'Species', '9606', (191, 199))	('NCT01970865', 'Var', (125, 136))	('NSCLC', 'Disease', 'MESH:D002289', (219, 224))	('NCT02927340', 'Var', (112, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (219, 224))	('ROS1', 'Gene', (205, 209))	('ROS1', 'Gene', '6098', (205, 209))
30845	28784178	Although no BRAF inhibitor has yet been granted approval for patients with BRAF V600E-mutant NSCLC by the CFDA, a second-generation BRAF inhibitor named BGB-283 developed in China has displayed potent inhibition in preclinical studies on BRAFV600E and EGFR mutation/amplification.	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('BRAFV600E', 'Mutation', 'rs113488022', (238, 247))	('BRAF', 'Gene', '673', (238, 242))	('NSCLC', 'Disease', (93, 98))	('V600E', 'Mutation', 'rs113488022', (242, 247))	('BRAF', 'Gene', (238, 242))	('patients', 'Species', '9606', (61, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('EGFR', 'Gene', '1956', (252, 256))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', (132, 136))	('CFDA', 'Chemical', '-', (106, 110))	('V600E', 'Mutation', 'rs113488022', (80, 85))	('BRAF', 'Gene', (12, 16))	('inhibition', 'NegReg', (201, 211))	('BRAF', 'Gene', '673', (12, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('252', '256'))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('mutation/amplification', 'Var', (257, 279))	('EGFR', 'Gene', (252, 256))
30848	28784178	NCT02330367, a dose escalation and expansion phase I/II study, aims to determine the safety profile and RP2D of avitinib in EGFR T790M-positive patients.	('T790M', 'Mutation', 'rs121434569', (129, 134))	('RP2', 'Gene', '6102', (104, 107))	('EGFR', 'Gene', '1956', (124, 128))	('T790M-positive', 'Var', (129, 143))	('EGFR', 'Gene', (124, 128))	('patients', 'Species', '9606', (144, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('avitinib', 'Chemical', '-', (112, 120))	('RP2', 'Gene', (104, 107))
30853	28784178	Five agents targeting different molecular abnormalities are being studied: INC280 for MET-positive patients; LDK378 for ALK or ROS1 rearrangement patients; BYL719 for patients with PIK3CA mutation/amplification; MEK162 for patients with KRAS, NRAS, or BRAF mutations; and allitinib for patients with HER2 or HER4 mutations.	('KRAS', 'Gene', (237, 241))	('ROS1', 'Gene', (127, 131))	('MEK', 'Gene', '5609', (212, 215))	('PIK3CA', 'Gene', (181, 187))	('molecular abnormalities', 'Disease', 'MESH:C567116', (32, 55))	('HER4', 'Gene', '2066', (308, 312))	('allitinib', 'Chemical', 'MESH:C568037', (272, 281))	('MEK', 'Gene', (212, 215))	('NRAS', 'Gene', '4893', (243, 247))	('patients', 'Species', '9606', (146, 154))	('HER2', 'Gene', '2064', (300, 304))	('BRAF', 'Gene', '673', (252, 256))	('ROS1', 'Gene', '6098', (127, 131))	('BRAF', 'Gene', (252, 256))	('mutation/amplification', 'Var', (188, 210))	('patients', 'Species', '9606', (99, 107))	('PIK3CA', 'Gene', '5290', (181, 187))	('ALK', 'Gene', '238', (120, 123))	('HER4', 'Gene', (308, 312))	('KRAS', 'Gene', '3845', (237, 241))	('ALK', 'Gene', (120, 123))	('patients', 'Species', '9606', (167, 175))	('NRAS', 'Gene', (243, 247))	('molecular abnormalities', 'Disease', (32, 55))	('patients', 'Species', '9606', (223, 231))	('patients', 'Species', '9606', (286, 294))	('HER2', 'Gene', (300, 304))
30857	28784178	Furthermore, the best intervention time for anti-resistance agents (such as osimertinib) will be explored through quantitative and dynamic analysis of EGFR-sensitive and resistant mutations in plasma cfDNA during the EGFR TKI treatment process.	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (217, 221))	('mutations', 'Var', (180, 189))	('EGFR', 'Gene', (151, 155))	('cfDNA', 'Gene', (200, 205))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('osimertinib', 'Chemical', 'MESH:C000603933', (76, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('EGFR', 'Gene', '1956', (151, 155))
30861	28784178	Second, most novel small molecular inhibitors target EGFR, PDGFR, HER2, or VEGFR; inhibitors targeting ALK, RAF, MEK, and JAK are relatively rare.	('JAK', 'molecular_function', 'GO:0004713', ('122', '125'))	('HER2', 'Gene', '2064', (66, 70))	('EGFR', 'Gene', (53, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('EGFR', 'Gene', (76, 80))	('target', 'Reg', (46, 52))	('small', 'Var', (19, 24))	('EGFR', 'Gene', '1956', (53, 57))	('VEGFR', 'Gene', '3791', (75, 80))	('HER2', 'Gene', (66, 70))	('MEK', 'Gene', '5609', (113, 116))	('RAF', 'Gene', '22882', (108, 111))	('VEGFR', 'Gene', (75, 80))	('EGFR', 'Gene', '1956', (76, 80))	('PDGFR', 'Gene', (59, 64))	('PDGFR', 'Gene', '5159', (59, 64))	('MEK', 'Gene', (113, 116))	('ALK', 'Gene', '238', (103, 106))	('RAF', 'Gene', (108, 111))	('ALK', 'Gene', (103, 106))
30863	28784178	To date, Chinese investigators have found liquid biopsy to be efficacious in monitoring the dynamic change of driver genes during treatment in several studies (FASTAC-2/NCT00883779; CTONG0901/NCT01024413).	('AST', 'Gene', (161, 164))	('CTONG0901/NCT01024413', 'Var', (182, 203))	('AST', 'Gene', '26503', (161, 164))
30864	28784178	Furthermore, in a prospective phase II study (BENEFIT, NCT02282267), the EGFR mutation status was determined by cfDNA in the plasma.	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (73, 77))	('mutation', 'Var', (78, 86))
30869	28392479	ctDNAs are detected and tracked primarily based on tumor-related genetic and epigenetic alterations.	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('epigenetic alterations', 'Var', (77, 99))	('tumor', 'Disease', (51, 56))
30901	28392479	detected mutated RAS gene fragments in the blood of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (66, 90))	('RAS gene', 'Gene', (17, 25))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('mutated', 'Var', (9, 16))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (107, 127))	('myelodysplastic syndrome', 'Disease', (66, 90))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (101, 127))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (66, 90))	('AML', 'Phenotype', 'HP:0004808', (129, 132))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))	('AML', 'Disease', (129, 132))	('acute myelogenous leukemia', 'Disease', (101, 127))	('MDS', 'Disease', (92, 95))	('MDS', 'Phenotype', 'HP:0002863', (92, 95))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (101, 127))	('MDS', 'Disease', 'MESH:D009190', (92, 95))	('patients', 'Species', '9606', (52, 60))
30902	28392479	demonstrated the presence of aberrant methylations on the promoters of five tumor-suppressor genes in the serum DNAs of patients with lung cancers.	('aberrant methylations', 'Var', (29, 50))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (76, 81))	('lung cancers', 'Disease', 'MESH:D008175', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (134, 146))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('methylations', 'Var', (38, 50))	('patients', 'Species', '9606', (120, 128))	('lung cancers', 'Disease', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
30912	28392479	Specific genetic variations in cancer cells can reflect the physical conditions and treatment responses of patients.	('genetic variations', 'Var', (9, 27))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('patients', 'Species', '9606', (107, 115))
30913	28392479	Detecting DNAs with tumor-specific mutations in the peripheral blood of patients with malignancies may help to identify dynamic changes in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (72, 80))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('mutations', 'Var', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('malignancies', 'Disease', (86, 98))	('DNAs', 'Gene', (10, 14))	('tumor', 'Disease', (20, 25))	('cancer', 'Disease', (139, 145))
30916	28392479	The aberrant methylations of ctDNAs have been described and investigated for clinical applications in most cancer types.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('methylations', 'Var', (13, 25))	('aberrant methylations', 'Var', (4, 25))	('ctDNAs', 'Gene', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('clinical', 'Species', '191496', (77, 85))	('cancer', 'Disease', (107, 113))
30931	28392479	screened for PIK3CA mutations in serum samples by beads, emulsification, amplification and magnetics (BEAMing) and reported sensitivities of 100% (14 of 14 patients).	('patients', 'Species', '9606', (156, 164))	('PIK3CA', 'Gene', '5290', (13, 19))	('mutations', 'Var', (20, 29))	('PIK3CA', 'Gene', (13, 19))
30936	28392479	demonstrated that pre-surgical ctDNAs with PIK3CA mutations from breast cancer patients showed sensitivities of 93.3% and specificities of 100% by droplet digital PCRs (ddPCRs).	('PIK3CA', 'Gene', '5290', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('pre', 'molecular_function', 'GO:0003904', ('18', '21'))	('patients', 'Species', '9606', (79, 87))	('PIK3CA', 'Gene', (43, 49))
30940	28392479	Aberrant ctDNA methylation offers a more consistent and broadly applicable marker of tumor DNA in serum in comparison to DNA mutations.	('tumor', 'Disease', (85, 90))	('methylation', 'Var', (15, 26))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('Aberrant', 'Var', (0, 8))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('ctDNA', 'Gene', (9, 14))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
30941	28392479	It has been shown that methylated RARB2 was reduced in blood of patients following surgical removal of the tumor.	('methylated', 'Var', (23, 33))	('RARB2', 'Gene', (34, 39))	('tumor', 'Disease', (107, 112))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
30942	28392479	Additional studies also reported that methylated RASSF1 in cancer patient can serve as an indicator of response to tamoxifen treatment.	('RASSF1', 'Gene', (49, 55))	('tamoxifen', 'Chemical', 'MESH:D013629', (115, 124))	('methylated', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patient', 'Species', '9606', (66, 73))	('RASSF1', 'Gene', '11186', (49, 55))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
30948	28392479	demonstrated the expression levels of KRAS mutant alleles in the plasma of patients using CRCs.	('KRAS', 'Gene', '3845', (38, 42))	('expression levels', 'MPA', (17, 34))	('patients', 'Species', '9606', (75, 83))	('mutant', 'Var', (43, 49))	('KRAS', 'Gene', (38, 42))
30949	28392479	KRAS mutations were detected in 41 patients with primary or metastatic tumors and the levels of the plasma mutant KRAS (pmKRAS) were lower than 75%.	('KRAS', 'Gene', (114, 118))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', (122, 126))	('KRAS', 'Gene', '3845', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('levels of', 'MPA', (86, 95))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('patients', 'Species', '9606', (35, 43))	('tumors', 'Disease', (71, 77))	('lower', 'NegReg', (133, 138))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (122, 126))	('KRAS', 'Gene', '3845', (0, 4))
30953	28392479	Using the SCODA assay, they demonstrated that the detected mutations were concordant between tissues and plasma in 93% of metastatic patients (n = 38) and 54% of non-metastatic patients.	('metastatic', 'Disease', (122, 132))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (59, 68))
30954	28392479	Additionally, the analysis of circulating mutant DNAs has been useful in monitoring of patients receiving anti-EGFR therapies.	('DNAs', 'Gene', (49, 53))	('mutant', 'Var', (42, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('EGFR', 'Gene', '1956', (111, 115))	('EGFR', 'Gene', (111, 115))	('patients', 'Species', '9606', (87, 95))
30955	28392479	Several studies have also established that the mutations of beta-catenin DNA were specifically associated with CRC tissues, suggesting that the mutations of ctDNAs could serve as promising targets for the detection of CRCs.	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('ctDNAs', 'Gene', (157, 163))	('mutations', 'Var', (47, 56))	('beta-catenin', 'Gene', (60, 72))	('CRC tissues', 'Disease', (111, 122))	('beta-catenin', 'Gene', '1499', (60, 72))	('associated', 'Reg', (95, 105))
30956	28392479	Regarding the aberrant methylations of ctDNAs, the hypermethylation of SEPT9 encoding septin 9 is highly associated with the progression of CRCs.	('SEPT9', 'Gene', '10801', (71, 76))	('CRCs', 'Disease', (140, 144))	('septin 9', 'Gene', '10801', (86, 94))	('hypermethylation', 'Var', (51, 67))	('SEPT9', 'Gene', (71, 76))	('septin 9', 'Gene', (86, 94))	('associated with', 'Reg', (105, 120))
30957	28392479	showed that the test for SEPT9 methylation correctly identified lung cancers in 31 of 70 (44%) samples, whereas positive results were only detected in 4 of 100 controls.	('lung cancers', 'Disease', 'MESH:D008175', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancers', 'Phenotype', 'HP:0100526', (64, 76))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('SEPT9', 'Gene', '10801', (25, 30))	('methylation', 'Var', (31, 42))	('SEPT9', 'Gene', (25, 30))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('lung cancers', 'Disease', (64, 76))
30958	28392479	In addition, hypermethylated RASSF1A and E-CAD have been considered as new biomarkers for CRCs as well.	('RASSF1A', 'Gene', '11186', (29, 36))	('E-CAD', 'Gene', '999', (41, 46))	('hypermethylated', 'Var', (13, 28))	('CRCs', 'Disease', (90, 94))	('RASSF1A', 'Gene', (29, 36))	('E-CAD', 'Gene', (41, 46))
30959	28392479	Tumor tissue genotyping is used routinely in cases of lung cancers to identify specific and targetable oncogenic alterations, including EGFR mutations and ALK rearrangements.	('lung cancers', 'Disease', 'MESH:D008175', (54, 66))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ALK', 'Gene', '238', (155, 158))	('mutations', 'Var', (141, 150))	('lung cancers', 'Phenotype', 'HP:0100526', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancers', 'Disease', (54, 66))	('rearrangements', 'Var', (159, 173))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('ALK', 'Gene', (155, 158))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('EGFR', 'Gene', (136, 140))
30961	28392479	In the past few years, studies have reported a series of achievements relevant to EGFR mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', (82, 86))	('mutations', 'Var', (87, 96))
30962	28392479	The cobas  EGFR Mutation Test v2 from Roche was the first liquid biopsy test approved by the USFDA in June 2016 for the detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations of NSCLC patients.	('patients', 'Species', '9606', (207, 215))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('L858R', 'Var', (168, 173))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('NSCLC', 'Disease', (201, 206))	('L858R', 'Mutation', 'rs121434568', (168, 173))	('deletions', 'Var', (146, 155))	('EGFR', 'Gene', '1956', (133, 137))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('EGFR', 'Gene', (133, 137))
30967	28392479	In addition, the sensitivities of detecting ctDNA mutations in primary pancreatic cancers are usually 30%-50%, and the specificities are usually higher (approximately 90%).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (50, 59))	('pancreatic cancers', 'Disease', 'MESH:D010190', (71, 89))	('pancreatic cancers', 'Disease', (71, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('ctDNA', 'Gene', (44, 49))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (71, 89))
30974	28392479	Unlike DNA mutations, the aberrant methylation of specific promoter regions that typically occurs at multiple sites may be a consistent characteristic of cancers.	('aberrant', 'Var', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('methylation', 'MPA', (35, 46))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))
30979	28392479	Due to recent technological advances, many methods are now available for detecting genetic mutations in cancers.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('genetic mutations', 'Var', (83, 100))
30986	28392479	TAm-Seq could identify TP53 mutations by tracking ctDNAs in ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('patients', 'Species', '9606', (75, 83))	('TAm', 'Chemical', 'MESH:D013629', (0, 3))	('ovarian cancer', 'Disease', (60, 74))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
30989	28392479	identified single nucleotide variants (SNVs) and copy number variations (CNVs) from the plasma of four HCC patients.	('single nucleotide variants', 'Var', (11, 37))	('patients', 'Species', '9606', (107, 115))	('copy', 'MPA', (49, 53))
30993	28392479	Application of CAPP-Seq in NSCLC samples lead to the identification of mutations in more than 95% of tumors.	('NSCLC', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('mutations', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
30994	28392479	For 100% of stage II-IV and 50% of stage I patients with NSCLCs, ctDNAs showed a specificity of 96% for mutant allele fractions down to approximately 0.02%.	('patients', 'Species', '9606', (43, 51))	('NSCLC', 'Disease', (57, 62))	('mutant', 'Var', (104, 110))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
30997	28392479	With a sensitivity of 92% and a specificity of more than 99.99% for the variant alleles, and concurrently, a sensitivity of 90% and a specificity of 96% in patients, iDES-enhanced CAPP-Seq enabled the biopsy-free profiling of mutations in the EGFR kinase domain (Table 3).	('patients', 'Species', '9606', (156, 164))	('EGFR', 'molecular_function', 'GO:0005006', ('243', '247'))	('iDES', 'Species', '69811', (166, 170))	('mutations', 'Var', (226, 235))	('EGFR', 'Gene', '1956', (243, 247))	('EGFR', 'Gene', (243, 247))	('variant', 'Var', (72, 79))
31002	28392479	In 2014, the cMethDNA assay, a new method based on the standard QM-MSP, was reported for the identification of novel methylated breast cancer genes in serum.	('methylated', 'Var', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
31007	28392479	In recent decades, an increasing number of studies have focused on the potential use of ctDNA methylations as biomarkers for early detection of cancers, for cancer screening, and for monitoring the efficacies of anticancer therapies.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ctDNA', 'Gene', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', (216, 222))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('methylations', 'Var', (94, 106))
31008	28392479	Shot-gun massively parallel bisulfite sequencing, another bisulfite sequencing-based technique, was also developed for the detection of ctDNA methylations.	('methylations', 'Var', (142, 154))	('ctDNA', 'Gene', (136, 141))	('bisulfite', 'Chemical', 'MESH:C042345', (58, 67))	('bisulfite', 'Chemical', 'MESH:C042345', (28, 37))
31009	28392479	Although tumor-specific mutations and methylations in ctDNAs are potential targets for the non-invasive cancer detection, and for the diagnoses, prognostic management, and guidance for treatments of these cancers, there are still barriers in the accurate detection of specific cell-free nucleic acids.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (205, 211))	('cancers', 'Disease', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('methylations', 'Var', (38, 50))	('tumor', 'Disease', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('ctDNAs', 'Gene', (54, 60))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
31025	28392479	As the identification of DMRs becomes easier, they are likely to be used as cancer biomarkers.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DMRs', 'Var', (25, 29))
31029	28392479	Additionally, in 2016, the EGFR Mutation Test v2 (cobas) became the first US FDA-approved in-vitro diagnostic (IVD) medical device for liquid biopsy for detecting EGFR mutations in NSCLCs.	('EGFR', 'Gene', '1956', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('EGFR', 'Gene', (27, 31))	('IVD', 'Disease', (111, 114))	('IVD', 'Disease', 'MESH:C538167', (111, 114))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('NSCLC', 'Disease', (181, 186))	('mutations', 'Var', (168, 177))
31055	28333143	The inheritance of mutated genes and somatic mutations are major causes for the development of cancer.	('mutations', 'Var', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('mutated genes', 'Var', (19, 32))	('causes', 'Reg', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
31057	28333143	AML is a Gas6-dependent cancer, and Gas6 expression predicts poor prognosis in AML.	('AML', 'Disease', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('AML', 'Phenotype', 'HP:0004808', (79, 82))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('AML', 'Disease', (0, 3))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('Gas6 expression', 'Var', (36, 51))
31058	28333143	Intriguingly, Gas6 inhibits intestinal cancer development.	('Gas6', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inhibits', 'NegReg', (19, 27))	('intestinal cancer', 'Disease', 'MESH:D007414', (28, 45))	('intestinal cancer', 'Disease', (28, 45))
31070	28333143	The Gla domain is generated by VKD gamma-carboxylation of a cluster of Glu residues and is believed to be involved in intramolecular and intermolecular protein-protein or protein-membrane interactions through Ca2+ binding.	('Ca2+', 'Chemical', 'MESH:D000069285', (209, 213))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('gamma-carboxylation', 'MPA', (35, 54))	('involved', 'Reg', (106, 114))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('VKD', 'Var', (31, 34))	('binding', 'molecular_function', 'GO:0005488', ('214', '221'))	('Glu residues', 'Protein', (71, 83))	('Glu', 'Chemical', 'MESH:D018698', (71, 74))	('membrane', 'cellular_component', 'GO:0016020', ('179', '187'))	('Gla', 'Gene', '2717', (4, 7))	('Gla', 'Gene', (4, 7))
31078	28333143	reported that a Gas6 mutant composed only of an SHBG-like domain retained both its receptor-binding and biological activities.	('SHBG', 'Gene', (48, 52))	('receptor-binding', 'molecular_function', 'GO:0005102', ('83', '99'))	('mutant', 'Var', (21, 27))	('biological activities', 'MPA', (104, 125))	('Gas6', 'Gene', (16, 20))	('SHBG', 'Gene', '6462', (48, 52))	('receptor-binding', 'Interaction', (83, 99))
31081	28333143	Gas6 stimulates TAM receptors and subsequently affects cell biological activity through downstream signalling pathways.	('Gas6', 'Var', (0, 4))	('TAM', 'Gene', '8205', (16, 19))	('downstream signalling pathways', 'Pathway', (88, 118))	('stimulates', 'PosReg', (5, 15))	('affects', 'Reg', (47, 54))	('cell biological activity', 'CPA', (55, 79))	('signalling', 'biological_process', 'GO:0023052', ('99', '109'))	('TAM', 'Gene', (16, 19))
31098	28333143	A microarray analysis demonstrated that Mer is a strong inducer of chemokines such as interleukin (IL)-8 in human prostate cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('interleukin (IL)-8', 'Gene', '3576', (86, 104))	('inducer', 'PosReg', (56, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('chemokines', 'MPA', (67, 77))	('human', 'Species', '9606', (108, 113))	('Mer', 'Var', (40, 43))	('IL)-8', 'molecular_function', 'GO:0005153', ('99', '104'))	('interleukin (IL)-8', 'Gene', (86, 104))	('prostate cancer', 'Disease', (114, 129))
31114	28333143	High expression of activated Axl is an independent predictor of a worse prognosis in osteosarcoma.	('activated Axl', 'Protein', (19, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('High', 'Var', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))
31130	28333143	It has been shown that patients expressing Gas6 (Gas6+), especially those with ages >=60 years, more often fail to achieve complete remission (CR) compared with those who do not express Gas6.	('patients', 'Species', '9606', (23, 31))	('complete', 'MPA', (123, 131))	('Gas6', 'Var', (43, 47))
31131	28333143	In all patients, Gas6+ patients exhibit shorter disease-free (DFS) and overall survival (OS) than those patients without Gas6 expression (Gas6-).	('patients', 'Species', '9606', (23, 31))	('disease-free', 'CPA', (48, 60))	('overall survival', 'CPA', (71, 87))	('Gas6+', 'Var', (17, 22))	('shorter', 'NegReg', (40, 47))	('patients', 'Species', '9606', (104, 112))	('patients', 'Species', '9606', (7, 15))
31146	28333143	In conclusion, all these results indicate that the expression of Gas6/TAM promotes the development of acute leukaemia.	('promotes', 'PosReg', (74, 82))	('acute leukaemia', 'Disease', 'MESH:D007938', (102, 117))	('TAM', 'Gene', (70, 73))	('acute leukaemia', 'Phenotype', 'HP:0002488', (102, 117))	('acute leukaemia', 'Disease', (102, 117))	('expression', 'Var', (51, 61))	('TAM', 'Gene', '8205', (70, 73))
31152	28333143	Specifically, Axl, Tyro3, Mer and their ligand Gas6 are expressed at higher levels in human primary schwannoma compared with those in normal Schwann cells.	('ligand', 'molecular_function', 'GO:0005488', ('40', '46'))	('schwannoma', 'Disease', (100, 110))	('human', 'Species', '9606', (86, 91))	('schwannoma', 'Disease', 'MESH:D009442', (100, 110))	('Mer', 'Var', (26, 29))	('Tyro3', 'Gene', '7301', (19, 24))	('Gas6', 'Gene', (47, 51))	('Tyro3', 'Gene', (19, 24))	('schwannoma', 'Phenotype', 'HP:0100008', (100, 110))	('higher levels', 'PosReg', (69, 82))
31186	28333143	found that shRNA knockdown of Mer or Axl significantly reduced NSCLC colony formation and the growth of subcutaneous xenografts in nude mice.	('nude mice', 'Species', '10090', (131, 140))	('Mer', 'Gene', (30, 33))	('NSCLC colony', 'Disease', 'MESH:D002289', (63, 75))	('reduced', 'NegReg', (55, 62))	('growth of subcutaneous xenografts', 'CPA', (94, 127))	('knockdown', 'Var', (17, 26))	('NSCLC colony', 'Disease', (63, 75))	('formation', 'biological_process', 'GO:0009058', ('76', '85'))
31187	28333143	Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('apoptosis', 'CPA', (102, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('Mer', 'Gene', (0, 3))	('promoting', 'PosReg', (92, 101))	('Axl', 'Protein', (7, 10))	('NSCLC', 'Disease', (44, 49))	('improved', 'PosReg', (26, 34))	('knockdown', 'Var', (11, 20))
31188	28333143	Significantly, when the effects of Mer and Axl knockdown were compared, Mer inhibition was found to achieve a more complete blockade of tumour growth, while Axl knockdown improved chemosensitivity more robustly.	('tumour growth', 'Disease', (136, 149))	('inhibition', 'NegReg', (76, 86))	('tumour growth', 'Disease', 'MESH:D006130', (136, 149))	('knockdown', 'Var', (161, 170))	('Axl', 'Protein', (157, 160))	('improved', 'PosReg', (171, 179))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
31200	28333143	Gas6-/- mice also exhibited more severe DSS-induced colitis.	('colitis', 'Disease', 'MESH:D003092', (52, 59))	('Gas6-/-', 'Var', (0, 7))	('colitis', 'Disease', (52, 59))	('colitis', 'Phenotype', 'HP:0002583', (52, 59))	('DSS', 'Chemical', '-', (40, 43))	('mice', 'Species', '10090', (8, 12))
31204	28333143	A study investigated the molecular basis of dormancy in the bone marrow microenvironment and found that in an osseous environment, a human prostate cancer cell line grew significantly better in vertebral body transplants derived from the Gas6-/- animals than in those derived from the Gas6+/+ animals.	('dormancy', 'biological_process', 'GO:0030431', ('44', '52'))	('prostate cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('better', 'PosReg', (184, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (139, 154))	('human', 'Species', '9606', (133, 138))	('grew', 'CPA', (165, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('Gas6-/-', 'Var', (238, 245))
31213	28333143	Therefore, Gas6 can be an independent potential biomarker for ovarian cancer both at the mRNA and protein levels.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Gas6', 'Var', (11, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('ovarian cancer', 'Disease', (62, 76))
31226	28333143	In summary, numerous studies have shown that Gas6 promote development of cancers from different systems (see Table 2), and targeting Gas6 therapy in the future can be more feasible.	('Gas6', 'Var', (45, 49))	('cancers', 'Disease', (73, 80))	('promote', 'PosReg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
31228	28333143	Numerous researches considering shRNA knockdown of TAM receptors have been shown effective in inhibition of different kinds of tumours including breast carcinoma, melanoma, PDA, osteosarcoma, NSCLC, thyroid cancer and AML.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('NSCLC', 'Disease', (192, 197))	('AML', 'Disease', 'MESH:D015470', (218, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('AML', 'Disease', (218, 221))	('AML', 'Phenotype', 'HP:0004808', (218, 221))	('breast carcinoma', 'Disease', 'MESH:D001943', (145, 161))	('osteosarcoma', 'Disease', (178, 190))	('osteosarcoma', 'Disease', 'MESH:D012516', (178, 190))	('inhibition', 'NegReg', (94, 104))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('TAM', 'Gene', (51, 54))	('tumours', 'Disease', (127, 134))	('thyroid cancer', 'Disease', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TAM', 'Gene', '8205', (51, 54))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('breast carcinoma', 'Phenotype', 'HP:0003002', (145, 161))	('tumours', 'Disease', 'MESH:D009369', (127, 134))	('breast carcinoma', 'Disease', (145, 161))	('thyroid cancer', 'Disease', 'MESH:D013964', (199, 213))	('osteosarcoma', 'Phenotype', 'HP:0002669', (178, 190))	('PDA', 'Disease', (173, 176))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('melanoma', 'Disease', (163, 171))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('thyroid cancer', 'Phenotype', 'HP:0002890', (199, 213))	('knockdown', 'Var', (38, 47))
31231	28333143	Several ongoing controlled trials involving R428 at various clinical centres are registered at ClinicalTrails.gov (Identifier: NCT02922777, NCT02488408, NCT02424617 and NCT02872259), which are aimed at identifying its maximum tolerated dose.	('NCT02424617', 'Var', (153, 164))	('NCT02872259', 'Var', (169, 180))	('R428', 'Chemical', '-', (44, 48))
31232	28333143	These studies include trials of R428 in NSCLC, AML and metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('R428', 'Chemical', '-', (32, 36))	('AML', 'Phenotype', 'HP:0004808', (47, 50))	('AML', 'Disease', (47, 50))	('NSCLC', 'Disease', (40, 45))	('R428', 'Var', (32, 36))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
31245	28331435	Methylation of circulating tumor DNA (ctDNA) has gained increasing attention as biomarkers for lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('tumor', 'Disease', (27, 32))	('Methylation', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
31256	28331435	Recent advances in the field of lung cancer epigenetics have revealed promising biomarkers, particularly involving ctDNA methylation and an emerging role of RNA methylation.	('ctDNA', 'Disease', (115, 120))	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('RNA', 'cellular_component', 'GO:0005562', ('157', '160'))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('methylation', 'Var', (121, 132))	('RNA methylation', 'biological_process', 'GO:0001510', ('157', '172'))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
31258	28331435	The cancer genome is globally hypomethylated, except for the dense methylation at CGIs that is associated with the permanent repression of tumor suppressor genes and other cancer-related genes, thus promotes cancer progression.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor suppressor', 'biological_process', 'GO:0051726', ('139', '155'))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('139', '155'))	('promotes', 'PosReg', (199, 207))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('CGIs', 'Gene', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('methylation', 'Var', (67, 78))
31259	28331435	In non-small cell lung cancer (NSCLC), CGI hypermethylation is associated with diagnosis, staging, cigarette smoking, histological subtype, molecular subtypes, progression, prognosis, and used as a potential therapeutic target.	('CGI', 'Gene', (39, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('NSCLC', 'Disease', (31, 36))	('associated', 'Reg', (63, 73))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('hypermethylation', 'Var', (43, 59))	('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))
31262	28331435	DNA hypomethylation in repetitive sequence occurred in early stage of squamous cell lung cancer, and individuals with hypomethylation in repetitive element are at a high risk of developing and dying from cancer.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('squamous cell lung cancer', 'Disease', (70, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('occurred', 'Reg', (43, 51))	('cancer', 'Disease', (89, 95))	('hypomethylation', 'Var', (118, 133))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('0', '19'))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (70, 95))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (70, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
31268	28331435	The concordant epigenetic alterations between ctDNA and corresponding tumor tissue DNA make ctDNA methylation a promising biomarker for cancer diagnosis and prognosis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('epigenetic alterations', 'Var', (15, 37))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
31277	28331435	Affinity enrichment-dependent methods utilize specific antibodies interacted with methylated cytosine or methyl-binding proteins to enrich methylated DNA, before further examination with whole-genome analysis by array-based hybridization or next generation sequencing as well as gene-specific determination by PCR.	('interacted', 'Interaction', (66, 76))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('binding', 'molecular_function', 'GO:0005488', ('112', '119'))	('cytosine', 'Chemical', 'MESH:D003596', (93, 101))	('methylated', 'Var', (139, 149))
31280	28331435	report hypermethylation at ECAD, p16, MGMT and DAPK from peripheral lymphocytes DNA as smoking specific epigenome alternation.	('hypermethylation', 'Var', (7, 23))	('DAPK', 'Gene', (47, 51))	('DAPK', 'Gene', '1612', (47, 51))	('p16', 'Gene', (33, 36))	('MGMT', 'Gene', '4255', (38, 42))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('MGMT', 'molecular_function', 'GO:0003908', ('38', '42'))	('p16', 'Gene', '1029', (33, 36))	('MGMT', 'Gene', (38, 42))
31281	28331435	identified 6 CpGs hypomethylation in 5 genes (AHRR, F2RL3, 2q37.1, 6p21.33 and 12q14.1) from peripheral blood related to smoking that may raise lung cancer risk, and 5 of them were lowest for current smokers and increased with time since quitting for former smokers.	('raise', 'PosReg', (138, 143))	('AHRR', 'Gene', '57491', (46, 50))	('lung cancer', 'Disease', (144, 155))	('F2RL3', 'Gene', '9002', (52, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('related', 'Reg', (110, 117))	('increased', 'PosReg', (212, 221))	('AHRR', 'Gene', (46, 50))	('hypomethylation', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('F2RL3', 'Gene', (52, 57))
31282	28331435	Methylation at these 6 CpGs can help improving prediction of lung cancer risk.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))
31285	28331435	These studies demonstrate the role of smoking in promoting lung cancer through DNA methylation.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('DNA methylation', 'Var', (79, 94))	('promoting', 'PosReg', (49, 58))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('DNA methylation', 'biological_process', 'GO:0006306', ('79', '94'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
31288	28331435	Methylation occurs at early stage of carcinogenesis, and has become an attractive biomarker for cancer screening and early detection, especially for ctDNA methylation with its convenience and non-invasion.	('carcinogenesis', 'Disease', 'MESH:D063646', (37, 51))	('ctDNA', 'Disease', (149, 154))	('carcinogenesis', 'Disease', (37, 51))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('methylation', 'Var', (155, 166))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))	('cancer', 'Disease', (96, 102))
31289	28331435	Many studies have reported the potential of ctDNA methylations for the screening and diagnosis of lung cancer.	('methylations', 'Var', (50, 62))	('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))
31290	28331435	Various gene promoter methylations (Table 1) and their combinations (Table 2) were found to be effective in discriminating lung cancer patients from non-cancer controls.	('non-cancer', 'Disease', (149, 159))	('patients', 'Species', '9606', (135, 143))	('non-cancer', 'Disease', 'MESH:D009369', (149, 159))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('methylations', 'Var', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
31296	28331435	The methylation was observed slightly frequent in patients with small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('small cell lung cancer', 'Disease', (64, 86))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('methylation', 'Var', (4, 15))	('small cell lung cancer', 'Disease', 'MESH:D055752', (64, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('frequent', 'Reg', (38, 46))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
31310	28331435	reported that patients with unmethylated CHFR promoter survived longer when receiving EGFR tyrosine kinase inhibitors as second-line treatment, compared to conventional chemotherapy.	('unmethylated', 'Var', (28, 40))	('CHFR', 'Gene', (41, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('EGFR', 'Gene', (86, 90))	('patients', 'Species', '9606', (14, 22))	('CHFR', 'Gene', '55743', (41, 45))
31311	28331435	With the significance of DNA methylation in cancer progression, epigenetic treatment became a potential therapeutic candidate.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('epigenetic', 'Var', (64, 74))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('DNA methylation', 'biological_process', 'GO:0006306', ('25', '40'))
31312	28331435	Effect of epigenetic therapy in lung cancer has been reported.	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('epigenetic therapy', 'Var', (10, 28))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
31313	28331435	investigated combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation respectively, in patients with recurrent metastatic NSCLC, and with demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer in serial blood samples, resulted in objective and durable responses.	('lung cancer', 'Disease', (284, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (284, 295))	('demethylation', 'Var', (198, 211))	('NSCLC', 'Disease', (182, 187))	('histone deacetylation', 'biological_process', 'GO:0016575', ('108', '129'))	('associated', 'Reg', (268, 278))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('demethylation', 'biological_process', 'GO:0070988', ('198', '211'))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('lung cancer', 'Disease', 'MESH:D008175', (284, 295))	('patients', 'Species', '9606', (147, 155))	('azacitidine', 'Chemical', 'MESH:D001374', (46, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('DNA methylation', 'biological_process', 'GO:0006306', ('88', '103'))
31314	28331435	Among more than a hundred types of nucleotide modifications identified in different RNA molecules, m6A modification has attracted most attention owing to its potential to regulate gene expression reversibly.	('regulate', 'Reg', (171, 179))	('m6A', 'Gene', '2823', (99, 102))	('m6A', 'Gene', (99, 102))	('gene expression', 'biological_process', 'GO:0010467', ('180', '195'))	('modification', 'Var', (103, 115))	('gene expression', 'MPA', (180, 195))	('RNA', 'cellular_component', 'GO:0005562', ('84', '87'))
31315	28331435	RNA with m6A modification does not activate TLR3, leading to non-recognition of viral components, and may stimulate a pathway involved in cancer development.	('pathway', 'Pathway', (118, 125))	('cancer', 'Disease', (138, 144))	('viral components', 'Protein', (80, 96))	('stimulate', 'PosReg', (106, 115))	('m6A', 'Gene', (9, 12))	('m6A', 'Gene', '2823', (9, 12))	('modification', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('TLR3', 'Gene', (44, 48))	('non-recognition', 'MPA', (61, 76))	('TLR3', 'Gene', '7098', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
31326	28331435	ctDNA/RNA methylation has been associated with the screening, diagnosis, prognosis, monitoring and treatment prediction of lung cancer.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('RNA methylation', 'biological_process', 'GO:0001510', ('6', '21'))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('methylation', 'Var', (10, 21))
31345	27419372	Aptamers can be selected to recognize purified cancer-related proteins such as VEGF, PDGF, even mutant EGFRvIII.	('PDGF', 'Gene', (85, 89))	('mutant', 'Var', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFRvIII', 'Gene', (103, 111))	('cancer', 'Disease', (47, 53))	('VEGF', 'Gene', '7422', (79, 83))	('PDGF', 'molecular_function', 'GO:0005161', ('85', '89'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('VEGF', 'Gene', (79, 83))
31354	27419372	As shown in Figure 3, four aptamers (S3, S5, S12 and S27, Table 1) could bind to target NPC 5-8F cells.	('bind', 'Interaction', (73, 77))	('S3', 'Var', (37, 39))	('S12', 'Gene', (45, 48))	('S27', 'Gene', '6232', (53, 56))	('NPC', 'Phenotype', 'HP:0100630', (88, 91))	('NPC', 'cellular_component', 'GO:0005643', ('88', '91'))	('S12', 'Gene', '6268', (45, 48))	('S27', 'Gene', (53, 56))
31367	27419372	Flow cytometric analysis demonstrated that aptamer S3 could recognize NPC 5-8F cells (Figure 6A), but not lung adenocarcinoma A549 cells dispersed in 1 mL of peripheral blood (Figure 6B) or white blood cells (WBCs) (Figure 6C).	('NPC', 'Phenotype', 'HP:0100630', (70, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('NPC 5-8F', 'Var', (70, 78))	('lung adenocarcinoma A549', 'Disease', (106, 130))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (106, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('NPC', 'cellular_component', 'GO:0005643', ('70', '73'))	('aptamer S3', 'Protein', (43, 53))
31396	27419372	Recently, some researchers suggested that high expression of CD109 regulates the phenotype of cancer stem-like cells/cancer-initiating cells (CSCs/CICs) in the novel epithelioid sarcoma cell line ESX and may be a CSCs/CICs biomarker in epithelioid sarcoma.	('epithelioid sarcoma', 'Disease', (166, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('high expression', 'Var', (42, 57))	('phenotype', 'MPA', (81, 90))	('epithelioid sarcoma', 'Disease', (236, 255))	('ESX', 'Gene', '1999', (196, 199))	('regulates', 'Reg', (67, 76))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (94, 100))	('CD109', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CD109', 'Gene', '135228', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (166, 185))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (236, 255))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('ESX', 'Gene', (196, 199))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
31488	27685944	beta0j, beta4j are unknown state-specific regression coefficients, and beta0j = beta0 + U0j and beta4j = beta4 + U1j are used to explain the observed variability between the states with respect to daily smoking.	('beta4', 'Gene', '10381', (96, 101))	('beta4', 'Gene', (96, 101))	('beta4', 'Gene', '10381', (8, 13))	('beta4', 'Gene', (8, 13))	('beta0j', 'Var', (71, 77))	('beta4', 'Gene', '10381', (105, 110))	('beta4', 'Gene', (105, 110))
31494	27685944	For White males, replacing Rij by 1 and Gij by 1 in Eq 2 gives the following equation of lung cancer incidence rate: Yij = (beta0j + beta1 + beta2) + (beta3 + beta5 + beta6)Tij + (beta4j + beta7 + beta8 + beta9Tij)Sij + epsilonij A one-percent increase in the White male daily cigarette smokers would result in an increase of (beta4j + beta7 + beta8 + beta9Tij) cases per 100,000 in the incidence of lung cancer for White males.	('increase', 'PosReg', (244, 252))	('lung cancer', 'Disease', (89, 100))	('beta4', 'Gene', '10381', (327, 332))	('beta4', 'Gene', '10381', (180, 185))	('lung cancer', 'Disease', 'MESH:D008175', (400, 411))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('beta4', 'Gene', (327, 332))	('beta4', 'Gene', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Yij', 'Var', (117, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (400, 411))	('beta0j + beta1 + beta2) + (beta3 + beta5', 'Gene', '10678;10383;1934;10382', (124, 164))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))	('lung cancer', 'Disease', (400, 411))
31552	33132332	also reported that the performance status (PS) in the emergency department was not an independent predictor of the overall survival, while improvement of PS and epidermal growth factor receptor (EGFR) mutation positivity were independent predictors of overall survival.	('EGFR', 'molecular_function', 'GO:0005006', ('195', '199'))	('epidermal growth factor receptor', 'Gene', (161, 193))	('EGFR', 'Gene', (195, 199))	('improvement', 'PosReg', (139, 150))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('161', '184'))	('epidermal growth factor receptor', 'Gene', '1956', (161, 193))	('mutation positivity', 'Var', (201, 220))	('EGFR', 'Gene', '1956', (195, 199))
31561	33132332	Polymerase chain reaction (PCR) with fine-needle aspiration cytology was performed to evaluate the EGFR mutation, and immunohistochemistry (IHC) screening was used for ALK gene tests.	('EGFR', 'Gene', (99, 103))	('ALK', 'Gene', (168, 171))	('mutation', 'Var', (104, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', '1956', (99, 103))	('ALK', 'Gene', '238', (168, 171))	('aspiration', 'Phenotype', 'HP:0002835', (49, 59))
31568	33132332	Two days after admission to the emergency department, EUS-B-FNA of the #4L lymph node was performed, and a diagnosis of lung adenocarcinoma was made, with PCR showing an EGFR (exon 19 deletion) mutation.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('mutation', 'Var', (194, 202))	('EGFR', 'Gene', '1956', (170, 174))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('170', '174'))	('EGFR', 'Gene', (170, 174))	('lung adenocarcinoma', 'Disease', (120, 139))
31575	33132332	On the day of admission to the emergency department, EUS-B-FNA of the #7 lymph node was performed, and a diagnosis of lung adenocarcinoma was made, with PCR showing an EGFR (exon 19 deletion) mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('mutation', 'Var', (192, 200))	('lung adenocarcinoma', 'Disease', (118, 137))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))
31589	33132332	reported that EUS-B-FNA is a practical and feasible method for obtaining tumor tissue to detect EGFR mutations and ALK fusion genes.	('ALK', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ALK', 'Gene', '238', (115, 118))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('tumor', 'Disease', (73, 78))	('EGFR', 'Gene', '1956', (96, 100))
31594	33132332	reported that improvement in the PS and EGFR mutation positivity were independent predictors of the overall survival in patients with NSCLC DFEA.	('DFEA', 'Chemical', '-', (140, 144))	('improvement', 'PosReg', (14, 25))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('mutation positivity', 'Var', (45, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (120, 128))	('NSCLC', 'Disease', (134, 139))	('positivity', 'Var', (54, 64))
31596	33132332	revealed that alectinib was effective in patients with NSCLC with ALK rearrangement positivity and poor PS, for whom chemotherapy was not indicated.	('alectinib', 'Chemical', 'MESH:C582670', (14, 23))	('ALK', 'Gene', '238', (66, 69))	('NSCLC', 'Disease', (55, 60))	('rearrangement positivity', 'Var', (70, 94))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('ALK', 'Gene', (66, 69))	('patients', 'Species', '9606', (41, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
31606	33912453	A total of seven randomized clinical trials were included in the meta-analysis and involved 1,283 NSCLC patients harboring EGFR mutations.	('EGFR', 'Gene', (123, 127))	('mutations', 'Var', (128, 137))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('EGFR', 'Gene', '1956', (123, 127))	('patients', 'Species', '9606', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
31608	33912453	No significant difference in DFS was observed between patients with EGFR exon 19 deletion and those with L858R mutation.	('L858R', 'Mutation', 'rs121434568', (105, 110))	('patients', 'Species', '9606', (54, 62))	('deletion', 'Var', (81, 89))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))
31617	33912453	Epidermal growth factor receptor (EGFR) mutations are common oncogenic driver mutations in NSCLC patients, such as EGFR exon 19 deletion and L858R mutation.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('L858R', 'Mutation', 'rs121434568', (141, 146))	('exon 19 deletion', 'Var', (120, 136))	('EGFR', 'Gene', (34, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'Gene', '1956', (115, 119))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('L858R mutation', 'Var', (141, 155))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (97, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('NSCLC', 'Disease', (91, 96))	('EGFR', 'Gene', '1956', (34, 38))	('deletion', 'Var', (128, 136))
31618	33912453	EGFR tyrosine kinase inhibitors (EGFR-TKIs) are considered as standard first-line treatment for advanced NSCLC harboring EGFR mutations, with improved progression-free survival (PFS) and quality of life.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (121, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('improved', 'PosReg', (142, 150))	('EGFR', 'Gene', (121, 125))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('mutations', 'Var', (126, 135))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Disease', (105, 110))	('EGFR', 'Gene', '1956', (0, 4))
31622	33912453	Furthermore, advanced NSCLC patients harboring EGFR exon 19 deletion experienced a better prognosis, compared with those harboring L858R mutation when treated with EGFR-TKIs.	('EGFR', 'Gene', (164, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('deletion', 'Var', (60, 68))	('EGFR', 'Gene', '1956', (164, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('NSCLC', 'Disease', (22, 27))	('EGFR', 'Gene', '1956', (47, 51))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('L858R', 'Mutation', 'rs121434568', (131, 136))	('EGFR', 'Gene', (47, 51))
31636	33912453	From each study, the first author name, clinical trial name, trial phase, EGFR mutation status, generation of adjuvant EGFR-TKIs, other baseline clinicopathologic characteristics, planned and received treatment and toxicity, survival outcomes, and relapse patterns were extracted.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('EGFR', 'Gene', '1956', (74, 78))	('mutation', 'Var', (79, 87))	('EGFR', 'Gene', '1956', (119, 123))	('toxicity', 'Disease', 'MESH:D064420', (215, 223))	('toxicity', 'Disease', (215, 223))	('EGFR', 'Gene', (74, 78))	('EGFR', 'Gene', (119, 123))
31641	33912453	The subgroup included EGFR mutation status (exon 19 deletion vs. L858R mutation), age (age >=65 years vs. <65 years), sex (male vs. female), smoking status (smokers vs. non-smokers), histology (adenocarcinoma vs. non-adenocarcinoma), generation of EGFR-TKIs (gefitinib or erlotinib vs. osimertinib), and the relapse patterns.	('exon 19 deletion', 'Var', (44, 60))	('EGFR', 'Gene', '1956', (248, 252))	('adenocarcinoma', 'Disease', 'MESH:D000230', (194, 208))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (213, 231))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'molecular_function', 'GO:0005006', ('248', '252'))	('osimertinib', 'Chemical', 'MESH:C000596361', (286, 297))	('non-adenocarcinoma', 'Disease', (213, 231))	('EGFR', 'Gene', (248, 252))	('L858R mutation', 'Var', (65, 79))	('adenocarcinoma', 'Disease', (217, 231))	('adenocarcinoma', 'Disease', 'MESH:D000230', (217, 231))	('L858R', 'Mutation', 'rs121434568', (65, 70))	('gefitinib', 'Chemical', 'MESH:D000077156', (259, 268))	('EGFR', 'Gene', '1956', (22, 26))	('adenocarcinoma', 'Disease', (194, 208))	('erlotinib', 'Chemical', 'MESH:D000069347', (272, 281))	('EGFR', 'Gene', (22, 26))
31643	33912453	All cases in five studies were diagnosed NSCLC with an activating EGFR mutation.	('NSCLC', 'Disease', (41, 46))	('mutation', 'Var', (71, 79))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('activating', 'PosReg', (55, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
31649	33912453	To further explore the effects of EGFR mutation status on DFS, subgroup analyses of DFS in patients with exon 19 deletion versus L858R mutation were performed.	('L858R mutation', 'Var', (129, 143))	('patients', 'Species', '9606', (91, 99))	('L858R', 'Mutation', 'rs121434568', (129, 134))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'Gene', '1956', (34, 38))
31650	33912453	The pooled survival estimates were based on 660 NSCLC patients harboring exon 19 deletion from seven RCTs and showed that EGFR-TKI treatment had a favorable effect on DFS (HR: 0.30; 95%CI: 0.12-0.72; P = 0.007,  Figure 2C ) There was significant heterogeneity in the analysis (I2 = 83.8%, P < 0.001).	('NSCLC', 'Disease', (48, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('exon', 'Var', (73, 77))	('patients', 'Species', '9606', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('DFS', 'MPA', (167, 170))	('deletion', 'Var', (81, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
31651	33912453	A total of 565 patients harboring L858R mutation experienced improved DFS with EGFR-TKI therapy compared with the control group (HR: 0.44; 95%CI: 0.33-0.60; P < 0.001,  Figure 2C ), with no significant heterogeneity (I2 = 0.9%, P = 0.401).	('improved', 'PosReg', (61, 69))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', '1956', (79, 83))	('L858R', 'Var', (34, 39))	('EGFR', 'Gene', (79, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('L858R', 'Mutation', 'rs121434568', (34, 39))	('DFS', 'MPA', (70, 73))
31652	33912453	No significant difference in DFS was observed between EGFR exon 19 deletion and L858R mutation subgroups (P for heterogeneity = 0.290).	('exon', 'Var', (59, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('EGFR', 'Gene', (54, 58))	('L858R', 'Var', (80, 85))	('EGFR', 'Gene', '1956', (54, 58))	('L858R', 'Mutation', 'rs121434568', (80, 85))
31658	33912453	The addition of EGFR-TKIs decreased the distant metastasis risk (OR: 0.59; 95%CI: 0.35-1.00;  Figure 4A ), although the difference was not statistically significant (P = 0.052).	('addition', 'Var', (4, 12))	('distant metastasis', 'CPA', (40, 58))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('decreased', 'NegReg', (26, 35))	('EGFR', 'Gene', (16, 20))
31673	33912453	In some meta-analyses, NSCLC patients with EGFR mutation reportedly obtained clinical benefit from adjuvant EGFR-TKI therapy.	('patients', 'Species', '9606', (29, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('benefit', 'PosReg', (86, 93))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('NSCLC', 'Disease', (23, 28))	('EGFR', 'Gene', '1956', (43, 47))	('mutation', 'Var', (48, 56))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('EGFR', 'Gene', (43, 47))
31676	33912453	In addition, the differences in clinical effects of EGFR-TKIs based on EGFR mutation status (exon 19 deletion vs. L858R mutation) were investigated in our meta-analysis.	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('L858R mutation', 'Var', (114, 128))	('EGFR', 'Gene', (71, 75))	('L858R', 'Mutation', 'rs121434568', (114, 119))
31679	33912453	In advanced NSCLC disease, patients harboring EGFR exon 19 deletion experienced improved PFS with EGFR-TKIs compared with those harboring L858R mutation.	('EGFR', 'Gene', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('PFS', 'MPA', (89, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('EGFR', 'Gene', '1956', (46, 50))	('patients', 'Species', '9606', (27, 35))	('improved', 'PosReg', (80, 88))	('L858R', 'Mutation', 'rs121434568', (138, 143))	('NSCLC disease', 'Disease', 'MESH:D003141', (12, 25))	('EGFR', 'Gene', (46, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', '1956', (98, 102))	('NSCLC disease', 'Disease', (12, 25))	('deletion', 'Var', (59, 67))
31681	33912453	Our meta-analysis shows that the clinical benefit of adjuvant EGFR-TKIs was observed in early-stage patients harboring EGFR exon 19 deletion or L858R mutation; the difference between the two mutation types was non-significant.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('L858R mutation', 'Var', (144, 158))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('L858R', 'Mutation', 'rs121434568', (144, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))
31684	33912453	Therefore, the abundance of EGFR mutations may be high in patients with metastatic NSCLC.	('EGFR', 'Gene', '1956', (28, 32))	('NSCLC', 'Disease', (83, 88))	('EGFR', 'Gene', (28, 32))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('mutations', 'Var', (33, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('patients', 'Species', '9606', (58, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))
31685	33912453	The clinical benefit of EGFR-TKIs was reportedly closely associated with the abundance of EGFR mutations.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('EGFR', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))
31701	33912453	Thus, some important information was not collected from subgroup results, such as smoking history, stage, sex, and EGFR mutation status.	('EGFR', 'Gene', (115, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', '1956', (115, 119))	('mutation', 'Var', (120, 128))
31720	33506582	Moreover, circ-ERBB2 knockdown enhanced the suppressive effect of propofol on tumor growth in vivo.	('enhanced', 'PosReg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('propofol', 'Chemical', 'MESH:D015742', (66, 74))	('suppressive effect', 'MPA', (44, 62))	('tumor', 'Disease', (78, 83))	('knockdown', 'Var', (21, 30))	('circ-ERBB2', 'Gene', (10, 20))
31741	33506582	15  Also, miRNAs aberrantly expressed in lung cancer have become promising diagnostic and prognostic biomarkers through their ability to regulate biological networks.	('biological networks', 'Pathway', (146, 165))	('regulate', 'Reg', (137, 145))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('aberrantly expressed', 'Var', (17, 37))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
31774	33506582	Following blocking with 5% non-fat milk, the membranes were probed with primary antibodies against FOXM1 (1:1500, ab180710, Abcam) or beta-actin (1:2500, ab8227, Abcam).	('ab180710', 'Var', (114, 122))	('beta-actin', 'Protein', (134, 144))	('1:1500', 'Var', (106, 112))	('FOXM1', 'Gene', (99, 104))	('FOXM1', 'Gene', '2305', (99, 104))	('1:2500', 'Var', (146, 152))
31790	33506582	Compared with human bronchial epithelial cells (HBE), circ-ERBB2 level was remarkably elevated in lung cancer cells (SK-MES-1, H1650, Calu-3, H460, H1299 and A549) (Figure 2(c)).	('elevated', 'PosReg', (86, 94))	('circ-ERBB2 level', 'MPA', (54, 70))	('H1299', 'CellLine', 'CVCL:0060', (148, 153))	('SK-MES-1', 'CellLine', 'CVCL:0630', (117, 125))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('H1650', 'Var', (127, 132))	('lung cancer', 'Disease', (98, 109))	('human', 'Species', '9606', (14, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('HBE', 'Gene', '3046', (48, 51))	('H1650', 'CellLine', 'CVCL:1483', (127, 132))	('H460', 'CellLine', 'CVCL:0459', (142, 146))	('HBE', 'Gene', (48, 51))	('H1299', 'Var', (148, 153))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
31807	33506582	Additionally, qRT-PCR analysis showed that the knockdown efficiency of circ-ERBB2 was significant after transfection with si-circ-ERBB2 in H1299 and A549 cells (Figure 4(h)).	('knockdown', 'MPA', (47, 56))	('circ-ERBB2', 'Gene', (71, 81))	('H1299', 'CellLine', 'CVCL:0060', (139, 144))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('si-circ-ERBB2', 'Var', (122, 135))
31808	33506582	In addition, circ-ERBB2 silence significantly increased miR-7-5p level, and circ-ERBB2 overexpression strikingly reduced miR-7-5p level (Figure 4(i)).	('miR-7-5p', 'Gene', (56, 64))	('miR-7-5p', 'Gene', '407045', (121, 129))	('silence', 'Var', (24, 31))	('miR-7-5p', 'Gene', '407045', (56, 64))	('increased', 'PosReg', (46, 55))	('reduced', 'NegReg', (113, 120))	('miR-7-5p', 'Gene', (121, 129))
31813	33506582	Subsequently, the transfected cells were exposed to 10 mug/ml propofol, and the results suggested that transfection of anti-miR-7-5p abated the increase in miR-7-5p level induced by propofol exposure (Figure 5(c)).	('miR-7-5p', 'Gene', (156, 164))	('miR-7-5p', 'Gene', '407045', (124, 132))	('miR-7-5p', 'Gene', '407045', (156, 164))	('propofol', 'Chemical', 'MESH:D015742', (182, 190))	('propofol', 'Chemical', 'MESH:D015742', (62, 70))	('mug', 'molecular_function', 'GO:0043739', ('55', '58'))	('transfection', 'Var', (103, 115))	('miR-7-5p', 'Gene', (124, 132))	('abated', 'NegReg', (133, 139))
31814	33506582	Rescue experiments revealed that knockdown of miR-7-5p overturned the suppressive effect of propofol on proliferation (Figure 5(d) and (e)) and invasion (Figure 5(g)) and the promotion of propofol on apoptosis (Figure 5(f)) in H1299 and A549 cells.	('propofol', 'Chemical', 'MESH:D015742', (92, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('miR-7-5p', 'Gene', (46, 54))	('propofol', 'Chemical', 'MESH:D015742', (188, 196))	('proliferation', 'CPA', (104, 117))	('knockdown', 'Var', (33, 42))	('miR-7-5p', 'Gene', '407045', (46, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('A549', 'CellLine', 'CVCL:0023', (237, 241))	('invasion', 'CPA', (144, 152))	('apoptosis', 'CPA', (200, 209))	('suppressive effect', 'NegReg', (70, 88))	('promotion', 'PosReg', (175, 184))	('H1299', 'CellLine', 'CVCL:0060', (227, 232))
31829	33506582	Also, Western blot assay suggested that FOXM1 transfection mitigated the decrease in FOXM1 protein level caused by propofol stimulation (Figure 7(c)).	('mitigated', 'NegReg', (59, 68))	('FOXM1', 'Gene', '2305', (40, 45))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('FOXM1', 'Gene', (40, 45))	('FOXM1', 'Gene', (85, 90))	('decrease', 'NegReg', (73, 81))	('propofol', 'Chemical', 'MESH:D015742', (115, 123))	('FOXM1', 'Gene', '2305', (85, 90))	('transfection', 'Var', (46, 58))
31836	33506582	Moreover, circ-ERBB2 silencing remarkably reduced FOXM1 protein expression in H1299 and A549 cells, while this change was abolished by cotransfecting with si-circ-ERBB2 and anti-miR-7-5p (Figure 8(c)).	('reduced', 'NegReg', (42, 49))	('H1299', 'CellLine', 'CVCL:0060', (78, 83))	('protein', 'Protein', (56, 63))	('FOXM1', 'Gene', (50, 55))	('miR-7-5p', 'Gene', (178, 186))	('FOXM1', 'Gene', '2305', (50, 55))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('miR-7-5p', 'Gene', '407045', (178, 186))	('silencing', 'Var', (21, 30))
31840	33506582	As shown in Figure 9(a) and (b), circ-ERBB2 knockdown markedly decreased tumor volume and weight, and this effect was enhanced by propofol.	('circ-ERBB2', 'Gene', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('propofol', 'Chemical', 'MESH:D015742', (130, 138))	('decreased', 'NegReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('knockdown', 'Var', (44, 53))
31841	33506582	In addition, transfection of sh-circ-ERBB2 reduced circ-ERBB2 expression and FOXM1 protein level and elevated miR-7-5p level, while these trends were reinforced after propofol stimulation (Figure 9(c)-(e)).	('elevated', 'PosReg', (101, 109))	('miR-7-5p', 'Gene', '407045', (110, 118))	('propofol', 'Chemical', 'MESH:D015742', (167, 175))	('transfection', 'Var', (13, 25))	('expression', 'MPA', (62, 72))	('FOXM1', 'Gene', (77, 82))	('reduced', 'NegReg', (43, 50))	('FOXM1', 'Gene', '2305', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('circ-ERBB2', 'Gene', (51, 61))	('miR-7-5p', 'Gene', (110, 118))	('sh-circ-ERBB2', 'Gene', (29, 42))
31842	33506582	These data suggested that circ-ERBB2 silencing strengthened the inhibitory effect of propofol on tumor growth in vivo.	('strengthened', 'PosReg', (47, 59))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('propofol', 'Chemical', 'MESH:D015742', (85, 93))	('inhibitory effect', 'MPA', (64, 81))	('silencing', 'Var', (37, 46))	('tumor', 'Disease', (97, 102))
31868	33634984	Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma Aberrant epigenetic reprogramming represents a hallmark of renal cell carcinoma (RCC) tumorigenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('JMJD6', 'Gene', '23210', (36, 41))	('renal cell carcinoma', 'Disease', (116, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('hallmark of renal cell carcinoma', 'Disease', (184, 216))	('epigenetic', 'Var', (146, 156))	('JMJD6', 'Gene', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('RCC', 'Disease', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (196, 216))	('tumor', 'Disease', (223, 228))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('hallmark of renal cell carcinoma', 'Disease', 'MESH:C538614', (184, 216))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 136))	('sunitinib', 'Chemical', 'MESH:D000077210', (91, 100))	('epigenetic vulnerability', 'MPA', (53, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))
31870	33634984	JMJD6 expression correlated with poor survival outcomes of RCC patients and promoted RCC progression in vitro and in vivo.	('JMJD6', 'Gene', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('patients', 'Species', '9606', (63, 71))	('promoted', 'PosReg', (76, 84))	('expression', 'Var', (6, 16))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
31874	33634984	Given the probable overlapped crosstalk between JMJD6 signature and tyrosine kinase inhibitors downstream targets, targeting JMJD6 sensitized RCC to sunitinib and was synergistic when they were combined together.	('JMJD6', 'Var', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('sunitinib', 'Chemical', 'MESH:D000077210', (149, 158))	('sensitized', 'Reg', (131, 141))	('targeting JMJD6', 'Var', (115, 130))
31875	33634984	Collectively, this study indicated that targeting JMJD6 was an effective approach to treat RCC patients.	('targeting', 'Var', (40, 49))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('JMJD6', 'Gene', (50, 55))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))
31881	33634984	3  Recently, high-throughput sequencing data and etiology analysis revealed that ccRCC harbors well-known mutations in a series of chromatin modifier genes, such as VHL, PBRM1, SETD2, and KDM5C.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('PBRM1', 'Gene', '55193', (170, 175))	('SETD2', 'Gene', '29072', (177, 182))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('SETD2', 'Gene', (177, 182))	('chromatin', 'cellular_component', 'GO:0000785', ('131', '140'))	('VHL', 'Gene', (165, 168))	('mutations', 'Var', (106, 115))	('PBRM1', 'Gene', (170, 175))	('VHL', 'Gene', '7428', (165, 168))
31882	33634984	4 ,  5  Aberrant epigenetic programming has been recognized as a hallmark of renal cell carcinoma (RCC) tumorigenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Aberrant epigenetic programming', 'Var', (8, 39))	('tumor', 'Disease', (104, 109))	('hallmark of renal cell carcinoma', 'Disease', 'MESH:C538614', (65, 97))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (77, 97))	('hallmark of renal cell carcinoma', 'Disease', (65, 97))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
31886	33634984	9 ,  10  As a result, screening and developing novel epigenetic inhibitors for use in RCC are worthy and promising endeavors.	('epigenetic inhibitors', 'Var', (53, 74))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
31897	33634984	24 ,  25  As a result, we combined the two powerful technologies incorporating GeCK screening results and sequencing data from TCGA/ICGC cohorts to identify robust epigenetic vulnerability in RCC.	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('RCC', 'Disease', (192, 195))	('epigenetic vulnerability', 'Var', (164, 188))
31899	33634984	26 ,  27  As reported, JMJD6 can alter downstream gene expression levels by interacting with a coactivator of BRD4 and demethylating histone H4 at arginine 3, resulting in abnormal distal promoter proximal pausing of Pol II release.	('interacting', 'Interaction', (76, 87))	('histone H4', 'Gene', (133, 143))	('alter', 'Reg', (33, 38))	('distal promoter proximal pausing of Pol II release', 'MPA', (181, 231))	('JMJD6', 'Var', (23, 28))	('demethylating', 'Var', (119, 132))	('arginine', 'Chemical', 'MESH:D001120', (147, 155))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('downstream gene expression levels', 'MPA', (39, 72))	('histone H4', 'Gene', '102641229', (133, 143))
31900	33634984	30  In addition, JMJD6 can also function as a lysyl-hydroxylase to constitute complexes that lead to p53 hydroxylation and inactivation.	('inactivation', 'MPA', (123, 135))	('p53', 'Gene', (101, 104))	('JMJD6', 'Var', (17, 22))	('lead to', 'Reg', (93, 100))	('complexes', 'Interaction', (78, 87))	('p53', 'Gene', '22060', (101, 104))
31901	33634984	31  Meanwhile, JMJD6 was reported to downregulate H4K16ac independently of the enzymatic activity that modulates the epigenome around DNA lesions.	('JMJD6', 'Var', (15, 20))	('downregulate', 'NegReg', (37, 49))	('modulates', 'Reg', (103, 112))	('epigenome', 'MPA', (117, 126))	('H4K16ac', 'Chemical', '-', (50, 57))	('H4K16ac', 'Protein', (50, 57))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
31903	33634984	33 ,  34  Knockouts of JMJD6 could lead to severe defects in mice, which suggested critical roles of JMJD6 in development.	('JMJD6', 'Gene', (23, 28))	('Knockouts', 'Var', (10, 19))	('lead', 'Reg', (35, 39))	('mice', 'Species', '10090', (61, 65))
31904	33634984	35  Furthermore, JMJD6 could accompany with BRD4 to regulate the activity of CDK9 and RNA polymerase II complex.	('activity', 'MPA', (65, 73))	('RNA polymerase II complex', 'Enzyme', (86, 111))	('CDK9', 'Gene', '107951', (77, 81))	('RNA polymerase II complex', 'cellular_component', 'GO:0005665', ('86', '111'))	('CDK9', 'Gene', (77, 81))	('JMJD6', 'Var', (17, 22))	('regulate', 'Reg', (52, 60))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))
31940	33634984	To optimize the tumor take rate of PDX models, we used the original patient specimens containing high amounts of viable cancer, which are defined as samples with (i) notable Ki67 expression, (ii) no remarkable damage, and (iii) >=50% cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('patient', 'Species', '9606', (68, 75))	('Ki67', 'Var', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Disease', (16, 21))	('cancer', 'Disease', (234, 240))
31958	33634984	Furthermore, JMJD6 knockdown remarkably suppressed RCC proliferation in three independent RCC cell lines (Figure 1F).	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', (90, 93))	('suppressed', 'NegReg', (40, 50))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('knockdown', 'Var', (19, 28))	('JMJD6', 'Gene', (13, 18))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
31962	33634984	To further figure out the oncogenic role of JMJD6 in RCC, we analyzed several cohorts to evaluate its clinical significance and found that JMJD6 was commonly higher in tumor samples than in normal tissues from the TCGA-KIRC cohort, GSE40435, GSE53757, and IGC-RCC cohort (Figure 2A-D).	('tumor', 'Disease', (168, 173))	('JMJD6', 'Var', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('RCC', 'Phenotype', 'HP:0005584', (260, 263))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('higher', 'PosReg', (158, 164))	('RCC', 'Disease', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC', 'Disease', (260, 263))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('SE', 'Gene', '6713', (243, 245))	('IGC-RCC', 'Disease', 'MESH:C538614', (256, 263))	('SE', 'Gene', '6713', (233, 235))	('IGC-RCC', 'Disease', (256, 263))
31966	33634984	Kaplan-Meier analysis further indicated that high JMJD6 levels correlated with worse overall survival (OS) and progression-free survival for patients from the TCGA-KIRC cohort and Ruijin-RCC dataset (Figures 2H and 2I).	('worse', 'NegReg', (79, 84))	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('progression-free survival', 'CPA', (111, 136))	('JMJD6', 'Gene', (50, 55))	('high', 'Var', (45, 49))	('overall survival', 'CPA', (85, 101))	('patients', 'Species', '9606', (141, 149))
31967	33634984	Simultaneously, we conducted a multivariate Cox analysis using age, pathological stage, and tumor grade and found that JMJD6 still remained one independent predictive marker for the prognosis of RCC (HR = 1.289, 95% CI, 1.136-1.463, P < 0.001, Figure 2J).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('JMJD6', 'Var', (119, 124))	('tumor', 'Disease', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('RCC', 'Disease', (195, 198))
31968	33634984	Taken together, these findings indicated that the JMJD6 level expressed highly in RCC and JMJD6 possessed the potentiality as an independent prognostic factor for RCC patients.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('RCC', 'Disease', (163, 166))	('patients', 'Species', '9606', (167, 175))	('JMJD6', 'Var', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('JMJD6', 'Var', (90, 95))
31971	33634984	In addition, JMJD6 deficiency significantly impeded RCC growth (786-O and Caki-1), which was completely rescued through the restoration of exogenously expressed JMJD6 tagged with FLAG (Figures 3C and 3D).	('impeded', 'NegReg', (44, 51))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('deficiency', 'Var', (19, 29))	('RCC growth', 'Disease', (52, 62))	('Caki-1', 'CellLine', 'CVCL:0234', (74, 80))	('RCC growth', 'Disease', 'MESH:C538614', (52, 62))	('JMJD6', 'Gene', (13, 18))
31973	33634984	Flow cytometry analysis further revealed that JMJD6 deficiency exerted a cytostatic effect and promoted cell apoptosis, in accordance with its oncogenic features in RCC (Figure S2C-D).	('exerted', 'MPA', (63, 70))	('promoted', 'PosReg', (95, 103))	('cytostatic effect', 'MPA', (73, 90))	('deficiency', 'Var', (52, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('cell apoptosis', 'CPA', (104, 118))	('JMJD6', 'Gene', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
31974	33634984	In addition, to determine the roles of JMJD6 in vivo, we performed tumor xenograft studies and observed that knocking out JMJD6 significantly suppressed tumor growth, as quantified by tumor size, compared with tumors derived from control group (Figures 3F and 3G).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('JMJD6', 'Gene', (122, 127))	('tumors', 'Disease', (210, 216))	('tumor', 'Disease', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('knocking out', 'Var', (109, 121))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('suppressed', 'NegReg', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
31975	33634984	In addition, the IHC results further revealed that Ki-67, an indicator of proliferation, was notably decreased in tumors derived from JMJD6-KO cells (Figure 3H).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Ki-67', 'Gene', (51, 56))	('decreased', 'NegReg', (101, 110))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('JMJD6-KO', 'Var', (134, 142))	('Ki-67', 'Gene', '17345', (51, 56))
31976	33634984	Furthermore, we also detected that ectopic expression of JMJD6 enhanced the migration and invasion of 786-O and Caki-1 cells (Figure S2B).	('ectopic expression', 'Var', (35, 53))	('migration', 'CPA', (76, 85))	('JMJD6', 'Gene', (57, 62))	('enhanced', 'PosReg', (63, 71))	('Caki-1', 'CellLine', 'CVCL:0234', (112, 118))	('invasion', 'CPA', (90, 98))
31978	33634984	As quantified by bioluminescence signals and number of lung metastatic nodes, JMJD6 overexpression remarkably promoted RCC lung metastasis, whereas JMJD6 deficiency dramatically inhibited the metastatic ability of RCC tumors to metastasize to the lung relative to the corresponding control groups (Figure 3I).	('JMJD6', 'Gene', (78, 83))	('RCC tumors', 'Disease', (214, 224))	('deficiency', 'Var', (154, 164))	('RCC lung metastasis', 'Disease', 'MESH:C538614', (119, 138))	('bioluminescence', 'biological_process', 'GO:0008218', ('17', '32'))	('RCC tumors', 'Disease', 'MESH:C538614', (214, 224))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('inhibited', 'NegReg', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('metastatic ability', 'CPA', (192, 210))	('RCC lung metastasis', 'Disease', (119, 138))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('JMJD6', 'Gene', (148, 153))	('promoted', 'PosReg', (110, 118))
31982	33634984	As previously reported, the p300/CPB complex mediates the catalytic process of cellular acetylation of H3K27ac, which directs H3K27me loss and reciprocal H3K27ac gain.	('H3K27me', 'Protein', (126, 133))	('gain', 'PosReg', (162, 166))	('p300', 'Gene', (28, 32))	('H3K27ac', 'Protein', (103, 110))	('p300', 'Gene', '2033', (28, 32))	('loss', 'NegReg', (134, 138))	('H3K27ac', 'Var', (154, 161))
31985	33634984	C646, a histone acetyltransferase inhibitor targeting p300, was selected to treat RCC cells, and we found a significant decrease in JMJD6 mRNA levels in a time- and dose-dependent manner (Figures 4E, 4F, and S2E).	('JMJD6', 'Gene', (132, 137))	('p300', 'Gene', '2033', (54, 58))	('C646', 'Var', (0, 4))	('decrease', 'NegReg', (120, 128))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('C646', 'Chemical', '-', (0, 4))	('p300', 'Gene', (54, 58))
31986	33634984	Performing western blot analysis, we found that the protein levels of JMJD6 and H3K27ac were reduced synchronously in 786-O and Caki-1 cells treated with C646 (Figure 4G).	('H3K27ac', 'Protein', (80, 87))	('Caki-1', 'CellLine', 'CVCL:0234', (128, 134))	('C646', 'Var', (154, 158))	('reduced', 'NegReg', (93, 100))	('C646', 'Chemical', '-', (154, 158))	('JMJD6', 'Gene', (70, 75))	('protein levels', 'MPA', (52, 66))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
31991	33634984	Neither C646 nor p300 knockdown could reduce the expression levels of CHD6 in RCC lines, suggesting the specific effect of p300 on CHD6 (Figure S2G-J).	('expression levels', 'MPA', (49, 66))	('p300', 'Gene', (17, 21))	('p300', 'Gene', (123, 127))	('C646', 'Chemical', '-', (8, 12))	('CHD6', 'Gene', (70, 74))	('p300', 'Gene', '2033', (123, 127))	('RCC', 'Disease', (78, 81))	('CHD6', 'Gene', (131, 135))	('CHD6', 'Gene', '84181', (70, 74))	('p300', 'Gene', '2033', (17, 21))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('CHD6', 'Gene', '84181', (131, 135))	('C646', 'Var', (8, 12))
31994	33634984	To determine the underlying mechanism by which JMJD6 promotes RCC growth and progression, we conducted transcriptome profiling analysis of JMJD6-WT and JMJD6-knockout cells.	('promotes', 'PosReg', (53, 61))	('progression', 'CPA', (77, 88))	('RCC growth', 'Disease', (62, 72))	('JMJD6', 'Var', (47, 52))	('RCC growth', 'Disease', 'MESH:C538614', (62, 72))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
32002	33634984	The western blot assay further demonstrated that wild-type JMJD6, but not the inactive JMJD6 mutant (H187A), maintained the high levels of VEGFA crosstalk and beta-catenin and could reverse the impaired effects induced by JMJD6 deficiency (Figure 5K).	('beta-catenin', 'Gene', (159, 171))	('JMJD6', 'Gene', (222, 227))	('beta-catenin', 'Gene', '1499', (159, 171))	('VEGFA', 'Protein', (139, 144))	('H187A', 'Mutation', 'p.H187A', (101, 106))	('high levels', 'MPA', (124, 135))	('deficiency', 'Var', (228, 238))
32003	33634984	Moreover, VEGFA or beta-catenin knockdown markedly impaired JMJD6-induced RCC growth in vitro (Figure 5L).	('beta-catenin', 'Gene', '1499', (19, 31))	('knockdown', 'Var', (32, 41))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('JMJD6-induced', 'Gene', (60, 73))	('beta-catenin', 'Gene', (19, 31))	('RCC growth', 'Disease', (74, 84))	('impaired', 'NegReg', (51, 59))	('VEGFA', 'Protein', (10, 15))	('RCC growth', 'Disease', 'MESH:C538614', (74, 84))
32007	33634984	Furthermore, we conducted RNA-seq to compare the fold change of SEs compared to SE-associated genes upon JQ1 treatment for 8 h. We observed that SE-associated genes in 786-O cells were particularly sensitive to JQ1, an observation also noted upon JMJD6 depletion (Figure 6C).	('sensitive', 'MPA', (198, 207))	('SE', 'Gene', '6713', (80, 82))	('JQ1', 'Var', (211, 214))	('SE', 'Gene', '6713', (145, 147))	('SE', 'Gene', '6713', (64, 66))	('SEs', 'Chemical', '-', (64, 67))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))
32008	33634984	Gene set enrichment analysis (GSEA) further indicated that JQ1 can selectively downregulate JMJD6 signature genes with enrichment mirroring the knockout of JMJD6 (Figure 6C).	('SE', 'Gene', '6713', (31, 33))	('downregulate', 'NegReg', (79, 91))	('JQ1', 'Var', (59, 62))	('enrichment mirroring', 'Phenotype', 'HP:0000298', (119, 139))	('JMJD6 signature genes', 'Gene', (92, 113))
32012	33634984	Considering that JMJD6 interacts with BRD4 to form SEs, we treated RCC cells with a BRD4 inhibitor and found that JQ1 largely reduced VEGFA levels in a dose-dependent manner (Figure 6H).	('JQ1', 'Var', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('VEGFA levels', 'MPA', (134, 146))	('reduced', 'NegReg', (126, 133))	('SEs', 'Chemical', '-', (51, 54))
32015	33634984	Similarly, there were no detectable alterations in VEGFA levels in sgVEGFA-SE-1 cells upon JMJD6 knockdown (Figure 6K).	('VEGFA levels', 'MPA', (51, 63))	('JMJD6', 'Gene', (91, 96))	('knockdown', 'Var', (97, 106))	('SE-1', 'CellLine', 'CVCL:6D91', (75, 79))
32016	33634984	Collectively, VEGFA-SE1 depletion can cause VEGFA to escape from JMJD6 manipulation.	('SE', 'Gene', '6713', (20, 22))	('cause', 'Reg', (38, 43))	('escape', 'PosReg', (53, 59))	('depletion', 'Var', (24, 33))
32019	33634984	Taken together, these data concluded that JMJD6 mainly interacts with BRD4 to constitute SEs that alter downstream targets in RCC, such as VEGFA.	('alter', 'Reg', (98, 103))	('interacts', 'Reg', (55, 64))	('JMJD6', 'Var', (42, 47))	('SEs', 'Chemical', '-', (89, 92))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('BRD4', 'Gene', (70, 74))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
32021	33634984	Given the essential roles of JMJD6 in regulating VEGA and other RCC identity drivers, we sought to determine the clinical utility of JMJD6 inhibitors in RCC.	('inhibitors', 'Var', (139, 149))	('JMJD6', 'Gene', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
32026	33634984	As determined by the sizes of the organoids, SKLB325 was observed to significantly suppress RCC organoid growth relative to the control PBS treatment (Figure 7D).	('SKLB325', 'Chemical', '-', (45, 52))	('PBS', 'Chemical', 'MESH:D007854', (136, 139))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('SKLB325', 'Var', (45, 52))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('suppress', 'NegReg', (83, 91))
32029	33634984	In the 786-O cell-bearing metastatic model, we confirmed that SKLB325 can also inhibit the growth of distal lung metastases, as quantified by serial bioluminescence signals and metastatic nodes in the lung (Figures 7G and S4C).	('inhibit', 'NegReg', (79, 86))	('SKLB325', 'Chemical', '-', (62, 69))	('bioluminescence', 'biological_process', 'GO:0008218', ('149', '164'))	('lung metastases', 'Disease', (108, 123))	('lung metastases', 'Disease', 'MESH:D009362', (108, 123))	('SKLB325', 'Var', (62, 69))	('metastatic nodes in the', 'CPA', (177, 200))
32035	33634984	In line with expectations, we found that overexpressed JMJD6 significantly attenuated sunitinib efficacy compared with that observed in the control group, whereas JMJD6 depletion sensitized RCC cells to sunitinib (Figure S4D).	('depletion', 'Var', (169, 178))	('sunitinib', 'Chemical', 'MESH:D000077210', (203, 212))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('sunitinib', 'Chemical', 'MESH:D000077210', (86, 95))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('sunitinib efficacy', 'MPA', (86, 104))	('attenuated', 'NegReg', (75, 85))	('JMJD6 depletion', 'Var', (163, 178))	('sensitized', 'Reg', (179, 189))	('JMJD6', 'Var', (55, 60))
32041	33634984	Intriguingly, SKLB325 treatment and JMJD6 deficiency exerted a remarkable reduction in tumor growth relative to that of the sunitinib-treated 786-O cell-SR or naive 786-O cell-SR mice, as quantified by serial bioluminescence signals (Figure 7H).	('bioluminescence', 'biological_process', 'GO:0008218', ('209', '224'))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mice', 'Species', '10090', (179, 183))	('SKLB325', 'Chemical', '-', (14, 21))	('reduction', 'NegReg', (74, 83))	('JMJD6', 'Gene', (36, 41))	('deficiency', 'Var', (42, 52))	('tumor', 'Disease', (87, 92))	('sunitinib', 'Chemical', 'MESH:D000077210', (124, 133))	('SR', 'Chemical', '-', (176, 178))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('SR', 'Chemical', '-', (153, 155))
32044	33634984	High JMJD6 levels might predict natural resistance to VEGF signaling inhibitors, and the combination of SKLB325 with sunitinib was shown to synergistically suppress RCC growth.	('combination', 'Var', (89, 100))	('SKLB325', 'Gene', (104, 111))	('RCC growth', 'Disease', (165, 175))	('suppress', 'NegReg', (156, 164))	('SKLB325', 'Chemical', '-', (104, 111))	('sunitinib', 'Chemical', 'MESH:D000077210', (117, 126))	('RCC growth', 'Disease', 'MESH:C538614', (165, 175))	('VEGF signaling', 'biological_process', 'GO:0038084', ('54', '68'))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('JMJD6', 'MPA', (5, 10))
32049	33634984	Aberrant expression levels or truncation mutations in chromatin modifiers have been recognized as vital pathological features in RCC.	('Aberrant', 'Var', (0, 8))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('chromatin', 'cellular_component', 'GO:0000785', ('54', '63'))	('expression levels', 'MPA', (9, 26))	('truncation mutations', 'Var', (30, 50))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))
32054	33634984	Mechanistically, JMJD6 altered a series of oncogenic signatures and mainly activated blood vessel development and beta-catenin signaling crosstalk.	('beta-catenin', 'Gene', (114, 126))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('activated', 'PosReg', (75, 84))	('beta-catenin', 'Gene', '1499', (114, 126))	('blood vessel development', 'CPA', (85, 109))	('JMJD6', 'Var', (17, 22))	('altered', 'Reg', (23, 30))	('oncogenic signatures', 'MPA', (43, 63))	('blood vessel development', 'biological_process', 'GO:0001568', ('85', '109'))
32055	33634984	In particular, JMJD6 was demonstrated to be a robust SE that drives VEGFA expression levels.	('drives', 'PosReg', (61, 67))	('JMJD6', 'Var', (15, 20))	('SE', 'Gene', '6713', (53, 55))	('VEGFA', 'Protein', (68, 73))	('expression levels', 'MPA', (74, 91))
32060	33634984	Therefore, we extracted and focused on epigenetic candidates in RCC cells based on the GeCK results.	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('epigenetic', 'Var', (39, 49))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
32062	33634984	Complementary to each other, these two screening strategies were combined together to identify JMJD6 as the pivotal epigenetic vulnerability in RCC, which had never been investigated in RCC.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('JMJD6', 'Var', (95, 100))	('RCC', 'Disease', (186, 189))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
32070	33634984	Genomic epigenetic marks such as H3K27ac or H3K4me1/2 or coactivators (MED1, BRD4, MED1/12, and c-Myc) are all essential enhancer indicators.	('c-Myc', 'Gene', '4609', (96, 101))	('c-Myc', 'Gene', (96, 101))	('H3K4me1/2', 'Var', (44, 53))	('MED1', 'Gene', '5469', (71, 75))	('MED1', 'Gene', (71, 75))	('MED1/12', 'Gene', '5469;9968', (83, 90))	('MED1', 'Gene', '5469', (83, 87))	('MED1/12', 'Gene', (83, 90))	('H3K27ac', 'Var', (33, 40))	('MED1', 'Gene', (83, 87))
32071	33634984	In line with previous conclusions, ChIP-seq data suggested that JMJD6 mainly binds to intragenic regions, not TSS loci, and alters enhancer profiles in RCC.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('enhancer profiles', 'MPA', (131, 148))	('JMJD6', 'Var', (64, 69))	('alters', 'Reg', (124, 130))	('binds', 'Interaction', (77, 82))
32072	33634984	As JMJD6 can interact with BRD4, we found that JMJD6 and BRD4 co-occupy at an adjacent VEGFA region to act as a putative SE, with an accompanying H3K27ac mark.	('BRD4', 'Gene', (57, 61))	('H3K27ac mark', 'Var', (146, 158))	('SE', 'Gene', '6713', (121, 123))	('JMJD6', 'Var', (47, 52))
32079	33634984	Interestingly, we further observed that JMJD6 status influenced sunitinib efficacy and combination of JMJD6 and sunitinib had synergistic effects in vitro and in vivo.	('influenced', 'Reg', (53, 63))	('JMJD6', 'Var', (102, 107))	('efficacy', 'MPA', (74, 82))	('sunitinib', 'Chemical', 'MESH:D000077210', (64, 73))	('sunitinib', 'Chemical', 'MESH:D000077210', (112, 121))	('combination', 'Interaction', (87, 98))
32081	33634984	48 ,  49  Encouragingly, SKLB325 could significantly suppress the tumor-derived VEGF levels in the circulation of mice and inhibit the expressions of CD34 and CD105 in renal cell orthotopic models, which were both the angiogenesis and proliferation markers.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('SKLB325', 'Chemical', '-', (25, 32))	('angiogenesis', 'biological_process', 'GO:0001525', ('218', '230'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibit', 'NegReg', (123, 130))	('suppress', 'NegReg', (53, 61))	('SKLB325', 'Var', (25, 32))	('CD34', 'Gene', (150, 154))	('mice', 'Species', '10090', (114, 118))	('CD105', 'Gene', '13805', (159, 164))	('CD105', 'Gene', (159, 164))	('expressions', 'MPA', (135, 146))	('CD34', 'Gene', '12490', (150, 154))
32082	33634984	Considering the high-throughput sequencing data, we think that JMJD6 might activate several overlapping tyrosine kinase inhibitor downstream targets, such as SRC or FGFR1.	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('activate', 'PosReg', (75, 83))	('SRC', 'Gene', (158, 161))	('FGFR1', 'Gene', (165, 170))	('SRC', 'Gene', '6714', (158, 161))	('JMJD6', 'Var', (63, 68))	('FGFR1', 'Gene', '2260', (165, 170))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('113', '129'))	('tyrosine kinase inhibitor downstream targets', 'MPA', (104, 148))
32084	33634984	Given that JMJD6 regulating a relatively wide spectrum of targets such as BRD4, the toxicity and optimal doses of SKLB325 were warranted to evaluate based on in vitro and in vivo models.	('BRD4', 'Gene', (74, 78))	('SKLB325', 'Chemical', '-', (114, 121))	('JMJD6', 'Var', (11, 16))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('toxicity', 'Disease', (84, 92))
32087	33634984	Taken together, the results obtained by integrating the GeCK screening, multiple RCC cohort, and experimental validation data enabled us to highlight JMJD6 as an independent predictive biomarker that is also a therapeutic vulnerability for RCC.	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('JMJD6', 'Var', (150, 155))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (240, 243))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))
32092	33469055	Impact of immune checkpoint gene CD155 Ala67Thr and CD226 Gly307Ser polymorphisms on small cell lung cancer clinical outcome This study was conducted to investigate the impact of genetic variants of immune checkpoint genes on the treatment outcome in small cell lung cancer (SCLC).	('SCLC', 'Phenotype', 'HP:0030357', (275, 279))	('Gly307Ser', 'SUBSTITUTION', 'None', (58, 67))	('CD155', 'Gene', (33, 38))	('Ala67Thr', 'Mutation', 'rs1058402', (39, 47))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('Gly307Ser', 'Var', (58, 67))	('small cell lung cancer', 'Disease', 'MESH:D055752', (85, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('SCLC', 'Disease', 'MESH:D018288', (275, 279))	('small cell lung cancer', 'Disease', 'MESH:D055752', (251, 273))	('Ser', 'cellular_component', 'GO:0005790', ('64', '67'))	('small cell lung cancer', 'Disease', (85, 107))	('CD226', 'Gene', (52, 57))	('lung cancer', 'Disease', 'MESH:D008175', (262, 273))	('small cell lung cancer', 'Disease', (251, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('CD155', 'Gene', '5817', (33, 38))	('CD226', 'Gene', '10666', (52, 57))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('SCLC', 'Disease', (275, 279))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (251, 273))
32095	33469055	Among the polymorphisms studied, CD155 rs1058402G > A (Ala67Thr, A67T) and CD226 rs763361C > T (Gly307Ser, G307S) were significantly associated with SCLC treatment outcome.	('SCLC', 'Disease', (149, 153))	('Ala67Thr', 'Mutation', 'rs1058402', (55, 63))	('CD155', 'Gene', (33, 38))	('SCLC', 'Phenotype', 'HP:0030357', (149, 153))	('A67T', 'Mutation', 'rs1058402', (65, 69))	('G307S', 'Var', (107, 112))	('Gly307Ser', 'SUBSTITUTION', 'None', (96, 105))	('G307S', 'Mutation', 'rs763361', (107, 112))	('Ser', 'cellular_component', 'GO:0005790', ('102', '105'))	('rs1058402G > A', 'Var', (39, 53))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (39, 53))	('SCLC', 'Disease', 'MESH:D018288', (149, 153))	('Gly307Ser', 'Var', (96, 105))	('CD226', 'Gene', (75, 80))	('or', 'Gene', '31118', (15, 17))	('CD155', 'Gene', '5817', (33, 38))	('associated with', 'Reg', (133, 148))	('rs763361C > T', 'DBSNP_MENTION', 'None', (81, 94))	('CD226', 'Gene', '10666', (75, 80))	('rs763361C > T', 'Var', (81, 94))
32096	33469055	The rs1058402G > A had a worse chemotherapy response and overall survival (under a dominant model, adjusted odds ratio [aOR] = 0.52, 95% confidence interval [CI] = 0.27-0.99, P = 0.05; adjusted hazard ratio [aHR] = 1.55, 95% CI = 1.12-2.14, P = 0.01, respectively).	('OR', 'Gene', '31118', (121, 123))	('HR', 'Gene', '36601', (209, 211))	('overall survival', 'CPA', (57, 73))	('chemotherapy response', 'CPA', (31, 52))	('rs1058402G > A', 'Var', (4, 18))	('or', 'Gene', '31118', (26, 28))	('aOR', 'molecular_function', 'GO:0033726', ('120', '123'))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (4, 18))
32097	33469055	The rs763361C > T had better chemotherapy response and overall survival (under a dominant model, aOR = 2.03, 95% CI = 1.10-3.75, P = 0.02; aHR = 0.69, 95% CI = 0.51-0.94, P = 0.02, respectively).	('rs763361C > T', 'Var', (4, 17))	('OR', 'Gene', '31118', (98, 100))	('overall survival', 'CPA', (55, 71))	('aOR', 'molecular_function', 'GO:0033726', ('97', '100'))	('rs763361C > T', 'DBSNP_MENTION', 'None', (4, 17))	('HR', 'Gene', '36601', (140, 142))	('better', 'PosReg', (22, 28))	('chemotherapy response', 'CPA', (29, 50))
32098	33469055	When the rs1058402GA/AA and rs763361CC genotypes were combined, the chemotherapy response and overall survival were significantly decreased as the number of bad genotypes increased (aOR = 0.52, 95% CI = 0.33-0.81, Ptrend = 0.004; aHR = 1.48, 95% CI = 1.19-1.84, Ptrend = 4 x 10-4, respectively).	('rs763361', 'Mutation', 'rs763361', (28, 36))	('chemotherapy response', 'CPA', (68, 89))	('overall survival', 'CPA', (94, 110))	('HR', 'Gene', '36601', (231, 233))	('rs1058402', 'Mutation', 'rs1058402', (9, 18))	('rs1058402GA/AA', 'Var', (9, 23))	('rs763361CC', 'Var', (28, 38))	('OR', 'Gene', '31118', (183, 185))	('aOR', 'molecular_function', 'GO:0033726', ('182', '185'))	('decreased', 'NegReg', (130, 139))
32099	33469055	The 3-D structural model showed that CD155 A67T created a new hydrogen bond and structural change on CD155.	('A67T', 'Var', (43, 47))	('hydrogen bond', 'MPA', (62, 75))	('CD155', 'Gene', (101, 106))	('structural', 'MPA', (80, 90))	('CD155', 'Gene', (37, 42))	('hydrogen', 'Chemical', 'MESH:D006859', (62, 70))	('CD155', 'Gene', '5817', (101, 106))	('A67T', 'Mutation', 'rs1058402', (43, 47))	('CD155', 'Gene', '5817', (37, 42))
32101	33469055	In conclusion, CD155 rs1058402G > A and CD226 rs763361C > T may be useful for predicting the clinical outcomes of SCLC patients after chemotherapy.	('CD155', 'Gene', '5817', (15, 20))	('SCLC', 'Disease', 'MESH:D018288', (114, 118))	('SCLC', 'Disease', (114, 118))	('CD155', 'Gene', (15, 20))	('patients', 'Species', '9606', (119, 127))	('rs1058402G > A', 'Var', (21, 35))	('or', 'Gene', '31118', (75, 77))	('CD226', 'Gene', (40, 45))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (21, 35))	('rs763361C > T', 'Var', (46, 59))	('CD226', 'Gene', '10666', (40, 45))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('rs763361C > T', 'DBSNP_MENTION', 'None', (46, 59))
32120	33469055	The genetic variants in immune checkpoints may affect the body's response to chemotherapy or lung cancer prognosis, considering the immune system's ability to prevent and kill cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('or', 'Gene', '31118', (90, 92))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('genetic variants', 'Var', (4, 20))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('affect', 'Reg', (47, 53))	('cancer', 'Disease', (98, 104))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('immune checkpoints', 'Gene', (24, 42))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('response to chemotherapy', 'CPA', (65, 89))
32121	33469055	We previously reported that genetic variants in immune checkpoint genes were associated with the prognosis of surgically resected NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('associated with', 'Reg', (77, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('SCLC', 'Phenotype', 'HP:0030357', (131, 135))	('genetic variants', 'Var', (28, 44))	('NSCLC', 'Disease', (130, 135))	('or', 'Gene', '31118', (17, 19))
32156	33469055	In order to evaluate the effect of the rs1058402G > A of CD155, which substitutes alanine with threonine at codon 67, The mutant structure of CD155(A67T) was modeled using MODELLER v9.12 with the crystal structures of wildtype CD155 (PDB : 6ISC).	('rs1058402G > A', 'Var', (39, 53))	('CD155', 'Gene', (142, 147))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (39, 53))	('or', 'Gene', '31118', (3, 5))	('CD155', 'Gene', '5817', (57, 62))	('A67T', 'Mutation', 'rs1058402', (148, 152))	('CD155', 'Gene', (57, 62))	('CD155', 'Gene', '5817', (227, 232))	('CD155', 'Gene', '5817', (142, 147))	('alanine with threonine at codon 67', 'Mutation', 'rs1058402', (82, 116))	('CD155', 'Gene', (227, 232))
32157	33469055	All images of CD226/CD155 (wild type vs. A67T mutant) were made in PyMOL (https://pymol.org/2/).	('CD226', 'Gene', '10666', (14, 19))	('A67T', 'Mutation', 'rs1058402', (41, 45))	('A67T', 'Var', (41, 45))	('CD155', 'Gene', '5817', (20, 25))	('or', 'Gene', '31118', (88, 90))	('CD155', 'Gene', (20, 25))	('CD226', 'Gene', (14, 19))
32161	33469055	Among the observed 96 polymorphisms, CD155 rs1058402G > A (Ala67Thr, A67T) and CD226 rs763361C > T (Gly307Ser, G307S) were associated with both chemotherapy response and OS.	('rs763361C > T', 'Var', (85, 98))	('rs1058402G > A', 'Var', (43, 57))	('associated', 'Reg', (123, 133))	('or', 'Gene', '31118', (27, 29))	('A67T', 'Mutation', 'rs1058402', (69, 73))	('rs763361C > T', 'DBSNP_MENTION', 'None', (85, 98))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (43, 57))	('Ala67Thr', 'Mutation', 'rs1058402', (59, 67))	('G307S', 'Var', (111, 116))	('chemotherapy response', 'CPA', (144, 165))	('Gly307Ser', 'Var', (100, 109))	('CD155', 'Gene', (37, 42))	('Gly307Ser', 'SUBSTITUTION', 'None', (100, 109))	('G307S', 'Mutation', 'rs763361', (111, 116))	('CD226', 'Gene', (79, 84))	('Ser', 'cellular_component', 'GO:0005790', ('106', '109'))	('CD226', 'Gene', '10666', (79, 84))	('CD155', 'Gene', '5817', (37, 42))
32163	33469055	The effect of rs1058402 on PFS had the same trend as OS, although it was not statistically significant (under a dominant model, aHR = 1.30, 95% CI = 0.96-1.76, P = 0.09).	('rs1058402', 'Mutation', 'rs1058402', (14, 23))	('rs1058402', 'Var', (14, 23))	('PFS', 'Disease', (27, 30))	('HR', 'Gene', '36601', (129, 131))
32164	33469055	The rs763361C > T showed significantly better chemotherapy response, OS, and PFS, respectively (under a dominant model, adjusted aOR = 2.03, 95% CI = 1.10-3.75, P = 0.02; aHR = 0.69, 95% CI = 0.51-0.94, P = 0.02; aHR = 0.73, 95% CI = 0.54-0.97, P = 0.03, respectively, Table 2 and Fig.	('rs763361C > T', 'Var', (4, 17))	('PFS', 'CPA', (77, 80))	('HR', 'Gene', '36601', (214, 216))	('rs763361C > T', 'DBSNP_MENTION', 'None', (4, 17))	('aOR', 'molecular_function', 'GO:0033726', ('129', '132'))	('HR', 'Gene', '36601', (172, 174))	('better', 'PosReg', (39, 45))	('chemotherapy response', 'CPA', (46, 67))	('OR', 'Gene', '31118', (130, 132))
32165	33469055	In the extensive-stage SCLC, both rs1058402 and rs763361 were associated with OS in univariated analysis (under a dominant model, Log Rank P = 0.03 and 0.006, respectively), but only rs1058402 was associated with OS in multivariated analysis (under a dominant model, aHR = 1.75, 95% CI = 1.21-2.53, P = 0.003) (Supplementary Table S2).	('rs763361', 'Mutation', 'rs763361', (48, 56))	('rs1058402', 'Mutation', 'rs1058402', (34, 43))	('HR', 'Gene', '36601', (268, 270))	('associated', 'Reg', (62, 72))	('SCLC', 'Disease', (23, 27))	('rs1058402', 'Var', (34, 43))	('SCLC', 'Disease', 'MESH:D018288', (23, 27))	('rs1058402', 'Mutation', 'rs1058402', (183, 192))	('SCLC', 'Phenotype', 'HP:0030357', (23, 27))	('rs1058402', 'Var', (183, 192))	('rs763361', 'Var', (48, 56))
32166	33469055	PFS showed the same trend as OS, although it was not statistically significant (under a dominant model, aHR for rs1058402 = 1.34, 95% CI = 0.94-1.90, P = 0.11; aHR for rs763361 = 0.79, 95% CI = 0.56-1.10, P = 0.16, respectively, Supplementary Table S2).	('rs763361', 'Mutation', 'rs763361', (168, 176))	('rs1058402', 'Var', (112, 121))	('HR', 'Gene', '36601', (105, 107))	('or', 'Gene', '31118', (109, 111))	('HR', 'Gene', '36601', (161, 163))	('rs763361', 'Var', (168, 176))	('rs1058402', 'Mutation', 'rs1058402', (112, 121))	('or', 'Gene', '31118', (165, 167))
32168	33469055	The rs1058402GA/AA and rs763361CC genotypes were associated with worse chemotherapy response and OS.	('or', 'Gene', '31118', (66, 68))	('rs1058402', 'Mutation', 'rs1058402', (4, 13))	('rs1058402GA/AA', 'Var', (4, 18))	('rs763361', 'Mutation', 'rs763361', (23, 31))	('rs763361CC', 'Var', (23, 33))
32171	33469055	In an analysis of only patients with extensive-stage, the combined effect of rs1058402 and rs763361 was still significant in chemotherapy response, OS, and PFS, respectively (aOR = 0.55, 95% CI = 0.33-0.93, Ptrend = 0.03; aHR = 1.55, 95% CI = 1.21-1.98, Ptrend = 6 x 10-4: aHR = 1.28, 95% CI = 1.07-1.59, Ptrend = 0.04, respectively, Supplementary Table S4).	('aOR', 'molecular_function', 'GO:0033726', ('175', '178'))	('rs763361', 'Var', (91, 99))	('patients', 'Species', '9606', (23, 31))	('rs1058402', 'Var', (77, 86))	('rs763361', 'Mutation', 'rs763361', (91, 99))	('HR', 'Gene', '36601', (274, 276))	('OR', 'Gene', '31118', (176, 178))	('rs1058402', 'Mutation', 'rs1058402', (77, 86))	('chemotherapy response', 'CPA', (125, 146))	('HR', 'Gene', '36601', (223, 225))
32172	33469055	The rs1058402G > A changes the amino acid of alanine to threonine at codon 67 of CD155.	('CD155', 'Gene', '5817', (81, 86))	('CD155', 'Gene', (81, 86))	('rs1058402G > A', 'Var', (4, 18))	('alanine to threonine at codon 67', 'Mutation', 'rs1058402', (45, 77))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (4, 18))	('amino acid of alanine to threonine', 'MPA', (31, 65))
32175	33469055	3, the alanine to threonine change at codon 67 provides distance shortening to S74 and G73 of CD155 (6.3 2.9 and 4.4 3.3 A, respectively; Fig.	('G73', 'Var', (87, 90))	('alanine to threonine change at codon 67', 'Mutation', 'rs1058402', (7, 46))	('S74', 'Var', (79, 82))	('CD155', 'Gene', (94, 99))	('distance', 'MPA', (56, 64))	('or', 'Gene', '31118', (67, 69))	('alanine', 'MPA', (7, 14))	('CD155', 'Gene', '5817', (94, 99))
32176	33469055	The shortened distance between T67 and S74 created a new hydrogen bond (Fig.	('hydrogen', 'Chemical', 'MESH:D006859', (57, 65))	('or', 'Gene', '31118', (6, 8))	('T67', 'Var', (31, 34))	('hydrogen bond', 'MPA', (57, 70))	('S74', 'Var', (39, 42))
32177	33469055	This change resulted in distance lengthening between S74 of CD155 and N116 of CD226 (2.7 6.0 A) and losing the hydrogen bond (Fig.	('hydrogen', 'Chemical', 'MESH:D006859', (111, 119))	('CD155', 'Gene', '5817', (60, 65))	('distance', 'MPA', (24, 32))	('hydrogen bond', 'MPA', (111, 124))	('N116', 'Var', (70, 74))	('N116', 'Chemical', '-', (70, 74))	('CD226', 'Gene', (78, 83))	('CD226', 'Gene', '10666', (78, 83))	('S74', 'Var', (53, 56))	('CD155', 'Gene', (60, 65))	('losing', 'NegReg', (100, 106))
32178	33469055	In addition, CD155 A67T also influenced other important interactions between G70 of CD155 and E185 of CD226 by distance extension (3.3 6.0 A), resulting in the loss of the hydrogen bond (Fig.	('hydrogen bond', 'MPA', (172, 185))	('E185', 'Var', (94, 98))	('influenced', 'Reg', (29, 39))	('loss', 'NegReg', (160, 164))	('or', 'Gene', '31118', (49, 51))	('CD155', 'Gene', '5817', (13, 18))	('CD155', 'Gene', (84, 89))	('A67T', 'Mutation', 'rs1058402', (19, 23))	('hydrogen', 'Chemical', 'MESH:D006859', (172, 180))	('interactions', 'Interaction', (56, 68))	('CD226', 'Gene', (102, 107))	('CD226', 'Gene', '10666', (102, 107))	('CD155', 'Gene', (13, 18))	('CD155', 'Gene', '5817', (84, 89))	('A67T', 'Var', (19, 23))	('G70', 'Var', (77, 80))
32182	33469055	Genetic variants in immune genes can also influence the host's immune activity, which affects the clinical cancer treatment outcome.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('affects', 'Reg', (86, 93))	('influence', 'Reg', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('immune genes', 'Gene', (20, 32))	('cancer', 'Disease', (107, 113))	('Genetic variants', 'Var', (0, 16))
32183	33469055	In this study, we investigated the association between variants in immune checkpoint genes and the clinical outcome of SCLC.	('investigated', 'Reg', (18, 30))	('variants', 'Var', (55, 63))	('SCLC', 'Disease', (119, 123))	('association', 'Interaction', (35, 46))	('SCLC', 'Disease', 'MESH:D018288', (119, 123))	('SCLC', 'Phenotype', 'HP:0030357', (119, 123))
32184	33469055	This is the first study to investigate the effects of genetic variants in immune checkpoint genes on chemotherapy response and prognosis in SCLC.	('genetic variants', 'Var', (54, 70))	('SCLC', 'Disease', (140, 144))	('SCLC', 'Disease', 'MESH:D018288', (140, 144))	('effects', 'Reg', (43, 50))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))
32185	33469055	We found that two variants, namely CD155 rs1058402G > A (A67T) and CD226 rs763361C > T (G307S), were significantly associated with chemotherapy response and survival outcomes.	('CD155', 'Gene', (35, 40))	('rs763361C > T', 'Var', (73, 86))	('survival outcomes', 'CPA', (157, 174))	('CD226', 'Gene', (67, 72))	('CD155', 'Gene', '5817', (35, 40))	('A67T', 'Mutation', 'rs1058402', (57, 61))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (41, 55))	('CD226', 'Gene', '10666', (67, 72))	('rs1058402G > A', 'Var', (41, 55))	('rs763361C > T', 'DBSNP_MENTION', 'None', (73, 86))	('chemotherapy response', 'CPA', (131, 152))	('associated with', 'Reg', (115, 130))	('G307S', 'Mutation', 'rs763361', (88, 93))
32200	33469055	The rs1058402G > A changes alanine amino acid to threonine at codon 67 of CD155.	('CD155', 'Gene', '5817', (74, 79))	('alanine amino acid to threonine at codon 67', 'Mutation', 'rs1058402', (27, 70))	('CD155', 'Gene', (74, 79))	('rs1058402G > A', 'Var', (4, 18))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (4, 18))	('alanine amino acid to threonine', 'MPA', (27, 58))
32201	33469055	3-D structure model showed that changing alanine to threonine at codon 67 shortened the distance to S74/G73 of CD155.	('S74/G73', 'Var', (100, 107))	('or', 'Gene', '31118', (76, 78))	('CD155', 'Gene', (111, 116))	('alanine', 'Var', (41, 48))	('distance', 'MPA', (88, 96))	('alanine to threonine at codon 67', 'Mutation', 'rs1058402', (41, 73))	('CD155', 'Gene', '5817', (111, 116))
32202	33469055	The shortened distance made a new hydrogen bond between T67 and S74 of CD155, and this change resulted in distance extension and loss of hydrogen bond between the S74 of CD155 and N116 of CD226.	('distance', 'MPA', (106, 114))	('or', 'Gene', '31118', (6, 8))	('CD155', 'Gene', '5817', (71, 76))	('CD155', 'Gene', (170, 175))	('hydrogen', 'Chemical', 'MESH:D006859', (137, 145))	('S74', 'Var', (163, 166))	('loss', 'NegReg', (129, 133))	('N116', 'Var', (180, 184))	('CD226', 'Gene', (188, 193))	('N116', 'Chemical', '-', (180, 184))	('CD155', 'Gene', (71, 76))	('hydrogen', 'Chemical', 'MESH:D006859', (34, 42))	('hydrogen bond', 'MPA', (137, 150))	('extension', 'PosReg', (115, 124))	('CD226', 'Gene', '10666', (188, 193))	('CD155', 'Gene', '5817', (170, 175))	('hydrogen bond', 'MPA', (34, 47))
32203	33469055	In addition, the structure modification due to rs1058402G > A (A67T) increased the coupling distance between the G70 of CD 155 and E185 of CD226, and resulted in hydrogen bond loss.	('A67T', 'Mutation', 'rs1058402', (63, 67))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (47, 61))	('G70', 'Var', (113, 116))	('increased', 'PosReg', (69, 78))	('rs1058402G > A', 'Var', (47, 61))	('loss', 'NegReg', (176, 180))	('E185', 'Var', (131, 135))	('CD226', 'Gene', (139, 144))	('hydrogen bond', 'MPA', (162, 175))	('structure', 'MPA', (17, 26))	('coupling distance', 'MPA', (83, 100))	('CD226', 'Gene', '10666', (139, 144))	('CD 155', 'Gene', '5817', (120, 126))	('CD 155', 'Gene', (120, 126))	('hydrogen', 'Chemical', 'MESH:D006859', (162, 170))
32204	33469055	In the interaction between CD155 and CD226, the S74/G70 of CD155 and N116/E185 of CD226 are important binding points.	('binding', 'Interaction', (102, 109))	('interaction', 'Interaction', (7, 18))	('N116/E185', 'Var', (69, 78))	('CD226', 'Gene', (37, 42))	('N116', 'Chemical', '-', (69, 73))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('CD226', 'Gene', '10666', (37, 42))	('CD226', 'Gene', '10666', (82, 87))	('or', 'Gene', '31118', (95, 97))	('CD155', 'Gene', '5817', (59, 64))	('CD226', 'Gene', (82, 87))	('CD155', 'Gene', '5817', (27, 32))	('S74/G70', 'Var', (48, 55))	('CD155', 'Gene', (59, 64))	('CD155', 'Gene', (27, 32))
32205	33469055	In this study, the 1058402G > A (A67T) was significantly associated with worse chemotherapy response and OS in SCLC patients.	('SCLC', 'Disease', (111, 115))	('1058402G > A', 'Mutation', 'g.1058402G>A', (19, 31))	('1058402G > A', 'Var', (19, 31))	('patients', 'Species', '9606', (116, 124))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('A67T', 'Mutation', 'rs1058402', (33, 37))	('or', 'Gene', '31118', (74, 76))	('SCLC', 'Disease', 'MESH:D018288', (111, 115))
32206	33469055	As shown in the 3-D structural model, the 1058402G > A (A67T) increased the binding point distance between CD155 and CD226.	('increased', 'PosReg', (62, 71))	('CD226', 'Gene', (117, 122))	('CD155', 'Gene', (107, 112))	('binding point distance', 'MPA', (76, 98))	('A67T', 'Mutation', 'rs1058402', (56, 60))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('1058402G > A', 'Mutation', 'g.1058402G>A', (42, 54))	('CD155', 'Gene', '5817', (107, 112))	('1058402G > A', 'Var', (42, 54))	('CD226', 'Gene', '10666', (117, 122))
32209	33469055	However, further functional studies are needed to determine whether CD155 rs1058402G > A (A67T) affects the CD155/CD226 interaction.	('interaction', 'Interaction', (120, 131))	('CD155', 'Gene', (108, 113))	('CD226', 'Gene', (114, 119))	('rs1058402G > A', 'Var', (74, 88))	('CD226', 'Gene', '10666', (114, 119))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (74, 88))	('CD155', 'Gene', '5817', (68, 73))	('A67T', 'Mutation', 'rs1058402', (90, 94))	('affects', 'Reg', (96, 103))	('CD155', 'Gene', (68, 73))	('CD155', 'Gene', '5817', (108, 113))
32210	33469055	This is the first review to report that a CD155 variant was associated with cancer clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CD155', 'Gene', '5817', (42, 47))	('or', 'Gene', '31118', (31, 33))	('cancer', 'Disease', (76, 82))	('CD155', 'Gene', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('variant', 'Var', (48, 55))	('associated', 'Reg', (60, 70))
32211	33469055	This variant may also affect the therapeutic effect of the drug to be developed in the future, considering that CD155 is being studied as a new therapeutic target in tumor immunology.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CD155', 'Gene', '5817', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('variant', 'Var', (5, 12))	('CD155', 'Gene', (112, 117))	('affect', 'Reg', (22, 28))	('therapeutic effect', 'MPA', (33, 51))
32212	33469055	In the present study, CD226 rs763361C > T was associated with better chemotherapy response and OS in SCLC patients.	('SCLC', 'Disease', 'MESH:D018288', (101, 105))	('SCLC', 'Phenotype', 'HP:0030357', (101, 105))	('better', 'PosReg', (62, 68))	('rs763361C > T', 'Var', (28, 41))	('CD226', 'Gene', (22, 27))	('rs763361C > T', 'DBSNP_MENTION', 'None', (28, 41))	('CD226', 'Gene', '10666', (22, 27))	('chemotherapy response', 'CPA', (69, 90))	('patients', 'Species', '9606', (106, 114))	('SCLC', 'Disease', (101, 105))
32213	33469055	The rs763361C > T is located in exon 7 encoding the cytoplasmic tail of CD226, which harbors two phosphorylation sites and is a non-synonymous mutation.	('rs763361C > T', 'Var', (4, 17))	('CD226', 'Gene', (72, 77))	('CD226', 'Gene', '10666', (72, 77))	('rs763361C > T', 'DBSNP_MENTION', 'None', (4, 17))	('or', 'Gene', '31118', (89, 91))	('or', 'Gene', '31118', (103, 105))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))
32214	33469055	The rs763361 C-to-T change results in the replacement of glycine to serine at codon 307.	('replacement of glycine to serine', 'MPA', (42, 74))	('rs763361', 'Var', (4, 12))	('glycine to serine at codon 307', 'Mutation', 'rs763361', (57, 87))	('results in', 'Reg', (27, 37))	('rs763361', 'Mutation', 'rs763361', (4, 12))
32215	33469055	A Gly307Ser substitution believed to affect CD226 expression by changing the phosphorylation or altering RNA splicing by disrupting the exon-splicing silencer sequence.	('RNA', 'cellular_component', 'GO:0005562', ('105', '108'))	('or', 'Gene', '31118', (83, 85))	('Ser', 'cellular_component', 'GO:0005790', ('8', '11'))	('altering', 'Reg', (96, 104))	('exon-splicing silencer sequence', 'MPA', (136, 167))	('changing', 'Reg', (64, 72))	('or', 'Gene', '31118', (93, 95))	('affect', 'Reg', (37, 43))	('Gly307Ser', 'SUBSTITUTION', 'None', (2, 11))	('RNA splicing', 'MPA', (105, 117))	('disrupting', 'NegReg', (121, 131))	('CD226', 'Gene', (44, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('CD226', 'Gene', '10666', (44, 49))	('Gly307Ser', 'Var', (2, 11))	('splicing', 'biological_process', 'GO:0045292', ('141', '149'))	('expression', 'MPA', (50, 60))	('RNA splicing', 'biological_process', 'GO:0008380', ('105', '117'))
32216	33469055	CD226 rs763361C > T is associated with multiple autoimmune diseases, including multiple sclerosis and rheumatoid arthritis.	('sclerosis', 'Disease', 'MESH:D012598', (88, 97))	('autoimmune diseases', 'Disease', 'MESH:D001327', (48, 67))	('rs763361C > T', 'Var', (6, 19))	('sclerosis', 'Disease', (88, 97))	('autoimmune diseases', 'Disease', (48, 67))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (48, 67))	('rs763361C > T', 'DBSNP_MENTION', 'None', (6, 19))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (102, 122))	('CD226', 'Gene', (0, 5))	('CD226', 'Gene', '10666', (0, 5))	('rheumatoid arthritis', 'Disease', (102, 122))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (102, 122))	('associated', 'Reg', (23, 33))	('arthritis', 'Phenotype', 'HP:0001369', (113, 122))
32217	33469055	Regarding cancer, the T allele of rs763361 has been reported to increase the risk of NSCLC in the Chinese Han population.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('or', 'Gene', '31118', (55, 57))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('SCLC', 'Phenotype', 'HP:0030357', (86, 90))	('increase', 'PosReg', (64, 72))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('rs763361', 'Var', (34, 42))	('rs763361', 'Mutation', 'rs763361', (34, 42))	('cancer', 'Disease', (10, 16))
32218	33469055	However, the exact biological function of CD226 rs763361C > T is not well-known, and further researches are needed.	('CD226', 'Gene', '10666', (42, 47))	('rs763361C > T', 'DBSNP_MENTION', 'None', (48, 61))	('CD226', 'Gene', (42, 47))	('rs763361C > T', 'Var', (48, 61))
32219	33469055	The CD226 rs1790947G > T has a strong LD (r2 = 0.91) with CD226 rs763361C > T and is located in the 3' untranslated region.	('rs763361C > T', 'DBSNP_MENTION', 'None', (64, 77))	('rs1790947G > T', 'Var', (10, 24))	('CD226', 'Gene', '10666', (58, 63))	('rs763361C > T', 'Var', (64, 77))	('CD226', 'Gene', (4, 9))	('CD226', 'Gene', (58, 63))	('CD226', 'Gene', '10666', (4, 9))	('rs1790947G > T', 'DBSNP_MENTION', 'None', (10, 24))
32220	33469055	Using RegulomDB (http://www.regulomedb.org/), the rs1790947G > T was likely expected to affect binding and linked to CD226 expression.	('CD226', 'Gene', (117, 122))	('expression', 'MPA', (123, 133))	('linked', 'Reg', (107, 113))	('affect', 'Reg', (88, 94))	('or', 'Gene', '31118', (39, 41))	('rs1790947G > T', 'DBSNP_MENTION', 'None', (50, 64))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('rs1790947G > T', 'Var', (50, 64))	('binding', 'Interaction', (95, 102))	('CD226', 'Gene', '10666', (117, 122))
32222	33469055	The association patterns between the rs1790947 genotypes and chemotherapy response and OS were similar to that of rs763361 (Supplementary Table S5).	('rs1790947', 'Var', (37, 46))	('rs1790947', 'Mutation', 'rs1790947', (37, 46))	('rs763361', 'Mutation', 'rs763361', (114, 122))	('chemotherapy response', 'CPA', (61, 82))
32223	33469055	Hence, the selected polymorphism was rs763361C > T, but rs1790947G > T could actually affect CD226 expression and clinical outcomes.	('expression', 'MPA', (99, 109))	('CD226', 'Gene', '10666', (93, 98))	('affect', 'Reg', (86, 92))	('rs763361C > T', 'DBSNP_MENTION', 'None', (37, 50))	('rs1790947G > T', 'Var', (56, 70))	('rs763361C > T', 'Var', (37, 50))	('rs1790947G > T', 'DBSNP_MENTION', 'None', (56, 70))	('or', 'Gene', '31118', (25, 27))	('clinical outcomes', 'CPA', (114, 131))	('CD226', 'Gene', (93, 98))
32226	33469055	Therefore, variants in CD155 and CD226 may have a greater impact on clinical outcomes with immunotherapy alone or in combination with chemotherapy than with chemotherapy alone.	('or', 'Gene', '31118', (6, 8))	('variants', 'Var', (11, 19))	('or', 'Gene', '31118', (111, 113))	('CD226', 'Gene', '10666', (33, 38))	('CD226', 'Gene', (33, 38))	('CD155', 'Gene', (23, 28))	('impact', 'Reg', (58, 64))	('CD155', 'Gene', '5817', (23, 28))
32229	33469055	Because CD155 and CD226 are co-stimulatory signal for immune cells, investigating the role of variants in CD155 and CD226 in SCLC patients who received combination immunotherapy and chemotherapy may yield interesting results.	('CD226', 'Gene', (18, 23))	('SCLC', 'Disease', (125, 129))	('CD155', 'Gene', '5817', (8, 13))	('or', 'Gene', '31118', (39, 41))	('CD155', 'Gene', '5817', (106, 111))	('CD155', 'Gene', (8, 13))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('patients', 'Species', '9606', (130, 138))	('CD226', 'Gene', (116, 121))	('variants', 'Var', (94, 102))	('CD155', 'Gene', (106, 111))	('CD226', 'Gene', '10666', (116, 121))	('CD226', 'Gene', '10666', (18, 23))	('SCLC', 'Disease', 'MESH:D018288', (125, 129))	('or', 'Gene', '31118', (51, 53))
32230	33469055	Although a theoretical model for the interactional changes caused by mutations of CD155 and CD226 has been presented, one of limitations is that it has not been confirmed experimentally.	('mutations', 'Var', (69, 78))	('or', 'Gene', '31118', (14, 16))	('CD155', 'Gene', '5817', (82, 87))	('interactional', 'Interaction', (37, 50))	('or', 'Gene', '31118', (30, 32))	('CD226', 'Gene', (92, 97))	('CD155', 'Gene', (82, 87))	('CD226', 'Gene', '10666', (92, 97))
32233	33469055	In summary, we investigated the association between the variants in immune checkpoint genes and SCLC prognosis.	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('association', 'Interaction', (32, 43))	('variants', 'Var', (56, 64))	('investigated', 'Reg', (15, 27))	('SCLC', 'Disease', (96, 100))	('SCLC', 'Disease', 'MESH:D018288', (96, 100))
32234	33469055	Two variants, namely CD155 rs1058402G > A (A67T) and CD226 rs763361C > T (G307S), were associated with chemotherapy response and OS outcomes.	('rs763361C > T', 'Var', (59, 72))	('OS outcomes', 'CPA', (129, 140))	('CD226', 'Gene', '10666', (53, 58))	('CD226', 'Gene', (53, 58))	('rs763361C > T', 'DBSNP_MENTION', 'None', (59, 72))	('chemotherapy response', 'CPA', (103, 124))	('associated with', 'Reg', (87, 102))	('G307S', 'Mutation', 'rs763361', (74, 79))	('CD155', 'Gene', '5817', (21, 26))	('rs1058402G > A', 'Var', (27, 41))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (27, 41))	('A67T', 'Mutation', 'rs1058402', (43, 47))	('CD155', 'Gene', (21, 26))
32235	33469055	CD155 rs1058402G > A (A67T) seems to influence the interaction between CD155 and CD226.	('influence', 'Reg', (37, 46))	('CD155', 'Gene', '5817', (71, 76))	('interaction', 'Interaction', (51, 62))	('CD155', 'Gene', '5817', (0, 5))	('CD226', 'Gene', (81, 86))	('CD155', 'Gene', (71, 76))	('rs1058402G > A', 'DBSNP_MENTION', 'None', (6, 20))	('CD226', 'Gene', '10666', (81, 86))	('rs1058402G > A', 'Var', (6, 20))	('A67T', 'Mutation', 'rs1058402', (22, 26))	('CD155', 'Gene', (0, 5))
32236	33469055	); Provision of study material or patients (S.S.Y., S.H.C., Y.H.L., H.W.S., J.H.L., S.Y.L., S.I.C., C.H.K., J.Y.P.	('S.I.C.', 'Var', (92, 98))	('C.H.K.', 'Var', (100, 106))	('patients', 'Species', '9606', (34, 42))	('S.Y.L.', 'Var', (84, 90))	('or', 'Gene', '31118', (31, 33))
32238	33469055	); Analysis and interpretation of Data (J.H.L., S.S.Y., S.Y.K., M.J.H., J.E.C., W.K.L., S.Y.L., S.I.C., C.H.K., J.Y.P.)	('J.E.C', 'CellLine', 'CVCL:0355', (72, 77))	('C.H.K.', 'Var', (104, 110))	('M.J.H.', 'Var', (64, 70))	('S.Y.L.', 'Var', (88, 94))	('S.I.C.', 'Var', (96, 102))
32259	32501471	In cancers, mutation of Cosmc results in elevated sTn levels that are associated with poor prognosis and outcome.	('Cosmc', 'Gene', '29071', (24, 29))	('elevated sTn', 'Phenotype', 'HP:0008151', (41, 53))	('Cosmc', 'Gene', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('elevated', 'PosReg', (41, 49))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('sTn levels', 'MPA', (50, 60))	('mutation', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
32264	32501471	In addition, we were unable to demonstrate enhanced TGF-beta secretion following Siglec-15 cross-linking in overexpressing THP-1 cells, but we did observe activation of the SYK/MAPK signaling pathway that may modulate their functional activity.	('enhanced', 'PosReg', (43, 51))	('TGF-beta secretion', 'biological_process', 'GO:0038044', ('52', '70'))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('SYK/MAPK signaling pathway', 'Pathway', (173, 199))	('modulate', 'Reg', (209, 217))	('cross-linking', 'Var', (91, 104))	('TGF-beta', 'Gene', (52, 60))	('functional', 'MPA', (224, 234))	('signaling pathway', 'biological_process', 'GO:0007165', ('182', '199'))	('THP-1', 'CellLine', 'CVCL:0006', (123, 128))	('MAPK signaling', 'biological_process', 'GO:0000165', ('177', '191'))	('TGF-beta', 'Gene', '7039', (52, 60))	('Siglec-15', 'Gene', (81, 90))	('activation', 'PosReg', (155, 165))
32270	32501471	The binding of Siglec-15-Fc to cancer cell lines was greatly reduced on mutation of the key Arg143 to Ala (Figure 1A and B and Supplementary Figure S1C and D).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Arg143', 'Var', (92, 98))	('binding', 'Interaction', (4, 11))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('Siglec-15-Fc', 'Protein', (15, 27))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('mutation', 'Var', (72, 80))	('cancer', 'Disease', (31, 37))	('reduced', 'NegReg', (61, 68))	('Arg143 to Ala', 'Mutation', 'p.R143A', (92, 105))
32271	32501471	Unlike a previous study, however, this mutation did not completely abrogate Siglec-15 binding to cancer cell lines.	('Siglec-15', 'Protein', (76, 85))	('mutation', 'Var', (39, 47))	('cancer', 'Disease', (97, 103))	('binding', 'Interaction', (86, 93))	('abrogate', 'NegReg', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
32283	32501471	To identify glycan ligands for Siglec-15 other than sTn, we performed glycan array analyses of Fc-chimeras of human Siglec-15 wildtype and Arg143Ala mutant and compared the results with those using the sTn specific 3F1 antibody (Figure 4).	('antibody', 'cellular_component', 'GO:0019814', ('219', '227'))	('antibody', 'molecular_function', 'GO:0003823', ('219', '227'))	('glycan', 'Chemical', 'MESH:D011134', (70, 76))	('human', 'Species', '9606', (110, 115))	('glycan', 'Chemical', 'MESH:D011134', (12, 18))	('antibody', 'cellular_component', 'GO:0042571', ('219', '227'))	('Siglec-15', 'Gene', (116, 125))	('antibody', 'cellular_component', 'GO:0019815', ('219', '227'))	('Arg143Ala', 'Var', (139, 148))	('Arg143Ala', 'SUBSTITUTION', 'None', (139, 148))
32292	32501471	With the Arg143 to Ala mutant the binding was markedly reduced, but not abolished.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('binding', 'Interaction', (34, 41))	('reduced', 'NegReg', (55, 62))	('Arg143 to Ala', 'Mutation', 'p.R143A', (9, 22))	('Arg143 to', 'Var', (9, 18))
32297	32501471	To determine whether cross-linking Siglec-15 on monocytic cells with antibodies enhanced TGF-beta levels, THP-1 mock- and Siglec-15-transfected cells were incubated with two monoclonal antibodies against Siglec-15, 25E9 and A9E8, followed by cross-linking with a secondary antibody.	('antibody', 'cellular_component', 'GO:0042571', ('273', '281'))	('antibody', 'cellular_component', 'GO:0019815', ('273', '281'))	('antibody', 'cellular_component', 'GO:0019814', ('273', '281'))	('TGF-beta', 'Gene', '7039', (89, 97))	('THP-1', 'CellLine', 'CVCL:0006', (106, 111))	('antibody', 'molecular_function', 'GO:0003823', ('273', '281'))	('antibodies', 'Var', (69, 79))	('enhanced', 'PosReg', (80, 88))	('TGF-beta', 'Gene', (89, 97))
32298	32501471	Consistent with the co-culture studies, cross-linking Siglec-15 on THP-1 cells did not increase TGF-beta secretion compared to the isotype control antibody (Figure 5D).	('antibody', 'molecular_function', 'GO:0003823', ('147', '155'))	('TGF-beta', 'Gene', (96, 104))	('THP-1', 'CellLine', 'CVCL:0006', (67, 72))	('cross-linking', 'Var', (40, 53))	('antibody', 'cellular_component', 'GO:0042571', ('147', '155'))	('TGF-beta', 'Gene', '7039', (96, 104))	('Siglec-15', 'Gene', (54, 63))	('increase TGF-beta', 'Phenotype', 'HP:0030269', (87, 104))	('TGF-beta secretion', 'biological_process', 'GO:0038044', ('96', '114'))	('antibody', 'cellular_component', 'GO:0019815', ('147', '155'))	('antibody', 'cellular_component', 'GO:0019814', ('147', '155'))
32301	32501471	Therefore, we explored whether cross-linking Siglec-15 triggered activation of ERK and p38 MAPK in THP-1 cells expressing Siglec-15.	('ERK', 'Gene', (79, 82))	('MAPK', 'molecular_function', 'GO:0004707', ('91', '95'))	('THP-1', 'CellLine', 'CVCL:0006', (99, 104))	('Siglec-15', 'Var', (122, 131))	('ERK', 'molecular_function', 'GO:0004707', ('79', '82'))	('p38 MAPK', 'Pathway', (87, 95))	('ERK', 'Gene', '5594', (79, 82))	('activation', 'PosReg', (65, 75))
32302	32501471	Cross-linking Siglec-15 on THP-1 cells expressing Siglec-15 with anti-Siglec-15 whole mouse IgG1 antibodies stimulated phosphorylation of ERK1/2 (at T202/Y204) unlike the isotype control antibody, while this was inhibited when cells were pretreated with the specific MEK1/2 inhibitor PD184352 or the SYK inhibitor BI1002494 (Figure 6A and Supplementary Figure S6).	('MEK1', 'molecular_function', 'GO:0004708', ('267', '271'))	('antibody', 'cellular_component', 'GO:0019814', ('187', '195'))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('MEK1/2', 'Gene', (267, 273))	('BI1002494', 'Chemical', 'MESH:C000619117', (314, 323))	('stimulated', 'PosReg', (108, 118))	('phosphorylation', 'MPA', (119, 134))	('PD184352', 'Var', (284, 292))	('mouse', 'Species', '10090', (86, 91))	('antibody', 'molecular_function', 'GO:0003823', ('187', '195'))	('THP-1', 'CellLine', 'CVCL:0006', (27, 32))	('BI1002494', 'Var', (314, 323))	('antibody', 'cellular_component', 'GO:0042571', ('187', '195'))	('PD184352', 'Chemical', 'MESH:C120227', (284, 292))	('IgG1', 'cellular_component', 'GO:0071735', ('92', '96'))	('ERK1', 'molecular_function', 'GO:0004707', ('138', '142'))	('antibody', 'cellular_component', 'GO:0019815', ('187', '195'))	('MEK1/2', 'Gene', '26395;26396', (267, 273))	('IgG1', 'Gene', (92, 96))	('IgG1', 'Gene', '105243590', (92, 96))
32303	32501471	Moreover, the anti-Siglec-15 human IgG KO antibody (L234A/L235A mutant), 25E09, which no longer binds Fcgamma receptors also enhanced ERK phosphorylation (Figure 6B and Supplementary Figure S7) indicating that ERK activation induced by the antibodies is independent of Fc receptor engagement.	('L234A', 'SUBSTITUTION', 'None', (52, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('L235A', 'Var', (58, 63))	('ERK', 'molecular_function', 'GO:0004707', ('134', '137'))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('ERK', 'Gene', '5594', (134, 137))	('ERK', 'molecular_function', 'GO:0004707', ('210', '213'))	('phosphorylation', 'MPA', (138, 153))	('L235A', 'SUBSTITUTION', 'None', (58, 63))	('ERK', 'Gene', '5594', (210, 213))	('human', 'Species', '9606', (29, 34))	('enhanced', 'PosReg', (125, 133))	('ERK', 'Gene', (134, 137))	('ERK', 'Gene', (210, 213))	('L234A', 'Var', (52, 57))
32311	32501471	Mutation of the conserved "essential arginine" Arg143 that is critical for interaction with sialic acid to alanine and sialidase pretreatment of cancer cells resulted in significant reduction of Siglec-15 binding.	('cancer', 'Disease', (145, 151))	('Arg143', 'Chemical', '-', (47, 53))	('Mutation', 'Var', (0, 8))	('sialic acid', 'Chemical', 'MESH:D019158', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('alanine', 'Chemical', 'MESH:D000409', (107, 114))	('Siglec-15', 'Protein', (195, 204))	('binding', 'Interaction', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('reduction', 'NegReg', (182, 191))	('arginine', 'Chemical', 'MESH:D001120', (37, 45))
32322	32501471	Cross-linking Siglec-15 with sialylated ligands activates ITAM signaling via DAP12 which is mediated by recruitment and activation of SYK tyrosine kinase.	('ITAM signaling', 'MPA', (58, 72))	('tyrosine', 'Chemical', 'MESH:D014443', (138, 146))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('SYK tyrosine kinase', 'Enzyme', (134, 153))	('DAP12', 'Gene', (77, 82))	('DAP12', 'Gene', '7305', (77, 82))	('activation', 'PosReg', (120, 130))	('Cross-linking', 'Var', (0, 13))	('activates', 'PosReg', (48, 57))
32323	32501471	Cross-linking macrophage-expressed Siglec-15 by sTn on cancer cells has been shown to enhance TGF-beta secretion.	('TGF-beta secretion', 'biological_process', 'GO:0038044', ('94', '112'))	('Siglec-15', 'Protein', (35, 44))	('enhance', 'PosReg', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TGF-beta', 'Gene', (94, 102))	('Cross-linking', 'Var', (0, 13))	('TGF-beta', 'Gene', '7039', (94, 102))	('cancer', 'Disease', (55, 61))
32327	32501471	We demonstrated by flow cytometry that cross-linking Siglec-15 on THP-1 cells triggers phosphorylation of ERK, but not p38 MAPK.	('cross-linking', 'Var', (39, 52))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('triggers', 'Reg', (78, 86))	('THP-1', 'CellLine', 'CVCL:0006', (66, 71))	('ERK', 'Gene', '5594', (106, 109))	('Siglec-15', 'Gene', (53, 62))	('ERK', 'molecular_function', 'GO:0004707', ('106', '109'))	('phosphorylation', 'MPA', (87, 102))	('ERK', 'Gene', (106, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
32332	32501471	Human Siglec-15 wildtype and R134A mutant were expressed as Fc fusion proteins by cloning the cDNAs of the extracellular domains fused to human IgG1 Fc region into pcDNA3 and transient transfection of CHO cells.	('Human', 'Species', '9606', (0, 5))	('IgG1', 'Gene', (144, 148))	('IgG1', 'cellular_component', 'GO:0071735', ('144', '148'))	('IgG1', 'Gene', '105243590', (144, 148))	('human', 'Species', '9606', (138, 143))	('CHO', 'molecular_function', 'GO:0043848', ('201', '204'))	('R134A', 'Var', (29, 34))	('R134A', 'Mutation', 'p.R134A', (29, 34))	('extracellular', 'cellular_component', 'GO:0005576', ('107', '120'))	('CHO', 'CellLine', 'CVCL:0213', (201, 204))
32333	32501471	Monoclonal antibodies against human Siglec-15, 25E9 (WO2011041894, Alethia Biotherapeutics) and A9E8 (WO2013034660, MedImmune) were produced by transient co-transfection of HEK293 cells with pIRES-DHFR containing the heavy chain cDNA (either murine IgG1 (25E9, A9E8) or huIgG1KO with Fc modifications to silence effector function (25E09; LALA mutant)) and pcDNA3 containing the light chain cDNA.	('human', 'Species', '9606', (30, 35))	('IgG1', 'Gene', (272, 276))	('WO2013034660', 'Var', (102, 114))	('IgG1', 'cellular_component', 'GO:0071735', ('249', '253'))	('IgG1', 'Gene', '105243590', (272, 276))	('IgG1', 'Gene', (249, 253))	('DHFR', 'molecular_function', 'GO:0004146', ('197', '201'))	('HEK293', 'CellLine', 'CVCL:0045', (173, 179))	('IgG1', 'Gene', '105243590', (249, 253))
32351	32501471	Immune complexes were prepared by mixing 1 mug/mL of Siglec-15-Fc wildtype or R143A mutant and 1 mug/mL of FITC-conjugated goat anti-human IgG Fc in 100 muL phosphate-buffered saline (PBS) containing 1% FetalClone II serum (FACS buffer), for 1 h on ice.	('FACS', 'Gene', '14081', (224, 228))	('phosphate-buffered saline', 'Chemical', '-', (157, 182))	('mug', 'molecular_function', 'GO:0043739', ('97', '100'))	('PBS', 'Chemical', '-', (184, 187))	('Siglec-15-Fc', 'Gene', (53, 65))	('ice', 'Chemical', 'MESH:D007053', (249, 252))	('mug', 'molecular_function', 'GO:0043739', ('43', '46'))	('R143A', 'Mutation', 'p.R143A', (78, 83))	('human', 'Species', '9606', (133, 138))	('R143A mutant', 'Var', (78, 90))	('FITC', 'Chemical', 'MESH:D016650', (107, 111))	('FACS', 'Gene', (224, 228))
32360	32501471	For inhibition experiments, THP-1 cells were pretreated with 2 muM PD184352 or 10 muM BI1002494 for 1 h at 37 C before cross-linking with anti-Siglec-15 antibodies.	('PD184352', 'Var', (67, 75))	('PD184352', 'Chemical', 'MESH:C120227', (67, 75))	('BI1002494', 'Var', (86, 95))	('THP-1', 'CellLine', 'CVCL:0006', (28, 33))	('BI1002494', 'Chemical', 'MESH:C000619117', (86, 95))
32363	32501471	The cells were washed twice with excess FACS buffer to remove the methanol before incubating first with 1:50 Fc block in FACS buffer and then with phospho-protein antibodies (1:50 p-ERK1/2 T202/Y204 or 1:50 p-p38 MAPK T180/Y182 antibodies from Cell Signaling Technologies) in FACS buffer for 1 h at room temperature.	('methanol', 'Chemical', 'MESH:D000432', (66, 74))	('Signaling', 'biological_process', 'GO:0023052', ('249', '258'))	('FACS', 'Gene', (121, 125))	('FACS', 'Gene', '14081', (121, 125))	('FACS', 'Gene', (276, 280))	('FACS', 'Gene', (40, 44))	('ice', 'Chemical', 'MESH:D007053', (24, 27))	('ERK1', 'molecular_function', 'GO:0004707', ('182', '186'))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('FACS', 'Gene', '14081', (276, 280))	('1:50 p-ERK1/2', 'Var', (175, 188))	('FACS', 'Gene', '14081', (40, 44))	('MAPK', 'molecular_function', 'GO:0004707', ('213', '217'))	('T180/Y182', 'Var', (218, 227))
32474	33142039	in which the targeted disruption of ACE2 in mice resulted in a severe heart contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart.	('angiotensin II levels', 'MPA', (108, 129))	('disruption', 'Var', (22, 32))	('upregulation', 'PosReg', (135, 147))	('ACE2', 'Gene', '59272', (36, 40))	('heart contractility defect', 'Disease', 'MESH:D006330', (70, 96))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('heart contractility defect', 'Disease', (70, 96))	('increased', 'PosReg', (98, 107))	('hypoxia', 'Disease', (151, 158))	('ACE2', 'Gene', (36, 40))	('mice', 'Species', '10090', (44, 48))
32483	33204104	A Novel ROS1-FBXL17 Fusion Co-Existing with CD74-ROS1 Fusion May Improve Sensitivity to Crizotinib and Prolong Progression-Free Survival of Patients with Lung Adenocarcinoma The rearrangement of ROS1 (C-ros oncogene 1) is an important driver of non-small cell lung cancer (NSCLC).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (249, 271))	('Improve', 'PosReg', (65, 72))	('ROS1', 'Gene', '6098', (195, 199))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (154, 173))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('Crizotinib', 'Chemical', 'MESH:D000077547', (88, 98))	('FBXL17', 'Gene', '64839', (13, 19))	('ROS1', 'Gene', (8, 12))	('Sensitivity to Crizotinib', 'MPA', (73, 98))	('lung cancer', 'Disease', (260, 271))	('Progression-Free Survival', 'CPA', (111, 136))	('rearrangement', 'Var', (178, 191))	('ROS1', 'Gene', '6098', (49, 53))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('Lung Adenocarcinoma', 'Disease', (154, 173))	('ROS1', 'Gene', (195, 199))	('C-ros oncogene 1', 'Gene', '6098', (201, 217))	('C-ros oncogene 1', 'Gene', (201, 217))	('lung cancer', 'Disease', 'MESH:D008175', (260, 271))	('NSCLC', 'Disease', (273, 278))	('ROS1', 'Gene', '6098', (8, 12))	('FBXL17', 'Gene', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (260, 271))	('NSCLC', 'Phenotype', 'HP:0030358', (273, 278))	('ROS1', 'Gene', (49, 53))	('Prolong', 'PosReg', (103, 110))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 173))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (245, 271))	('Patients', 'Species', '9606', (140, 148))	('Fusion', 'Var', (20, 26))
32486	33204104	Furthermore, non-reciprocal/reciprocal ROS1 translocations are rare and have not yet been reported.	('ROS1', 'Gene', (39, 43))	('ROS1', 'Gene', '6098', (39, 43))	('translocations', 'Var', (44, 58))
32488	33204104	Targeted next-generation sequencing panel was used to identify ROS1 rearrangements in a Chinese patient with advanced lung adenocarcinoma.	('rearrangements', 'Var', (68, 82))	('ROS1', 'Gene', (63, 67))	('lung adenocarcinoma', 'Disease', (118, 137))	('patient', 'Species', '9606', (96, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('ROS1', 'Gene', '6098', (63, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))
32489	33204104	We identified a non-reciprocal/reciprocal ROS1 translocation which contained a novel ROS1-FBXL17 (F-box and leucine-rich repeat protein 17) fusion co-existing with the CD74-ROS1 fusion and the patient was sensitive to crizotinib.	('ROS1', 'Gene', '6098', (173, 177))	('ROS1', 'Gene', (85, 89))	('crizotinib', 'Chemical', 'MESH:D000077547', (218, 228))	('fusion', 'Var', (140, 146))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('ROS1', 'Gene', '6098', (85, 89))	('FBXL17', 'Gene', (90, 96))	('leucine', 'Chemical', 'MESH:D007930', (108, 115))	('ROS1', 'Gene', (42, 46))	('ROS1', 'Gene', '6098', (42, 46))	('patient', 'Species', '9606', (193, 200))	('ROS1', 'Gene', (173, 177))	('FBXL17', 'Gene', '64839', (90, 96))
32491	33204104	Thus, this non-reciprocal/reciprocal ROS1 translocation patient had an excellent efficacy to crizotinib which was different from that in ALK.	('ROS1', 'Gene', '6098', (37, 41))	('translocation', 'Var', (42, 55))	('ALK', 'Gene', (137, 140))	('crizotinib', 'MPA', (93, 103))	('patient', 'Species', '9606', (56, 63))	('ALK', 'Gene', '238', (137, 140))	('ROS1', 'Gene', (37, 41))	('crizotinib', 'Chemical', 'MESH:D000077547', (93, 103))
32492	33204104	And it may be possible that the ROS1-FBXL17 fusion in this patient synergistically promotes the sensitivity of the CD74-RSO1 fusion to crizotinib.	('fusion', 'Var', (44, 50))	('sensitivity', 'MPA', (96, 107))	('patient', 'Species', '9606', (59, 66))	('FBXL17', 'Gene', '64839', (37, 43))	('promotes', 'PosReg', (83, 91))	('ROS1', 'Gene', (32, 36))	('FBXL17', 'Gene', (37, 43))	('ROS1', 'Gene', '6098', (32, 36))	('crizotinib', 'Chemical', 'MESH:D000077547', (135, 145))
32494	33204104	Our study adds new data to the ROS1 fusion database and provides a reference strategy for the clinical treatment of patients with double ROS1 fusions or non-reciprocal/reciprocal ROS1 translocation.	('fusions', 'Var', (142, 149))	('ROS1', 'Gene', (137, 141))	('ROS1', 'Gene', '6098', (137, 141))	('ROS1', 'Gene', (179, 183))	('patients', 'Species', '9606', (116, 124))	('ROS1', 'Gene', '6098', (179, 183))	('ROS1', 'Gene', (31, 35))	('ROS1', 'Gene', '6098', (31, 35))
32495	33204104	ROS1 (C-ros oncogene 1) rearrangement is a proven driver of non-small cell lung cancer (NSCLC) and occurs in approximately 1-3% of the patients with NSCLC worldwide.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('patients', 'Species', '9606', (135, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('ROS1', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('C-ros oncogene 1', 'Gene', (6, 22))	('C-ros oncogene 1', 'Gene', '6098', (6, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('NSCLC', 'Disease', (149, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('lung cancer', 'Disease', (75, 86))	('rearrangement', 'Var', (24, 37))	('ROS1', 'Gene', '6098', (0, 4))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('occurs', 'Reg', (99, 105))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('NSCLC', 'Disease', (88, 93))
32499	33204104	It is widely known that the EML4-ALK variants (V1-V7) or EGFR mutations (L858R/T790M/C797S/19 del.)	('ALK', 'Gene', (33, 36))	('C797S', 'Mutation', 'rs1057519861', (85, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('T790M', 'SUBSTITUTION', 'None', (79, 84))	('EML4', 'Gene', (28, 32))	('ALK', 'Gene', '238', (33, 36))	('EGFR', 'Gene', '1956', (57, 61))	('L858R', 'Var', (73, 78))	('L858R', 'SUBSTITUTION', 'None', (73, 78))	('T790M', 'Var', (79, 84))	('EML4', 'Gene', '27436', (28, 32))	('EGFR', 'Gene', (57, 61))
32503	33204104	Here, we identified a novel ROS1-FBXL17 (F-box and leucine-rich repeat protein 17) fusion that co-existed with the CD74-ROS1 fusion in one patient who was sensitive to crizotinib and was with a stable disease (SD) for more than 15 months, thus identifying a rare sensitive double fusion mode (a non-reciprocal/reciprocal translocation) for ROS1.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('ROS1', 'Gene', (120, 124))	('ROS1', 'Gene', '6098', (120, 124))	('ROS1', 'Gene', (340, 344))	('FBXL17', 'Gene', '64839', (33, 39))	('leucine', 'Chemical', 'MESH:D007930', (51, 58))	('ROS1', 'Gene', '6098', (340, 344))	('ROS1', 'Gene', (28, 32))	('crizotinib', 'Chemical', 'MESH:D000077547', (168, 178))	('ROS1', 'Gene', '6098', (28, 32))	('FBXL17', 'Gene', (33, 39))	('fusion', 'Var', (83, 89))	('patient', 'Species', '9606', (139, 146))
32505	33204104	The clinical stage of the cancer was determined as T3N2M0 (stage IIIb).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('T3N2M0', 'Var', (51, 57))
32511	33204104	The results showed 5-10% PD-L1 positive cells and a TMB value of 5.6 mutations per megabase.	('PD-L1', 'Gene', '29126', (25, 30))	('mutations', 'Var', (69, 78))	('TMB', 'Chemical', '-', (52, 55))	('PD-L1', 'Gene', (25, 30))
32526	33204104	There is little information regarding the efficacy of crizotinib for patients harboring double genes fused with ROS1.	('ROS1', 'Gene', (112, 116))	('double genes', 'Var', (88, 100))	('ROS1', 'Gene', '6098', (112, 116))	('crizotinib', 'Chemical', 'MESH:D000077547', (54, 64))	('patients', 'Species', '9606', (69, 77))
32527	33204104	A Chinese study in 2018 identified a patient who harbored a CD74-ROS1 fusion that coexisted with the SDC4-ROS1 fusion, and another patient who harbored a SDC4-ROS1 fusion that coexisted with the EZR-ROS1 fusion.	('ROS1', 'Gene', (106, 110))	('SDC4', 'Gene', (154, 158))	('patient', 'Species', '9606', (37, 44))	('ROS1', 'Gene', '6098', (106, 110))	('ROS1', 'Gene', (199, 203))	('SDC4', 'Gene', '6385', (101, 105))	('SDC4', 'Gene', (101, 105))	('ROS1', 'Gene', (65, 69))	('ROS1', 'Gene', '6098', (199, 203))	('fusion', 'Var', (70, 76))	('ROS1', 'Gene', (159, 163))	('ROS1', 'Gene', '6098', (65, 69))	('patient', 'Species', '9606', (131, 138))	('ROS1', 'Gene', '6098', (159, 163))	('SDC4', 'Gene', '6385', (154, 158))
32530	33204104	But nothing was known about the efficacy of non-reciprocal/reciprocal ROS1 translocation patients treated with crizotinib.	('translocation', 'Var', (75, 88))	('patients', 'Species', '9606', (89, 97))	('ROS1', 'Gene', (70, 74))	('ROS1', 'Gene', '6098', (70, 74))	('crizotinib', 'Chemical', 'MESH:D000077547', (111, 121))
32531	33204104	Presence of non-reciprocal/reciprocal ALK translocation was predictive for worse survival and greater likelihood of baseline brain metastases in first-line crizotinib treated NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('metastases', 'Disease', (131, 141))	('crizotinib', 'Chemical', 'MESH:D000077547', (156, 166))	('ALK', 'Gene', '238', (38, 41))	('non-reciprocal/reciprocal', 'Var', (12, 37))	('greater', 'PosReg', (94, 101))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('patients', 'Species', '9606', (181, 189))	('ALK', 'Gene', (38, 41))	('NSCLC', 'Disease', (175, 180))	('worse', 'NegReg', (75, 80))
32540	33204104	Xu et al have reported a ROS1-ADGRG6 rearrangement alone that is generated by the fusion of the exons 1-33 of ROS1 on chr6: q22.1 to exons 2-26 of ADGRG6 on chr6: q24.2 and is clearly sensitive to crizotinib.	('exons 1-33', 'Var', (96, 106))	('ADGRG6', 'Gene', (147, 153))	('ROS1', 'Gene', (25, 29))	('crizotinib', 'Chemical', 'MESH:D000077547', (197, 207))	('ADGRG6', 'Gene', '57211', (30, 36))	('ROS1', 'Gene', '6098', (25, 29))	('ROS1', 'Gene', (110, 114))	('ROS1', 'Gene', '6098', (110, 114))	('ADGRG6', 'Gene', '57211', (147, 153))	('ADGRG6', 'Gene', (30, 36))
32545	33204104	Thus, multi-point sampling and multiple detections may be important steps for determining the ROS1 fusions, and for molecular subtyping, which can dictate the clinical treatment strategies for patients.	('patients', 'Species', '9606', (193, 201))	('fusions', 'Var', (99, 106))	('dictate', 'Reg', (147, 154))	('ROS1', 'Gene', (94, 98))	('ROS1', 'Gene', '6098', (94, 98))
32547	33204104	In summary, we identified a novel ROS1-FBXL17 fusion that coexisted with the CD74-ROS1 fusion in an advanced NSCLC patient sensitive to crizotinib.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('ROS1', 'Gene', (82, 86))	('ROS1', 'Gene', (34, 38))	('ROS1', 'Gene', '6098', (82, 86))	('FBXL17', 'Gene', '64839', (39, 45))	('ROS1', 'Gene', '6098', (34, 38))	('crizotinib', 'Chemical', 'MESH:D000077547', (136, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('FBXL17', 'Gene', (39, 45))	('patient', 'Species', '9606', (115, 122))	('fusion', 'Var', (46, 52))	('NSCLC', 'Disease', (109, 114))
32550	33204104	Although fusion partners determination is not required for patients treated with crizotinib, due to the presence of intratumor heterogeneity and non-reciprocal/reciprocal translocations, molecular subtyping of ROS1 fusions should be accurately and timely identified.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('fusions', 'Var', (215, 222))	('crizotinib', 'Chemical', 'MESH:D000077547', (81, 91))	('ROS1', 'Gene', (210, 214))	('tumor', 'Disease', (121, 126))	('ROS1', 'Gene', '6098', (210, 214))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
32582	32937891	Besides that, ROS activate signaling pathways associated with cell growth, e.g., p38MAPK, p70S6K, p90Rsk, JAK/STAT, JNK, ERK, RAS, AKT and phospholipase D. Moreover, ROS can oxidize cysteine residues in tyrosine phosphatases, for example PTEN and PTP-1B, and decrease their activities.	('AKT', 'Gene', '207', (131, 134))	('PTEN', 'Gene', '5728', (238, 242))	('tyrosine phosphatases', 'Enzyme', (203, 224))	('activities', 'MPA', (274, 284))	('RA', 'Chemical', 'MESH:C041376', (126, 128))	('decrease', 'NegReg', (259, 267))	('ERK', 'Gene', '5594', (121, 124))	('MAPK', 'molecular_function', 'GO:0004707', ('84', '88'))	('p38', 'Gene', (81, 84))	('ROS', 'Chemical', 'MESH:D017382', (166, 169))	('p70S6K', 'Gene', '6198', (90, 96))	('cysteine', 'Chemical', 'MESH:D003545', (182, 190))	('ERK', 'Gene', (121, 124))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('AKT', 'Gene', (131, 134))	('oxidize cysteine residues', 'MPA', (174, 199))	('PTP-1B', 'Gene', (247, 253))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('ROS', 'Var', (166, 169))	('JNK', 'molecular_function', 'GO:0004705', ('116', '119'))	('JNK', 'Gene', (116, 119))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('JNK', 'Gene', '5599', (116, 119))	('p38', 'Gene', '1432', (81, 84))	('PTEN', 'Gene', (238, 242))	('p70S6K', 'Gene', (90, 96))	('JAK', 'molecular_function', 'GO:0004713', ('106', '109'))
32583	32937891	Such changes promote hyper-activation of the PI3K and AKT pathways.	('changes', 'Var', (5, 12))	('AKT', 'Gene', '207', (54, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('AKT', 'Gene', (54, 57))	('hyper-activation', 'PosReg', (21, 37))
32586	32937891	In addition, iron-induced oxidative stress by ferric nitrilotriacetate (Fe-NTA) assesses in p16/p15 tumor suppressor genes deletion which results in carcinogenesis.	('ferric nitrilotriacetate', 'Chemical', 'MESH:C020326', (46, 70))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('carcinogenesis', 'Disease', (149, 163))	('p16', 'Gene', (92, 95))	('Fe-NTA', 'Chemical', 'MESH:C020326', (72, 78))	('tumor', 'Disease', (100, 105))	('p15', 'Gene', (96, 99))	('deletion', 'Var', (123, 131))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))	('p15', 'Gene', '1030', (96, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('p16', 'Gene', '1029', (92, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('iron', 'Chemical', 'MESH:D007501', (13, 17))	('results in', 'Reg', (138, 148))
32590	32937891	In fact, mutant p53 isoforms cannot apply antioxidant activities, and rather induce intracellular ROS and promote a pro-tumorigenic survival.	('induce', 'PosReg', (77, 83))	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('rat', 'Species', '10116', (70, 73))	('mutant', 'Var', (9, 15))	('p53', 'Gene', (16, 19))	('promote', 'PosReg', (106, 113))	('intracellular', 'cellular_component', 'GO:0005622', ('84', '97'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('intracellular ROS', 'MPA', (84, 101))	('p53', 'Gene', '7157', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
32624	32937891	showed that rosmarinic acid in thyme increases the activity of superoxide dismutase, catalase, and glutathione peroxidase with a reduction in malondialdehyde.	('activity', 'MPA', (51, 59))	('superoxide dismutase', 'Gene', '6647', (63, 83))	('catalase', 'Enzyme', (85, 93))	('rosmarinic', 'Var', (12, 22))	('superoxide dismutase', 'Gene', (63, 83))	('reduction', 'NegReg', (129, 138))	('malondialdehyde', 'MPA', (142, 157))	('malondialdehyde', 'Chemical', 'MESH:D008315', (142, 157))	('increases', 'PosReg', (37, 46))	('thyme', 'Species', '49992', (31, 36))	('glutathione peroxidase', 'Enzyme', (99, 121))	('glutathione', 'Chemical', 'MESH:D005978', (99, 110))	('rosmarinic acid', 'Chemical', 'MESH:C041376', (12, 27))
32722	32937891	Primrose reduced H2O2-induced DNA damage in a concentration-dependent manner in fibroblast cells compared to the positive controls (only 20 muM H2O2 treatment).	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('DNA damage', 'MPA', (30, 40))	('reduced', 'NegReg', (9, 16))	('rat', 'Species', '10116', (53, 56))	('H2O2-induced', 'Var', (17, 29))	('men', 'Species', '9606', (154, 157))	('H2O2', 'Chemical', 'MESH:D006861', (17, 21))	('H2O2', 'Chemical', 'MESH:D006861', (144, 148))
32761	32937891	It was reported that P. granatum has the ability to down-regulate various signaling pathways like NF-KB, P13K/AKT/mTOR and Wnt, as well as reduece the expression of genes that are associated with cancer development, such as anti-apoptotic genes, MMPs, VEGF, c-met, pro-inflammatory cytokines, cyclines, and Cdks.	('men', 'Species', '9606', (210, 213))	('signaling pathways', 'Pathway', (74, 92))	('P13K', 'SUBSTITUTION', 'None', (105, 109))	('AKT', 'Gene', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('VEGF', 'Gene', (252, 256))	('anti-apoptotic genes', 'Gene', (224, 244))	('MMPs', 'Gene', (246, 250))	('NF-KB', 'Gene', (98, 103))	('Wnt', 'Gene', (123, 126))	('mTOR', 'Gene', (114, 118))	('down-regulate', 'NegReg', (52, 65))	('P13K', 'Var', (105, 109))	('c-met', 'Gene', (258, 263))	('AKT', 'Gene', '207', (110, 113))	('reduece', 'NegReg', (139, 146))	('expression', 'MPA', (151, 161))	('mTOR', 'Gene', '2475', (114, 118))	('cancer', 'Disease', (196, 202))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))	('P. granatum', 'Species', '22663', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('genes', 'Gene', (165, 170))	('VEGF', 'Gene', '7422', (252, 256))
32807	32937891	Furthermore, antioxidant properties of four Lamiaceae species have shown that M. officinalis has the highest total phenolic content and antioxidant activity compared to the other species.	('M. officinalis', 'Species', '39338', (78, 92))	('antioxidant activity', 'MPA', (136, 156))	('total phenolic content', 'MPA', (109, 131))	('M. officinalis', 'Var', (78, 92))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('136', '156'))	('antioxidant', 'MPA', (13, 24))
32829	32937891	Moreover, the extract and its active ingradients enhanced the antiproliferative effect (synergistic effect) of cisplatin in both A2780 and A2780CP70 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('enhanced', 'PosReg', (49, 57))	('extract', 'Chemical', '-', (14, 21))	('A2780', 'CellLine', 'CVCL:0134', (139, 144))	('A2780', 'CellLine', 'CVCL:0134', (129, 134))	('antiproliferative effect', 'MPA', (62, 86))	('rat', 'Species', '10116', (73, 76))	('A2780CP70', 'Var', (139, 148))
32831	32937891	Furthermore, A2780 cells were more sensitive to carnosol, carnosic acid and rosmarinic acid than A2780CP70 cells.	('rosmarinic acid', 'MPA', (76, 91))	('A2780', 'CellLine', 'CVCL:0134', (13, 18))	('A2780', 'Var', (13, 18))	('carnosic acid', 'MPA', (58, 71))	('A2780', 'CellLine', 'CVCL:0134', (97, 102))	('more', 'PosReg', (30, 34))	('carnosic acid', 'Chemical', 'MESH:C018381', (58, 71))	('sensitive to carnosol', 'MPA', (35, 56))	('rosmarinic acid', 'Chemical', 'MESH:C041376', (76, 91))	('carnosol', 'Chemical', 'MESH:C068623', (48, 56))
32841	32937891	In addition, Nrf2 gene silencing increased rosemary cytotoxic effects.	('gene silencing', 'biological_process', 'GO:0016458', ('18', '32'))	('rosemary cytotoxic effects', 'CPA', (43, 69))	('Nrf2', 'Gene', (13, 17))	('rosemary', 'Chemical', '-', (43, 51))	('increased', 'PosReg', (33, 42))	('gene silencing', 'Var', (18, 32))	('Nrf2', 'Gene', '4780', (13, 17))
32863	32937891	In contrast to a previous study which showed that ginger interferes with iron absorption, a recent study concluded that ginger improves iron absorption, and therefore, it is beneficial as a supplement in the therapy of anemia.	('ginger', 'Species', '94328', (120, 126))	('men', 'Species', '9606', (196, 199))	('anemia', 'Phenotype', 'HP:0001903', (219, 225))	('iron', 'Chemical', 'MESH:D007501', (73, 77))	('improves', 'PosReg', (127, 135))	('anemia', 'Disease', (219, 225))	('anemia', 'Disease', 'MESH:D000740', (219, 225))	('ginger', 'Species', '94328', (50, 56))	('iron absorption', 'MPA', (136, 151))	('ginger', 'Var', (120, 126))	('iron', 'Chemical', 'MESH:D007501', (136, 140))
32867	32937891	It was shown that H. sabdariffa has no significant effect on blood TC, HDL, and TG, however, H. sabdariffa was able to lower both FPG and LDL.	('LDL', 'MPA', (138, 141))	('lower', 'NegReg', (119, 124))	('H. sabdariffa', 'Species', '183260', (93, 106))	('H. sabdariffa', 'Species', '183260', (18, 31))	('HDL', 'molecular_function', 'GO:0005321', ('71', '74'))	('TG', 'Chemical', 'MESH:D014280', (80, 82))	('H. sabdariffa', 'Var', (93, 106))	('blood TC', 'MPA', (61, 69))	('FPG', 'MPA', (130, 133))	('LDL', 'molecular_function', 'GO:0005322', ('138', '141'))	('HDL', 'MPA', (71, 74))	('TC', 'Chemical', '-', (67, 69))
32869	32937891	For example, P. granatum seed oil exhibited a hormetic effect when applied to mouse mammary organ culture.	('oil', 'Chemical', 'MESH:D009821', (30, 33))	('P. granatum', 'Var', (13, 24))	('mouse', 'Species', '10090', (78, 83))	('P. granatum', 'Species', '22663', (13, 24))	('hormetic effect', 'MPA', (46, 61))
32887	32917154	Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients Recent studies have shown that chemotherapy destabilizes the blood vasculature and increases circulating tumor cell (CTC) influx into the circulation of metastatic cancer patients (Met-pa).	('cancer', 'Disease', (112, 118))	('blood vasculature', 'MPA', (233, 250))	('Met-pa', 'Chemical', '-', (353, 359))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('cancer', 'Disease', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('chemotherapy', 'Var', (203, 215))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (343, 351))	('increases', 'PosReg', (255, 264))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('destabilizes', 'NegReg', (216, 228))	('tumor', 'Disease', (277, 282))	('cancer', 'Disease', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
32950	32917154	Then, cells were incubated with 100 muL of 10 mug/mL Streptavidin-Alexa Fluor 594 (Biolegend), 10 mug/mL of anti-cytokeratin conjugated with FITC (CK, Clone CAM5.2, BD) and 10 mug/mL of anti-vimentin conjugated with Alexa Fluor 647 (Clone W16220A, Biolegend) in 0.02% Tween-20 (Research Products) for 45 min.	('FITC', 'Chemical', 'MESH:D016650', (141, 145))	('mug', 'molecular_function', 'GO:0043739', ('98', '101'))	('Tween-20', 'Chemical', 'MESH:D011136', (268, 276))	('vimentin', 'Gene', '7431', (191, 199))	('Alexa Fluor 647', 'Chemical', 'MESH:C569686', (216, 231))	('vimentin', 'Gene', (191, 199))	('vimentin', 'cellular_component', 'GO:0045099', ('191', '199'))	('mug', 'molecular_function', 'GO:0043739', ('176', '179'))	('W16220A', 'Var', (239, 246))	('mug', 'molecular_function', 'GO:0043739', ('46', '49'))	('Alexa Fluor 594', 'Chemical', '-', (66, 81))	('vimentin', 'cellular_component', 'GO:0045098', ('191', '199'))	('W16220A', 'SUBSTITUTION', 'None', (239, 246))
32958	32917154	To generate 100 nm unilamellar liposomes, the multilamellar liposomes were subjected to 10 extrusion cycles using polycarbonate membranes of two different sizes (200 nm and 100 nm) at 55  C. Freshly made liposomes were incubated with E-selectin (17.5 mug/mL) and TRAIL (15 mug/mL) at 37  C for 15 min.	('E-selectin', 'Gene', '6401', (234, 244))	('E-selectin', 'Gene', (234, 244))	('selectin', 'molecular_function', 'GO:0030246', ('236', '244'))	('mug', 'molecular_function', 'GO:0043739', ('273', '276'))	('mug', 'molecular_function', 'GO:0043739', ('251', '254'))	('17.5', 'Var', (246, 250))	('selectin', 'molecular_function', 'GO:0008337', ('236', '244'))
32970	32917154	This is expected due to the theory that tumor cells migrate in aggregate form with stromal cells such as CAFs, consistent with the aggregates we have observed in several Met-pa (Fig.	('Met-pa', 'Chemical', '-', (170, 176))	('CAF', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CAF', 'Gene', '8850', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Met-pa', 'Var', (170, 176))
33046	32043828	The confirmed polymorphisms were -174 C/G (rs1800795)-6331 T/C (rs10499563) and -634 C/G (rs1800796).	('rs1800795)-6331 T/C (rs10499563', 'Var', (43, 74))	('-6331 T/C', 'Mutation', 'rs10499563', (53, 62))	('rs10499563', 'Mutation', 'rs10499563', (64, 74))	('rs1800796', 'Var', (90, 99))	('-174 C/G', 'Mutation', 'rs1800795', (33, 41))	('rs1800795', 'Mutation', 'rs1800795', (43, 52))	('-634 C/G', 'Mutation', 'rs1800796', (80, 88))	('rs10499563', 'Var', (64, 74))	('rs1800796', 'Mutation', 'rs1800796', (90, 99))
33047	32043828	The relationship between IL6 polymorphisms and lung cancer risk is controversial.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('IL6', 'Gene', '3569', (25, 28))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('IL6', 'Gene', (25, 28))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('polymorphisms', 'Var', (29, 42))	('IL6', 'molecular_function', 'GO:0005138', ('25', '28'))
33048	32043828	Several meta-analyses have concluded that IL6-174C/G polymorphism was not associated with lung cancer risk, while IL6-634C/G polymorphism may be associated with lung cancer susceptibility, suggesting that IL6-634c /G polymorphism is a smaller risk factor for lung cancer in the overall study population.7 Further studies have shown that IL-6-634 polymorphism is associated with lung cancer risk in female non-smokers (OR = 2.45, 95% CI: 1.54-3.90).	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('lung cancer', 'Disease', 'MESH:D008175', (378, 389))	('IL6', 'molecular_function', 'GO:0005138', ('114', '117'))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (378, 389))	('polymorphism', 'Var', (346, 358))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('IL-6', 'Gene', '3569', (337, 341))	('IL6', 'molecular_function', 'GO:0005138', ('205', '208'))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('IL6', 'molecular_function', 'GO:0005138', ('42', '45'))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('IL-6', 'Gene', (337, 341))	('lung cancer', 'Disease', (259, 270))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Disease', (378, 389))	('associated', 'Reg', (362, 372))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('IL-6', 'molecular_function', 'GO:0005138', ('337', '341'))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('lung cancer', 'Disease', (161, 172))
33084	31450665	Epigenome-Wide Association Analysis of Differentially Methylated Signals in Blood Samples of Patients with Non-Small-Cell Lung Cancer Lung cancer is a common form of cancer and the leading cause of cancer-related deaths worldwide.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Small-Cell Lung Cancer', 'Phenotype', 'HP:0030357', (111, 133))	('Lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('Non-Small-Cell Lung Cancer', 'Disease', 'MESH:D002289', (107, 133))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (198, 204))	('Lung cancer', 'Disease', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Differentially Methylated Signals', 'Var', (39, 72))	('cancer', 'Disease', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (139, 145))	('Patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Lung Cancer', 'Phenotype', 'HP:0100526', (122, 133))	('Non-Small-Cell Lung Cancer', 'Phenotype', 'HP:0030358', (107, 133))	('Non-Small-Cell Lung Cancer', 'Disease', (107, 133))
33090	31450665	This analysis showed two significant differentially methylated changes (cg12169243 [DPH6] and cg25429010 [IMP3]) associated with NSCLC in current smokers, six changes (cg09245319, cg17183999 [USP7], cg06366994 [CPE], cg24992236 [MEG9], cg22144719, and cg22448179 [epidermal growth factor receptor]) associated with epidermal growth factor receptor mutation in patients with adenocarcinoma, and four changes (cg25021476 [RSL24D1], cg04989085 [FAM113B], cg20905681 [CKAP4], and cg26379694) associated with advanced-stage NSCLC compared with stage I NSCLC.	('DPH6', 'Gene', '89978', (84, 88))	('IMP3', 'Gene', (106, 110))	('NSCLC', 'Disease', (547, 552))	('IMP3', 'Gene', '55272', (106, 110))	('cg24992236 [', 'Var', (217, 229))	('IMP', 'cellular_component', 'GO:0042720', ('106', '109'))	('associated with', 'Reg', (488, 503))	('IMP', 'molecular_function', 'GO:0004244', ('106', '109'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (374, 388))	('epidermal growth factor receptor', 'Gene', (315, 347))	('epidermal growth factor receptor', 'Gene', '1956', (315, 347))	('MEG9', 'Chemical', 'MESH:C484916', (229, 233))	('DPH6', 'Gene', (84, 88))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('264', '287'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('315', '338'))	('cg06366994 [', 'Var', (199, 211))	('CKAP4', 'Gene', '10970', (464, 469))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('RSL24D1', 'Gene', '51187', (420, 427))	('cg17183999 [', 'Var', (180, 192))	('cg26379694', 'Var', (476, 486))	('associated', 'Reg', (299, 309))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (519, 524))	('USP', 'molecular_function', 'GO:0051748', ('192', '195'))	('patients', 'Species', '9606', (360, 368))	('mutation', 'Var', (348, 356))	('cg22144719', 'Var', (236, 246))	('RSL24D1', 'Gene', (420, 427))	('cg09245319', 'Var', (168, 178))	('FAM113B', 'Gene', (442, 449))	('adenocarcinoma', 'Disease', (374, 388))	('NSCLC', 'Disease', (519, 524))	('NSCLC', 'Disease', 'MESH:D002289', (547, 552))	('FAM113B', 'Gene', '91523', (442, 449))	('epidermal growth factor receptor', 'Gene', (264, 296))	('cg22448179', 'Var', (252, 262))	('CKAP4', 'Gene', (464, 469))	('epidermal growth factor receptor', 'Gene', '1956', (264, 296))	('cg25429010', 'Var', (94, 104))	('associated', 'Reg', (113, 123))
33091	31450665	The validation of these DNA methylation changes and further research on the related genes may help develop easily accessible biomarkers for the early diagnosis or prognosis of NSCLC.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('changes', 'Var', (40, 47))	('NSCLC', 'Disease', (176, 181))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))
33098	31450665	Meanwhile, several studies have described epigenetic signatures based on DNA methylation, which are associated with the outcome in early-stage NSCLC.	('NSCLC', 'Disease', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('associated', 'Reg', (100, 110))	('DNA', 'Gene', (73, 76))	('epigenetic signatures', 'Var', (42, 63))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))
33101	31450665	Recently, studies have provided evidence that methylation changes, also associated with smoking, in peripheral blood may predict lung cancer-related mortality and improve the prediction of the risk of lung cancer.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', (201, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('predict', 'Reg', (121, 128))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('improve', 'PosReg', (163, 170))	('methylation changes', 'Var', (46, 65))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
33119	31450665	Furthermore, we used a robust linear regression model with each subtype as the response variable and methylation values as the predictor variable to evaluate the association between the methylation values and pathological/molecular subtypes (i.e., adenocarcinoma or squamous cell carcinoma, EGFR mutant or EGFR wild type).	('EGFR', 'Gene', (291, 295))	('mutant', 'Var', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('EGFR', 'Gene', '1956', (306, 310))	('EGFR', 'molecular_function', 'GO:0005006', ('291', '295'))	('methylation', 'biological_process', 'GO:0032259', ('186', '197'))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('EGFR', 'Gene', (306, 310))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('EGFR', 'molecular_function', 'GO:0005006', ('306', '310'))	('squamous cell carcinoma', 'Disease', (266, 289))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (266, 289))	('EGFR', 'Gene', '1956', (291, 295))	('adenocarcinoma', 'Disease', (248, 262))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (248, 262))
33126	31450665	Among the 108 patients with adenocarcinoma, 70 had mutant EGFR.	('EGFR', 'Gene', '1956', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('EGFR', 'Gene', (58, 62))	('mutant', 'Var', (51, 57))	('adenocarcinoma', 'Disease', (28, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (28, 42))	('patients', 'Species', '9606', (14, 22))
33136	31450665	Cg03636183 (F2RL3) and cg05934812 (AHRR), two established gene sites for smoking and NSCLC, were found to be significantly associated with smoking in the NSCLC patient group.	('NSCLC', 'Disease', (85, 90))	('associated', 'Reg', (123, 133))	('cg05934812', 'Var', (23, 33))	('F2RL3', 'Gene', (12, 17))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('AHRR', 'Gene', (35, 39))	('F2RL3', 'Gene', '9002', (12, 17))	('Cg03636183', 'Var', (0, 10))	('patient', 'Species', '9606', (160, 167))	('AHRR', 'Gene', '57491', (35, 39))	('smoking', 'Disease', (139, 146))	('NSCLC', 'Disease', (154, 159))
33138	31450665	Additionally, we evaluated DMPs significantly associated with disease stage and mutant EGFR status.	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('mutant', 'Var', (80, 86))	('EGFR', 'Gene', (87, 91))	('DMP', 'Chemical', 'MESH:C027804', (27, 30))	('associated', 'Reg', (46, 56))	('DMPs', 'MPA', (27, 31))
33140	31450665	According to the association analysis for EGFR mutation in patients with adenocarcinoma (n = 108, EGFR mutant = 64), we found 159 suggestive DMPs and six significant DMPs (cg09245319, cg17183999 [USP7], cg06366994 [CPE], cg24992236 [MEG9], cg22144719, and cg22448179 [EGFR]) (Table 3).	('DMP', 'Chemical', 'MESH:C027804', (141, 144))	('DMP', 'Chemical', 'MESH:C027804', (166, 169))	('EGFR', 'Gene', (98, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (73, 87))	('EGFR', 'Gene', '1956', (268, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('EGFR', 'Gene', (42, 46))	('cg09245319', 'Var', (172, 182))	('cg22144719', 'Var', (240, 250))	('patients', 'Species', '9606', (59, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('268', '272'))	('cg24992236 [MEG9', 'Var', (221, 237))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('cg17183999 [USP7', 'Var', (184, 200))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (42, 46))	('USP', 'molecular_function', 'GO:0051748', ('196', '199'))	('EGFR', 'Gene', (268, 272))	('adenocarcinoma', 'Disease', (73, 87))	('MEG9', 'Chemical', 'MESH:C484916', (233, 237))	('cg06366994 [', 'Var', (203, 215))
33141	31450665	From the association analysis of patients with advanced-stage NSCLC (stages IIIb and IV, n = 67) versus those with stage I disease (n = 46), we identified 58 suggestive DMPs and four significant DMPs (cg25021476 [RSL24D1], cg04989085 [FAM113B], cg20905681 [CKAP4], and cg26379694) (Table 4).	('NSCLC', 'Disease', (62, 67))	('FAM113B', 'Gene', (235, 242))	('CKAP4', 'Gene', '10970', (257, 262))	('cg26379694', 'Var', (269, 279))	('patients', 'Species', '9606', (33, 41))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('RSL24D1', 'Gene', (213, 220))	('FAM113B', 'Gene', '91523', (235, 242))	('DMP', 'Chemical', 'MESH:C027804', (195, 198))	('RSL24D1', 'Gene', '51187', (213, 220))	('CKAP4', 'Gene', (257, 262))	('DMP', 'Chemical', 'MESH:C027804', (169, 172))
33142	31450665	From the survival analysis, cg25429010 tended to be associated with longer progression-free survival in the low-methylation group versus the high-methylation group in patients with stage I and II NSCLC (n = 60) (hazard ratio: 1.836;  = 0.163).	('low-methylation', 'Var', (108, 123))	('NSCLC', 'Disease', (196, 201))	('longer', 'PosReg', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('patients', 'Species', '9606', (167, 175))	('cg25429010', 'Var', (28, 38))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('rat', 'Species', '10116', (219, 222))	('progression-free survival', 'CPA', (75, 100))
33143	31450665	cg04989085 (FAM113B) was significantly associated with longer progression-free survival in the high-methylation group versus the low-methylation group in patients with stage IIIb and IV NSCLC (n = 67; hazard ratio: 0.559;  = 0.024) (Figure 2).	('high-methylation', 'Var', (95, 111))	('methylation', 'biological_process', 'GO:0032259', ('133', '144'))	('progression-free survival', 'CPA', (62, 87))	('rat', 'Species', '10116', (208, 211))	('FAM113B', 'Gene', '91523', (12, 19))	('NSCLC', 'Disease', (186, 191))	('patients', 'Species', '9606', (154, 162))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('longer', 'PosReg', (55, 61))	('FAM113B', 'Gene', (12, 19))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
33145	31450665	In addition, DMPs significantly associated with NSCLC in current smokers, the EGFR mutation status in patients with adenocarcinoma, and the survival rate in patients with advanced-stage NSCLC were identified.	('rat', 'Species', '10116', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('NSCLC', 'Disease', (48, 53))	('adenocarcinoma', 'Disease', (116, 130))	('DMP', 'Chemical', 'MESH:C027804', (13, 16))	('adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', (186, 191))	('patients', 'Species', '9606', (157, 165))	('mutation', 'Var', (83, 91))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('EGFR', 'Gene', '1956', (78, 82))	('associated', 'Reg', (32, 42))	('EGFR', 'Gene', (78, 82))
33152	31450665	Aberrant methylation changes in NSCLC have been reported in several genomic regions from various samples, such as the sputum, bronchial aspirates, and tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Aberrant', 'Var', (0, 8))	('rat', 'Species', '10116', (140, 143))	('reported', 'Reg', (48, 56))	('tumor', 'Disease', (151, 156))	('NSCLC', 'Disease', (32, 37))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'MPA', (9, 20))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
33157	31450665	Recently, in several case-control studies nested within prospective cohorts (NOWAC, MCCS, NSHDS, EPIC-Heidelberg, and EPIC-Italy cohort), it has been repeatedly reported that DNA methylation changes measured in peripheral blood samples were associated with the risk and mortality of lung cancer.	('changes', 'Var', (191, 198))	('DNA', 'Gene', (175, 178))	('DNA methylation', 'biological_process', 'GO:0006306', ('175', '190'))	('lung cancer', 'Disease', 'MESH:D008175', (283, 294))	('associated with', 'Reg', (241, 256))	('methylation changes', 'Var', (179, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (283, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('lung cancer', 'Disease', (283, 294))
33159	31450665	Among the discovered loci, CpGs in the F2RL3 and AHRR were repeatedly associated with smoking and the risk of developing lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('F2RL3', 'Gene', (39, 44))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('AHRR', 'Gene', (49, 53))	('associated with', 'Reg', (70, 85))	('lung cancer', 'Disease', (121, 132))	('smoking', 'Disease', (86, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('F2RL3', 'Gene', '9002', (39, 44))	('AHRR', 'Gene', '57491', (49, 53))	('CpGs', 'Var', (27, 31))	('CpGs', 'Chemical', 'MESH:C024660', (27, 31))
33160	31450665	It could be hypothesized that the hypomethylation of these CpG sites may mediate the effect of tobacco on the risk of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tobacco', 'Species', '4097', (95, 102))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('hypomethylation', 'Var', (34, 49))
33161	31450665	Our study also showed that cg03636183 (F2RL3) and cg05934812 (AHRR) were significantly associated with smoking in the NSCLC patient group, but not in the control group.	('cg05934812', 'Var', (50, 60))	('F2RL3', 'Gene', (39, 44))	('cg03636183', 'Var', (27, 37))	('AHRR', 'Gene', (62, 66))	('associated', 'Reg', (87, 97))	('smoking', 'Disease', (103, 110))	('NSCLC', 'Disease', (118, 123))	('patient', 'Species', '9606', (124, 131))	('F2RL3', 'Gene', '9002', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('AHRR', 'Gene', '57491', (62, 66))
33163	31450665	In a multicenter study performed in Eastern and Central Europe, no association between global DNA methylation in peripheral blood and the risk of lung cancer in nonsmoking women was reported.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('methylation', 'Var', (98, 109))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('women', 'Species', '9606', (172, 177))	('DNA methylation', 'biological_process', 'GO:0006306', ('94', '109'))
33164	31450665	Further characterization of the mechanism through which methylation is linked to the risk of lung cancer in prospective studies including larger cohorts is warranted for the clinical application of blood DNA methylation markers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('DNA methylation', 'biological_process', 'GO:0006306', ('204', '219'))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('linked', 'Reg', (71, 77))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('methylation', 'Var', (56, 67))
33165	31450665	In our study, we identified two significant DMPs, namely, cg12169243 (DPH6) and cg25429010 (IMP3), associated with NSCLC in current smokers.	('IMP3', 'Gene', (92, 96))	('IMP3', 'Gene', '55272', (92, 96))	('cg12169243', 'Var', (58, 68))	('DMP', 'Chemical', 'MESH:C027804', (44, 47))	('DPH6', 'Gene', (70, 74))	('NSCLC', 'Disease', (115, 120))	('IMP', 'cellular_component', 'GO:0042720', ('92', '95'))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('IMP', 'molecular_function', 'GO:0004244', ('92', '95'))	('DPH6', 'Gene', '89978', (70, 74))	('cg25429010', 'Var', (80, 90))	('associated', 'Reg', (99, 109))
33169	31450665	We also identified six DMPs significantly associated with EGFR mutation in patients with adenocarcinoma.	('EGFR', 'Gene', '1956', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('DMP', 'Chemical', 'MESH:C027804', (23, 26))	('adenocarcinoma', 'Disease', (89, 103))	('associated', 'Reg', (42, 52))	('EGFR', 'Gene', (58, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (89, 103))	('patients', 'Species', '9606', (75, 83))	('mutation', 'Var', (63, 71))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))
33170	31450665	Although the five associated loci have not been associated with EGFR mutation, cg22448179 was identified on the EGFR gene.	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', (64, 68))	('cg22448179', 'Var', (79, 89))
33171	31450665	This result suggests that there is a change in the EGFR of white blood cells, following changes in the EGFR mutation in NSCLC.	('EGFR', 'Gene', '1956', (103, 107))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('changes', 'Reg', (88, 95))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (103, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('mutation', 'Var', (108, 116))	('change', 'Reg', (37, 43))	('NSCLC', 'Disease', (120, 125))	('EGFR', 'Gene', '1956', (51, 55))
33176	31450665	Despite being not a well-studied gene region, cg04989085 (FAM113B) was associated with advanced-stage disease compared with stage I NSCLC, as well as longer survival in patients with advanced-stage NSCLC.	('longer', 'PosReg', (150, 156))	('patients', 'Species', '9606', (169, 177))	('FAM113B', 'Gene', (58, 65))	('advanced-stage disease', 'Disease', (87, 109))	('NSCLC', 'Disease', (132, 137))	('FAM113B', 'Gene', '91523', (58, 65))	('cg04989085', 'Var', (46, 56))	('NSCLC', 'Disease', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))
33178	31450665	To indirectly determine whether observed methylation changes affect the expression of proximal genes, for the five probes (cg12169243 in DPH6; cg25429010 in IMP3; cg25021476 in RSL24D1; cg04989085 in FAM113B; and cg20905681 in CKAP4), we analyzed the correlation between methylation and expression (RNA sequencing) using The Cancer Genome Atlas (TCGA, ) data.	('RSL24D1', 'Gene', '51187', (177, 184))	('cg04989085', 'Var', (186, 196))	('affect', 'Reg', (61, 67))	('FAM113B', 'Gene', (200, 207))	('RSL24D1', 'Gene', (177, 184))	('DPH6', 'Gene', '89978', (137, 141))	('FAM113B', 'Gene', '91523', (200, 207))	('expression', 'MPA', (72, 82))	('IMP3', 'Gene', (157, 161))	('CKAP4', 'Gene', '10970', (227, 232))	('Cancer', 'Phenotype', 'HP:0002664', (325, 331))	('RNA', 'cellular_component', 'GO:0005562', ('299', '302'))	('IMP3', 'Gene', '55272', (157, 161))	('IMP', 'cellular_component', 'GO:0042720', ('157', '160'))	('DPH6', 'Gene', (137, 141))	('cg12169243', 'Var', (123, 133))	('IMP', 'molecular_function', 'GO:0004244', ('157', '160'))	('cg20905681', 'Var', (213, 223))	('cg25021476', 'Var', (163, 173))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('methylation', 'Var', (41, 52))	('cg25429010', 'Var', (143, 153))	('CKAP4', 'Gene', (227, 232))	('methylation', 'biological_process', 'GO:0032259', ('271', '282'))
33182	31450665	Firstly, this was a cross-sectional study that could not guarantee the causal relationship between methylation changes and NSCLC or related outcomes.	('methylation changes', 'Var', (99, 118))	('changes', 'Var', (111, 118))	('NSCLC', 'Disease', (123, 128))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))
33185	31450665	This genome-wide DNA methylation analysis identified two significant differentially methylated changes associated with NSCLC, six changes associated with EGFR mutation, and four changes associated with advanced stage in peripheral blood samples obtained from patients with NSCLC.	('EGFR', 'Gene', (154, 158))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('patients', 'Species', '9606', (259, 267))	('mutation', 'Var', (159, 167))	('DNA methylation', 'biological_process', 'GO:0006306', ('17', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('NSCLC', 'Disease', (273, 278))	('differentially methylated', 'MPA', (69, 94))	('NSCLC', 'Disease', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('EGFR', 'Gene', '1956', (154, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('154', '158'))
33186	31450665	The validation of these DNA methylation changes and further research on the related genes may help to develop easily accessible biomarkers for the early diagnosis or prognosis of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('changes', 'Var', (40, 47))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('NSCLC', 'Disease', (179, 184))
33187	31450665	Differentially methylated probes (DMPs), suggestive of an association with NSCLC, Table S3.	('association', 'Interaction', (58, 69))	('DMP', 'Chemical', 'MESH:C027804', (34, 37))	('Differentially methylated', 'Var', (0, 25))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
33193	31450665	Epigenome-wide association plot associated with non-small-cell lung cancer, Figure S2.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Epigenome-wide', 'Var', (0, 14))	('non-small-cell lung cancer', 'Disease', (48, 74))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (48, 74))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (48, 74))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('associated', 'Reg', (32, 42))
33194	31450665	Epigenome-wide association plot associated with non-small-cell lung cancer in non-smokers group, Figure S3.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('non-small-cell lung cancer', 'Disease', (48, 74))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (48, 74))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (48, 74))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('associated', 'Reg', (32, 42))	('Epigenome-wide association', 'Var', (0, 26))
33196	31450665	Correlation of IMP3 methylation with expression in The Cancer Genome Atlas (TCGA) data, Figure S6.	('IMP3', 'Gene', '55272', (15, 19))	('IMP', 'cellular_component', 'GO:0042720', ('15', '18'))	('methylation', 'Var', (20, 31))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('expression', 'MPA', (37, 47))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('IMP', 'molecular_function', 'GO:0004244', ('15', '18'))	('IMP3', 'Gene', (15, 19))
33197	31450665	Correlation of FAM113B IMP3 methylation with expression in The Cancer Genome Atlas (TCGA) data.	('IMP3', 'Gene', '55272', (23, 27))	('FAM113B', 'Gene', (15, 22))	('IMP', 'cellular_component', 'GO:0042720', ('23', '26'))	('IMP', 'molecular_function', 'GO:0004244', ('23', '26'))	('FAM113B', 'Gene', '91523', (15, 22))	('expression', 'MPA', (45, 55))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('IMP3', 'Gene', (23, 27))
33202	31341411	In this review, we provide an overview of recognized mechanisms underlying molecular heterogeneity in lung cancer, including epigenetic mechanisms, mutant allele specific imbalance, genomic instability, chromosomal aberrations, tumor mutational burden, somatic mutations.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (203, 226))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mutant', 'Var', (148, 154))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('tumor', 'Disease', (228, 233))	('imbalance', 'Phenotype', 'HP:0002172', (171, 180))
33208	31341411	Distinct cellular populations within a tumour could differ in a wide spectrum of features from the expression of cell markers to the genetic or epigenetic alterations which could cause heterogeneity.	('tumour', 'Disease', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('epigenetic alterations', 'Var', (144, 166))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('differ', 'Reg', (52, 58))
33212	31341411	Furthermore, a high degree of genetic diversity between the primary lung tumor and corresponding metastatic lesions could play a pivotal role in the therapeutic context of lung cancer patients.	('lung tumor', 'Phenotype', 'HP:0100526', (68, 78))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('lung tumor', 'Disease', 'MESH:D008175', (68, 78))	('role', 'Reg', (137, 141))	('play', 'Reg', (122, 126))	('lung tumor', 'Disease', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('genetic diversity', 'Var', (30, 47))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
33215	31341411	Lung tumours are characterized by extensive genomic aberrations including aneusomy, gains and losses of large chromosome regions, gene rearrangements, copy number gain, amplifications.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('losses', 'NegReg', (94, 100))	('gains', 'PosReg', (84, 89))	('Lung tumours', 'Disease', 'MESH:D008175', (0, 12))	('Lung tumours', 'Disease', (0, 12))	('amplifications', 'Disease', (169, 183))	('copy number', 'Var', (151, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('aneusomy', 'Disease', (74, 82))
33216	31341411	Genomic instability represents one of the hallmarks in human cancer resulting in various genetic aberrations at different level from mutations in single or few nucleotides to changes of part or entire chromosomes.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('human', 'Species', '9606', (55, 60))	('mutations in single or few nucleotides', 'Var', (133, 171))	('changes', 'Reg', (175, 182))	('resulting', 'Reg', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
33217	31341411	The term chromosomal instability (CIN) defines a type of genomic instability associated to numerical and structural variations of part or whole chromosomes, for example gain or loss of chromosome fragments, translocations, deletions and amplifications of DNA.	('DNA', 'Gene', (255, 258))	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('CIN', 'Disease', (34, 37))	('amplifications', 'Var', (237, 251))	('chromosome fragments', 'CPA', (185, 205))	('translocations', 'Var', (207, 221))	('gain', 'PosReg', (169, 173))	('loss', 'NegReg', (177, 181))	('deletions', 'Var', (223, 232))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('CIN', 'Disease', 'MESH:D007674', (34, 37))	('CIN', 'Phenotype', 'HP:0040012', (34, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (9, 32))	('chromosomal instability', 'Disease', (9, 32))
33221	31341411	Moreover, genomic diversity facilitates the adaptation of cancer cell populations in the context of tumor microenvironment resulting in tumor progression and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', (100, 105))	('genomic diversity', 'Var', (10, 27))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('facilitates', 'PosReg', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (136, 141))	('adaptation', 'CPA', (44, 54))
33223	31341411	Their results showed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations, particularly an elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P = 4.4x10-4), statistically significant in multivariate analysis.	('recurrence', 'CPA', (205, 215))	('associated', 'Reg', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('death', 'Disease', 'MESH:D003643', (219, 224))	('tumor', 'Disease', (37, 42))	('death', 'Disease', (219, 224))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('copy-number heterogeneity', 'Var', (138, 163))
33229	31341411	Previous studies proposed a mathematical modeling related to a clonal mutation burden in several cancer types, suggesting that lung cancer reflects predominantly mutations accumulated early during tumorigenesis compared to others cancers with late mutation rate.	('lung cancer', 'Disease', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Disease', (230, 236))	('cancers', 'Disease', (230, 237))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', (132, 138))	('mutations', 'Var', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Disease', (197, 202))
33230	31341411	Mutant allele specific imbalance (MASI) represents another genetic mechanism that could promote heterogeneity and impact tumorigenesis, progression, metastasis, prognosis and potentially therapeutic responses in cancer.	('impact', 'Reg', (114, 120))	('metastasis', 'CPA', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('progression', 'CPA', (136, 147))	('Mutant allele', 'Var', (0, 13))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', (121, 126))	('imbalance', 'Phenotype', 'HP:0002172', (23, 32))	('prognosis', 'CPA', (161, 170))	('heterogeneity', 'MPA', (96, 109))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
33231	31341411	MASI could occur with copy neutral alteration defined as acquired uniparental disomy (UPD), or with loss of heterozygosity (LOH) due to the loss of the wild-type allele.	('UPD', 'Disease', (86, 89))	('occur', 'Reg', (11, 16))	('uniparental disomy', 'Disease', (66, 84))	('UPD', 'Disease', 'MESH:D024182', (86, 89))	('copy neutral alteration', 'Var', (22, 45))	('uniparental disomy', 'Disease', 'MESH:D024182', (66, 84))	('MASI', 'Disease', (0, 4))	('loss', 'NegReg', (100, 104))
33233	31341411	In lung cancer, EGFR MASI is a frequent event counted approximately in 26-37% of cases, more commonly associated with exon 19 deletion than with exon 21 mutation.	('associated', 'Reg', (102, 112))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('exon 19 deletion', 'Var', (118, 134))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('EGFR', 'Gene', (16, 20))
33235	31341411	Although intratumoral molecular heterogeneity in human cancer has historically attributed to genetic alterations, to date a high degree of heterogeneity has been related to epigenetic mechanisms, including DNA methylation, chromatin remodeling, and post-translational modification of histones.	('DNA methylation', 'Var', (206, 221))	('tumor', 'Disease', (14, 19))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('223', '243'))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('histones', 'Protein', (284, 292))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('DNA methylation', 'biological_process', 'GO:0006306', ('206', '221'))	('chromatin', 'cellular_component', 'GO:0000785', ('223', '232'))	('post-translational modification', 'Var', (249, 280))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('post-translational modification', 'biological_process', 'GO:0043687', ('249', '280'))	('cancer', 'Disease', (55, 61))
33236	31341411	Recently, several studies analyzed a potential predictive role of epigenetic modifications in lung cancer, particularly microRNA (miRNAs) and DNA methylation.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('DNA methylation', 'biological_process', 'GO:0006306', ('142', '157'))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('microRNA', 'MPA', (120, 128))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('epigenetic modifications', 'Var', (66, 90))	('DNA', 'MPA', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
33238	31341411	Recent findings showed a promising predictive role of miRNA signatures for chemotherapy response and clinical outcome in NSCLC patients, particularly miR-1290, miR-196b, and miR-135a in tumor tissue and miR-25, miR-27b, miR-21, and miR-326 in blood.	('miR-25', 'Gene', '407014', (203, 209))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('miR-1290', 'Gene', (150, 158))	('miR-27b', 'Gene', (211, 218))	('miR-21', 'Gene', (220, 226))	('miR-196b', 'Gene', '442920', (160, 168))	('miR-27b', 'Gene', '407019', (211, 218))	('miR-135a', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('miR-25', 'Gene', (203, 209))	('NSCLC', 'Disease', (121, 126))	('miR-326', 'Gene', (232, 239))	('miR-196b', 'Gene', (160, 168))	('patients', 'Species', '9606', (127, 135))	('miR-326', 'Gene', '442900', (232, 239))	('miR-1290', 'Gene', '100302276', (150, 158))	('miR-21', 'Gene', '406991', (220, 226))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
33258	31341411	NSCLC is one of the tumors with a higher mutation rate of protein-altering mutations, particularly adenocarcinomas showed a rate of 3.5 per Mb and squamous cell carcinomas a rate of 3.9, compared to the rate of 1.8 across all tumor types.	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('adenocarcinomas', 'Disease', 'MESH:D000230', (99, 114))	('adenocarcinomas', 'Disease', (99, 114))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('tumor', 'Disease', (226, 231))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (147, 171))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('protein-altering', 'Protein', (58, 74))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (20, 26))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (147, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('squamous cell carcinomas', 'Disease', (147, 171))	('mutations', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('NSCLC', 'Disease', (0, 5))	('tumor', 'Disease', (20, 25))
33261	31341411	EGFR activating mutation, ALK rearrangements (ALK-R) and ROS1 rearrangements (ROS1-R) represent genetic hallmarks that predict a good response to treatment with specific tyrosine kinase inhibitor (TKI) in lung cancer with adenocarcinoma histology.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('179', '195'))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung cancer', 'Disease', (205, 216))	('ROS1', 'Gene', (78, 82))	('adenocarcinoma', 'Disease', 'MESH:D000230', (222, 236))	('ALK', 'Gene', '238', (26, 29))	('ALK', 'Gene', (26, 29))	('ROS1', 'Gene', '6098', (57, 61))	('EGFR', 'Gene', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('mutation', 'Var', (16, 24))	('activating', 'PosReg', (5, 15))	('ROS1', 'Gene', '6098', (78, 82))	('ALK', 'Gene', '238', (46, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('ALK', 'Gene', (46, 49))	('EGFR', 'Gene', '1956', (0, 4))	('ROS1', 'Gene', (57, 61))	('adenocarcinoma', 'Disease', (222, 236))
33262	31341411	Beyond these targetable alterations, other genomic aberrations have been reported in adenocarcinoma, including mutations, copy number gene alterations, as well as fusion mechanisms involving the receptor tyrosine kinase, such as ROS1, NTRK1 and RET (Table 1).	('mutations', 'Var', (111, 120))	('RET', 'Gene', (245, 248))	('adenocarcinoma', 'Disease', (85, 99))	('NTRK1', 'Gene', '4914', (235, 240))	('ROS1', 'Gene', '6098', (229, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('copy number gene alterations', 'Var', (122, 150))	('RET', 'Gene', '5979', (245, 248))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('NTRK1', 'Gene', (235, 240))	('ROS1', 'Gene', (229, 233))
33266	31341411	Several recurrent mutations have been found in SqCC, including DDR2 mutations, FGFR1 amplification, FGFR2,3,4 mutations and rearrangements (Table 1).	('SqCC', 'Phenotype', 'HP:0002860', (47, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('SqCC', 'Gene', (47, 51))	('FGFR2', 'Gene', (100, 105))	('mutations', 'Var', (110, 119))	('FGFR2', 'Gene', '2263', (100, 105))	('rearrangements', 'Var', (124, 138))	('FGFR1', 'Gene', (79, 84))	('DDR2', 'Gene', '4921', (63, 67))	('amplification', 'Var', (85, 98))	('FGFR1', 'Gene', '2260', (79, 84))	('mutations', 'Var', (68, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('DDR2', 'Gene', (63, 67))
33269	31341411	Sequencing results show that the genes most differentially mutated between ADC and SqCC were KRAS (19% versus 2%), TP53 (44% versus 69%), and STK11 (21% versus 2%); furthermore aberrations in receptor tyrosine kinase/RAS signaling were detected in approximately 70% of ADCs analyzed.	('STK11', 'molecular_function', 'GO:0033868', ('142', '147'))	('KRAS', 'Gene', (93, 97))	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('TP53', 'Gene', '7157', (115, 119))	('aberrations', 'Var', (177, 188))	('SqCC', 'Phenotype', 'HP:0002860', (83, 87))	('KRAS', 'Gene', '3845', (93, 97))	('receptor tyrosine kinase/RAS signaling', 'MPA', (192, 230))	('STK11', 'Gene', (142, 147))	('TP53', 'Gene', (115, 119))	('detected', 'Reg', (236, 244))	('STK11', 'Gene', '6794', (142, 147))	('ADC', 'Disease', (75, 78))
33272	31341411	Previous studies analysing genomic aberrations in SCLC shown that the most frequent are inactivating mutations in TP53 and Rb1 genes, whereas activating mutations of EGFR, KRAS, as well mutations of PIK3CA, c-Myc amplification, c-KIT overexpression and PTEN mutation/loss are rare.	('KRAS', 'Gene', '3845', (172, 176))	('EGFR', 'Gene', '1956', (166, 170))	('TP53', 'Gene', '7157', (114, 118))	('frequent', 'Reg', (75, 83))	('PIK3CA', 'Gene', '5290', (199, 205))	('PTEN', 'Gene', '5728', (253, 257))	('c-KIT', 'Gene', (228, 233))	('KIT', 'molecular_function', 'GO:0005020', ('230', '233'))	('Rb1', 'Gene', '5925', (123, 126))	('c-KIT', 'Gene', '3815', (228, 233))	('KRAS', 'Gene', (172, 176))	('c-Myc', 'Gene', (207, 212))	('mutations', 'Var', (101, 110))	('PIK3CA', 'Gene', (199, 205))	('SCLC', 'Gene', '7864', (50, 54))	('c-Myc', 'Gene', '4609', (207, 212))	('EGFR', 'Gene', (166, 170))	('SCLC', 'Gene', (50, 54))	('Rb1', 'Gene', (123, 126))	('TP53', 'Gene', (114, 118))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('PTEN', 'Gene', (253, 257))
33273	31341411	Recently, Simbolo and colleagues performed a comprehensive molecular analysis of LNETs, showing a prognostic impact of aberrations involved in RB1 and TERT in all histological subtypes, MEN1 mutations in SCLCs and KMT2D in ACs.	('RB1', 'Gene', '5925', (143, 146))	('ACs', 'molecular_function', 'GO:0043884', ('223', '226'))	('KMT2D', 'Gene', '8085', (214, 219))	('TERT', 'Gene', (151, 155))	('mutations', 'Var', (191, 200))	('KMT2D', 'Gene', (214, 219))	('MEN1', 'Gene', '4221', (186, 190))	('SCLC', 'Gene', '7864', (204, 208))	('MEN1', 'Gene', (186, 190))	('SCLC', 'Gene', (204, 208))	('TERT', 'Gene', '7015', (151, 155))	('ACs', 'molecular_function', 'GO:0003987', ('223', '226'))	('RB1', 'Gene', (143, 146))
33274	31341411	In the context of the predictive value of target therapies, preliminary data showed that the alterations involved in PI3K/AKT/mTOR pathway activation could be a potential therapeutic target, particularly PIK3CA mutations and copy gains of PIK3CA and RICTOR.	('PIK3CA', 'Gene', (239, 245))	('PIK3CA', 'Gene', '5290', (204, 210))	('RICTOR', 'Gene', (250, 256))	('mutations', 'Var', (211, 220))	('PIK3CA', 'Gene', '5290', (239, 245))	('RICTOR', 'Gene', '253260', (250, 256))	('AKT', 'Gene', '207', (122, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('PIK3CA', 'Gene', (204, 210))	('mTOR', 'Gene', (126, 130))	('copy gains', 'Var', (225, 235))	('mTOR', 'Gene', '2475', (126, 130))	('AKT', 'Gene', (122, 125))
33276	31341411	In the last decade, the therapeutic decision-making approach based on the presence of oncogenic "driver" aberrations has incredibly changed the treatment of NSCLC patients with the development of target therapies, particularly specific inhibitor of EGFR, ALK and ROS1 aberrations.	('ROS1', 'Gene', '6098', (263, 267))	('patients', 'Species', '9606', (163, 171))	('EGFR', 'molecular_function', 'GO:0005006', ('247', '251'))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('presence', 'Var', (74, 82))	('changed', 'Reg', (132, 139))	('ALK', 'Gene', (255, 258))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (249, 253))	('NSCLC', 'Disease', (157, 162))	('ALK', 'Gene', '238', (255, 258))	('ROS1', 'Gene', (263, 267))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
33277	31341411	In NSCLC, oncogenic driver mutations are frequently associated with specific clinical and pathological features, including histologic subtypes, gender, ethnic, age, past smoking history/status of other common oncogenes.	('mutations', 'Var', (27, 36))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('associated', 'Reg', (52, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
33278	31341411	Dietz and colleagues investigated the spatial distribution of allele frequencies of KRAS and EGFR mutations in lung adenocarcinomas throughout whole tumor sections in correlation to all different histopathological patterns.	('lung adenocarcinomas', 'Disease', (111, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (111, 131))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EGFR', 'Gene', (93, 97))	('KRAS', 'Gene', (84, 88))	('mutations', 'Var', (98, 107))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (111, 131))	('KRAS', 'Gene', '3845', (84, 88))	('tumor', 'Disease', (149, 154))
33279	31341411	The variant allele frequencies (VAFs) of KRAS and EGFR mutations were determined for all segments by digital PCR and their results showed that mutant allele frequencies were significantly higher in segments with a predominant solid pattern compared to all other histologies (p < 0.01).	('KRAS', 'Gene', '3845', (41, 45))	('mutant', 'Var', (143, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('higher', 'PosReg', (188, 194))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (50, 54))	('KRAS', 'Gene', (41, 45))
33280	31341411	Heterogeneous distribution of EGFR mutations was observed within a primary tumor composed of mixed atypical adenomatous hyperplasia, bronchoalveolar carcinoma, and adenocarcinoma.	('adenomatous hyperplasia', 'Disease', 'MESH:D011125', (108, 131))	('bronchoalveolar carcinoma', 'Disease', 'MESH:D002277', (133, 158))	('EGFR', 'Gene', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('adenocarcinoma', 'Disease', (164, 178))	('observed', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (164, 178))	('bronchoalveolar carcinoma', 'Phenotype', 'HP:0006519', (133, 158))	('adenomatous hyperplasia', 'Disease', (108, 131))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('bronchoalveolar carcinoma', 'Disease', (133, 158))	('EGFR', 'Gene', '1956', (30, 34))	('tumor', 'Disease', (75, 80))	('mutations', 'Var', (35, 44))
33281	31341411	Previously, we demonstrated that homogeneity in EGFR aberrations occur within lung mixed ADCs regardless histological patterns, contrary to ALK rearrangements that are generally observed in solid patterns and exclusively in the adenocarcinoma areas of adenosquamous lung carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (271, 281))	('EGFR', 'Gene', '1956', (48, 52))	('adenocarcinoma areas of adenosquamous lung carcinomas', 'Disease', 'MESH:D018196', (228, 281))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('ALK', 'Gene', (140, 143))	('aberrations', 'Var', (53, 64))	('ALK', 'Gene', '238', (140, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
33283	31341411	NSCLC patients harboring targetable driver mutations generally respond well to specific inhibitors, however some patients show short responses and TKIs resistance that could be frequently explained through molecular heterogeneity between the primary lung tumors and the metastases.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('lung tumors', 'Phenotype', 'HP:0100526', (250, 261))	('lung tumors', 'Disease', (250, 261))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('patients', 'Species', '9606', (113, 121))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('metastases', 'Disease', (270, 280))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (6, 14))	('lung tumors', 'Disease', 'MESH:D008175', (250, 261))	('lung tumor', 'Phenotype', 'HP:0100526', (250, 260))	('metastases', 'Disease', 'MESH:D009362', (270, 280))	('NSCLC', 'Disease', (0, 5))
33285	31341411	In literature, several studies in lung cancer series reported discrepancies in EGFR, ALK and KRAS mutational status between primary tumors and corresponding metastases.	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('KRAS', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('lung cancer', 'Disease', (34, 45))	('ALK', 'Gene', (85, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('mutational', 'Var', (98, 108))	('KRAS', 'Gene', '3845', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('ALK', 'Gene', '238', (85, 88))	('metastases', 'Disease', (157, 167))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
33289	31341411	Heterogeneity of EGFR mutations was higher (rate of 24.4%; 10 of 41) in patients with multiple pulmonary nodules resulting in significant clinical implications since the current guidelines recommend biopsy in only one lesion.	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('EGFR', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('patients', 'Species', '9606', (72, 80))
33290	31341411	For ALK gene, some data revealed disconcordance between ALK rearrangement in primary NSCLC tumor and corresponding metastases.	('ALK', 'Gene', '238', (4, 7))	('metastases', 'Disease', (115, 125))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('ALK', 'Gene', '238', (56, 59))	('ALK', 'Gene', (4, 7))	('NSCLC tumor', 'Disease', 'MESH:D009369', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('NSCLC tumor', 'Disease', (85, 96))	('ALK', 'Gene', (56, 59))	('rearrangement', 'Var', (60, 73))
33291	31341411	In conclusion, discordances between oncogenic driver mutations status in primary lesions and metastases may have significant implications in treatment with specific inhibitors of NSCLC patients.	('metastases', 'Disease', (93, 103))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('implications', 'Reg', (125, 137))	('mutations', 'Var', (53, 62))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('oncogenic driver', 'Gene', (36, 52))	('patients', 'Species', '9606', (185, 193))	('NSCLC', 'Disease', (179, 184))
33296	31341411	Particularly, a classical model for development of metastases proposes that primary tumor cells have a low metastatic potential, thus the acquirement of enough genetic aberrations improve the metastatic progression.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('metastatic progression', 'CPA', (192, 214))	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('genetic aberrations', 'Var', (160, 179))	('improve', 'PosReg', (180, 187))	('low metastatic potential', 'CPA', (103, 127))	('metastases', 'Disease', (51, 61))
33299	31341411	TRACERx analyzed the intratumor variability of several genetic aberrations including single or dinucleotide base substitutions, small insertions and deletions, somatic copy-number alterations.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('single', 'Var', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('deletions', 'Var', (149, 158))	('small insertions', 'Var', (128, 144))	('dinucleotide base substitutions', 'Var', (95, 126))
33300	31341411	Jamal-Hanjani and colleagues demonstrated that some targetable driver mutations involved in EGFR, MET and BRAF are generally clonal and early, compared to other aberrations in genes such as PIK3CA, NF1, KRAS, TP53, and NOTCH family members that are subclonal and appear later in tumor evolution.	('KRAS', 'Gene', (203, 207))	('PIK3CA', 'Gene', '5290', (190, 196))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', (209, 213))	('KRAS', 'Gene', '3845', (203, 207))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('MET', 'Gene', (98, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('NF1', 'Gene', (198, 201))	('tumor', 'Disease', (279, 284))	('BRAF', 'Gene', '673', (106, 110))	('NF1', 'Gene', '4763', (198, 201))	('BRAF', 'Gene', (106, 110))	('EGFR', 'Gene', '1956', (92, 96))	('PIK3CA', 'Gene', (190, 196))	('EGFR', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (209, 213))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
33301	31341411	Beyond heterogeneity of druggable driver mutations, previous studies have analyzed the presence of mutational signatures across human cancer types, proving that specific mutational signatures could correlate with defined tumors.	('tumors', 'Disease', (221, 227))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('mutational', 'Var', (170, 180))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('human', 'Species', '9606', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
33302	31341411	In ADCs, SqCCs and SCLC a higher prevalence of mutational signature associated with smoking has been reported.	('SqCC', 'Phenotype', 'HP:0002860', (9, 13))	('mutational', 'Var', (47, 57))	('SCLC', 'Gene', '7864', (19, 23))	('SCLC', 'Gene', (19, 23))
33305	31341411	Never-smokers showed a higher rate of ALK-rearrangement (26% vs. 4%, p < .001) and EGFR mutations (36% vs. 8%, p < .001).	('EGFR', 'Gene', '1956', (83, 87))	('ALK', 'Gene', '238', (38, 41))	('EGFR', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('ALK', 'Gene', (38, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))
33306	31341411	Genome-wide studies identified several potential genetic marker of susceptibility in LCINS, such as chromosomal locus 5p15.33 comprising TERT and CLPTMIL genes, the hypoxia-inducible factor-2alpha EPAS1, specific SNPs in CSF1R, p63, TP63 genes, a functional polymorphism in CSF1R gene.	('EPAS1', 'Gene', (197, 202))	('hypoxia-inducible factor-2alpha', 'Gene', '2034', (165, 196))	('hypoxia-inducible factor-2alpha', 'Gene', (165, 196))	('CSF1', 'molecular_function', 'GO:0005011', ('221', '225'))	('SNPs', 'Var', (213, 217))	('TP63', 'Gene', '8626', (233, 237))	('CSF1R', 'Gene', '1436', (274, 279))	('CIN', 'Phenotype', 'HP:0040012', (86, 89))	('CSF1R', 'Gene', (274, 279))	('p63', 'Gene', (228, 231))	('CIN', 'Disease', 'MESH:D007674', (86, 89))	('EPAS1', 'Gene', '2034', (197, 202))	('p63', 'Gene', '8626', (228, 231))	('TERT', 'Gene', (137, 141))	('TERT', 'Gene', '7015', (137, 141))	('CSF1R', 'Gene', '1436', (221, 226))	('CSF1', 'molecular_function', 'GO:0005011', ('274', '278'))	('CSF1R', 'Gene', (221, 226))	('CIN', 'Disease', (86, 89))	('TP63', 'Gene', (233, 237))
33308	31341411	Discordance of molecular profiles between primary lesions and their corresponding metastases in the context of druggable driver mutations could be the key point in personalized medicine of lung cancer patients.	('patients', 'Species', '9606', (201, 209))	('mutations', 'Var', (128, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', (189, 200))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))
33311	31341411	CSCs cancer stem cells CIN chromosomal instability NSCLC non-small cell lung cancer TMB tumor mutational burden MASI mutant allele specific imbalance miRNAs microRNA SCLC small-cell lung carcinoma ADC adenocarcinoma SqCC squamous cell carcinoma LNETs lung neuroendocrine tumours ALK-R ALK rearrangements ROS1-R ROS1 rearrangements TKI tyrosine kinase inhibitor	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (57, 83))	('CIN', 'Disease', (23, 26))	('ROS1', 'Gene', (311, 315))	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('SqCC', 'Phenotype', 'HP:0002860', (216, 220))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('SCLC', 'Gene', '7864', (166, 170))	('SCLC', 'Gene', (166, 170))	('TMB', 'Chemical', '-', (84, 87))	('ROS1', 'Gene', '6098', (304, 308))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('lung neuroendocrine tumours', 'Disease', (251, 278))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('non-small cell lung cancer', 'Disease', (57, 83))	('tumours', 'Phenotype', 'HP:0002664', (271, 278))	('CIN', 'Phenotype', 'HP:0040012', (23, 26))	('lung carcinoma', 'Disease', 'MESH:D008175', (182, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('tumor', 'Disease', (88, 93))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('344', '360'))	('ALK', 'Gene', '238', (279, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('SCLC', 'Gene', '7864', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('SCLC', 'Gene', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('mutant', 'Var', (117, 123))	('cancer', 'Disease', (77, 83))	('CIN', 'Disease', 'MESH:D007674', (23, 26))	('ROS1', 'Gene', '6098', (311, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (221, 244))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('ALK', 'Gene', (279, 282))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('adenocarcinoma', 'Disease', (201, 215))	('ROS1', 'Gene', (304, 308))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('imbalance', 'Phenotype', 'HP:0002172', (140, 149))	('ALK', 'Gene', '238', (285, 288))	('cancer', 'Disease', (5, 11))	('NSCLC', 'Disease', (51, 56))	('chromosomal instability', 'Phenotype', 'HP:0040012', (27, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ALK', 'Gene', (285, 288))	('squamous cell carcinoma', 'Disease', (221, 244))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('lung carcinoma', 'Disease', (182, 196))	('lung neuroendocrine tumours', 'Disease', 'MESH:D008175', (251, 278))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
33331	31092844	MB49-I BC cells displayed aggressively invasive behavior in vitro and in vivo, and such invasiveness is probably due to elevated expression levels of decorin (DCN), yet its relevance to human BC has not yet been confirmed.	('MB49', 'CellLine', 'CVCL:7076', (0, 4))	('invasive behavior', 'CPA', (39, 56))	('MB49-I', 'Var', (0, 6))	('human', 'Species', '9606', (186, 191))	('BC', 'Phenotype', 'HP:0009725', (192, 194))	('elevated', 'PosReg', (120, 128))	('BC', 'Phenotype', 'HP:0009725', (7, 9))	('expression levels', 'MPA', (129, 146))	('aggressively', 'PosReg', (26, 38))
33402	31092844	Similarly, it has been reported that the expression of Snail and Twist in breast cancer cells can induce EMT and a stem cell-like character that would lead to increased metastatic potential.	('breast cancer', 'Disease', (74, 87))	('metastatic potential', 'CPA', (169, 189))	('induce', 'PosReg', (98, 104))	('stem cell-like character', 'CPA', (115, 139))	('Twist', 'Gene', (65, 70))	('Snail', 'Gene', (55, 60))	('increased', 'PosReg', (159, 168))	('EMT', 'CPA', (105, 108))	('Snail', 'Gene', '20613', (55, 60))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('expression', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
33500	30909610	We searched the PubMed and ISI Web of Science databases for relevant articles from inception to 17 September, 2018, using the following keyword combinations: ((lung OR pulmonary) AND (cancer OR carcinoma OR neoplasm OR tumor OR adenocarcinoma OR squamous carcinoma OR malignancy) AND (microRNA* OR miRNA* OR miR* OR let-7*) AND (detection OR diagnosis OR biomarker OR marker) AND (blood OR serum OR plasma)).	('cancer', 'Disease', (184, 190))	('miR', 'Gene', (308, 311))	('miR', 'Gene', '220972', (298, 301))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('miR', 'Gene', (298, 301))	('carcinoma OR neoplasm OR tumor', 'Disease', 'MESH:D009369', (194, 224))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('adenocarcinoma OR squamous carcinoma OR malignancy', 'Disease', (228, 278))	('adenocarcinoma OR squamous carcinoma OR malignancy', 'Disease', 'MESH:D002294', (228, 278))	('neoplasm', 'Phenotype', 'HP:0002664', (207, 215))	('carcinoma OR neoplasm OR tumor', 'Disease', (194, 224))	('microRNA', 'Var', (285, 293))	('miR', 'Gene', '220972', (308, 311))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (246, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('let-7*', 'Var', (316, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
33555	30909610	Aberrant expression of specific circulating miRNAs may provide important information for distinguishing LC histological subtypes or stages.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (9, 19))
33579	30909610	used a combination of F2RL3 methylation in whole blood and smoking exposure to predict LC incidence with an AUC value of 0.86 for participants >=65 years.	('F2RL3', 'Gene', (22, 27))	('participants', 'Species', '9606', (130, 142))	('F2RL3', 'Gene', '9002', (22, 27))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))
33589	30399449	The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly metastatic and resistant to therapy.	('proliferation', 'CPA', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('self-renewal', 'CPA', (65, 77))	('CD133high', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('rat', 'Species', '10116', (86, 89))
33595	30399449	PROM1 mutations are harbored in the populations suffering from retinitis pigmentosa, macular degeneration and cone-rod retinal dystrophy.	('retinitis pigmentosa', 'Disease', (63, 83))	('retinal dystrophy', 'Disease', (119, 136))	('retinitis pigmentosa', 'Disease', 'MESH:D012174', (63, 83))	('retinal dystrophy', 'Disease', 'MESH:D058499', (119, 136))	('rod retinal dystrophy', 'Phenotype', 'HP:0000510', (115, 136))	('macular degeneration', 'Phenotype', 'HP:0000608', (85, 105))	('PROM1', 'Gene', (0, 5))	('PROM1', 'Gene', '8842', (0, 5))	('rat', 'Species', '10116', (99, 102))	('macular degeneration', 'Disease', (85, 105))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (119, 136))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (63, 83))	('cone-rod retinal dystrophy', 'Phenotype', 'HP:0000548', (110, 136))	('retinitis', 'Phenotype', 'HP:0032118', (63, 72))	('mutations', 'Var', (6, 15))
33599	30399449	This is because cancer cells that express high levels of CD133 are more metastatic and resistant to chemotherapy and radiation therapy.	('more', 'PosReg', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('metastatic', 'CPA', (72, 82))	('high levels', 'Var', (42, 53))	('cancer', 'Disease', (16, 22))	('CD133', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
33600	30399449	Given that CD133+ cells are capable of self-renewal, proliferation and differentiation into different types of cells, known as stem cell properties, CD133+ cancer cells are cancer stem cells (CSCs).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (173, 179))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CD133+', 'Var', (149, 155))
33616	30399449	A major body of evidence has demonstrated that the isolated CD133+ cancer cells from patients are capable of forming cancers in immune-comprised xenograft mice, implicating the involvement of CSCs in cancer initiation.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer initiation', 'Disease', 'MESH:D009369', (200, 217))	('CD133+', 'Var', (60, 66))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer initiation', 'Disease', (200, 217))	('rat', 'Species', '10116', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mice', 'Species', '10090', (155, 159))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancer', 'Disease', (200, 206))	('cancers', 'Disease', (117, 124))
33618	30399449	It suggested that CD133+ colon cancer cells are the colon cancer initiating cells.	('colon cancer', 'Disease', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (25, 37))	('colon cancer', 'Disease', 'MESH:D015179', (25, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('CD133+', 'Var', (18, 24))	('colon cancer', 'Disease', (25, 37))
33621	30399449	In addition to recapitulating the parental heterogeneous cancer phenotype, the isolated CD133+ ovarian tumor cells have a higher tumor-forming ability in vivo as compared to the CD133- ovarian tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (57, 63))	('ovarian tumor', 'Phenotype', 'HP:0100615', (95, 108))	('ovarian tumor', 'Disease', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (129, 134))	('ovarian tumor', 'Disease', 'MESH:D010051', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (193, 198))	('CD133+', 'Var', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('higher', 'PosReg', (122, 128))	('ovarian tumor', 'Disease', (95, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ovarian tumor', 'Disease', 'MESH:D010051', (95, 108))	('ovarian tumor', 'Phenotype', 'HP:0100615', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
33623	30399449	It clearly showed that CD133 is sufficient to initiate tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD133', 'Var', (23, 28))
33627	30399449	In several pancreatic cancer cell lines as well as human PDAC patient xenografts, FACS sorted CD133+ population was DCLK1high and acetylated alpha-tubulinhigh.	('PDAC', 'Disease', (57, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (11, 28))	('PDAC', 'Disease', 'MESH:D021441', (57, 61))	('alpha-tubulin', 'Gene', (141, 154))	('pancreatic cancer', 'Disease', (11, 28))	('DCLK1high', 'Var', (116, 125))	('patient', 'Species', '9606', (62, 69))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('human', 'Species', '9606', (51, 56))	('acetyl', 'Chemical', 'MESH:C011632', (130, 136))	('alpha-tubulin', 'Gene', '10376', (141, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
33629	30399449	In head and neck cancer initiating cells (HNCIC), knockdown of CD133 reduced the stemness gene expressions of OCT4 and NANOG, enhanced epithelial differentiation and promoted apoptosis.	('cancer', 'Disease', (17, 23))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('promoted', 'PosReg', (166, 174))	('CD133', 'Gene', (63, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('OCT4', 'Gene', (110, 114))	('knockdown', 'Var', (50, 59))	('stemness gene', 'Disease', 'MESH:D058495', (81, 94))	('enhanced', 'PosReg', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('epithelial differentiation', 'CPA', (135, 161))	('stemness gene', 'Disease', (81, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('NANOG', 'Gene', '79923', (119, 124))	('reduced', 'NegReg', (69, 76))	('apoptosis', 'CPA', (175, 184))	('NANOG', 'Gene', (119, 124))	('OCT4', 'Gene', '5460', (110, 114))
33630	30399449	In addition, these effects were also observed in the tumor tissues from the shCD133 derived xenograft mice, indicating that CD133 initiates tumor formation via upregulation of cell stemness and downregulation of cell differentiation as well as cell death.	('cell stemness', 'CPA', (176, 189))	('mice', 'Species', '10090', (102, 106))	('downregulation', 'NegReg', (194, 208))	('upregulation', 'PosReg', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cell death', 'biological_process', 'GO:0008219', ('244', '254'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('downregulation of cell differentiation', 'biological_process', 'GO:0045596', ('194', '232'))	('formation', 'biological_process', 'GO:0009058', ('146', '155'))	('cell death', 'CPA', (244, 254))	('tumor', 'Disease', (53, 58))	('CD133', 'Var', (124, 129))	('cell differentiation', 'CPA', (212, 232))	('tumor', 'Disease', (140, 145))
33632	30399449	Primary heterogeneous glioblastoma can be derived from either CD133+ or CD133- CSCs.	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('CD133+', 'Var', (62, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('CD133-', 'Var', (72, 78))
33637	30399449	Blockade of Notch through its gene silencing or a gamma secretase inhibitor suppressed the glioblastoma tumor formation in the xenograted mice.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('rat', 'Species', '10116', (132, 135))	('gene silencing', 'Var', (30, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('mice', 'Species', '10090', (138, 142))	('suppressed', 'NegReg', (76, 86))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (91, 109))	('glioblastoma tumor', 'Disease', (91, 109))	('gene silencing', 'biological_process', 'GO:0016458', ('30', '44'))
33638	30399449	In addition, this Notch inhibition decreased several CSC markers including CD133, nestin, Bmi1 and OLIG2.	('Notch', 'Var', (18, 23))	('Bmi1', 'Gene', '648', (90, 94))	('OLIG2', 'Gene', (99, 104))	('nestin', 'Gene', '10763', (82, 88))	('decreased', 'NegReg', (35, 44))	('CD133', 'Gene', (75, 80))	('CSC', 'Disease', (53, 56))	('OLIG2', 'Gene', '10215', (99, 104))	('nestin', 'Gene', (82, 88))	('Bmi1', 'Gene', (90, 94))
33639	30399449	In a xenograft mouse model, the size of tumor derived from the high CD133+ HEK293 cells is dramatically larger than that from the low CD133+ HEK293 cells, suggesting that a role of CD133 in regulating cell growth during cancer development.	('high CD133+ HEK293', 'Var', (63, 81))	('HEK293', 'CellLine', 'CVCL:0045', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HEK293', 'CellLine', 'CVCL:0045', (141, 147))	('tumor', 'Disease', (40, 45))	('cell growth', 'biological_process', 'GO:0016049', ('201', '212'))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancer', 'Disease', (220, 226))	('larger', 'PosReg', (104, 110))
33646	30399449	Knockout of DCLK1 specifically in the pancreas reduced KrasG12D-induced PanIN formations and the size of the formed PanIN lesions.	('DCLK1', 'Gene', (12, 17))	('PanIN', 'Disease', (116, 121))	('PanIN', 'Disease', 'MESH:D018290', (72, 77))	('KrasG12D-induced', 'Var', (55, 71))	('PanIN', 'Disease', (72, 77))	('PanIN', 'Disease', 'MESH:D018290', (116, 121))	('Knockout', 'Var', (0, 8))	('reduced', 'NegReg', (47, 54))
33652	30399449	Furthermore, inhibition of STAT3 by short hairpin RNA or pharmacological compounds, Stattic and LLL12 in this population decreased cancer cell metabolic activity, CD133 protein level and gene expressions that are associated with cell proliferation including cyclin D1, survivin, Bcl-2, and Notch.	('cancer', 'Disease', (131, 137))	('CD133 protein level', 'MPA', (163, 182))	('Bcl-2', 'Gene', (279, 284))	('Bcl-2', 'Gene', '596', (279, 284))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('decreased', 'NegReg', (121, 130))	('gene expressions', 'MPA', (187, 203))	('cell proliferation', 'biological_process', 'GO:0008283', ('229', '247'))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('cyclin D1', 'Gene', '595', (258, 267))	('cyclin', 'molecular_function', 'GO:0016538', ('258', '264'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('279', '284'))	('rat', 'Species', '10116', (241, 244))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cyclin D1', 'Gene', (258, 267))
33653	30399449	The STAT3 inhibition also led to a smaller size of the CD133+/ALDH+-generated xenograft tumors.	('rat', 'Species', '10116', (72, 75))	('inhibition', 'NegReg', (10, 20))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('ALDH', 'molecular_function', 'GO:0004030', ('62', '66'))	('CD133+/ALDH+-generated', 'Var', (55, 77))	('smaller', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
33659	30399449	In addition, overexpressed CD133 promotes the attachment of ovarian adenocarcinoma cells including Kuramochi, OVCA429 and Skov3IP cells to mesothelial cells in vitro and the mesothelium in ex vivo.	('promotes', 'PosReg', (33, 41))	('attachment of ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (46, 82))	('CD133', 'Gene', (27, 32))	('attachment of ovarian adenocarcinoma', 'Disease', (46, 82))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (60, 82))	('overexpressed', 'Var', (13, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
33661	30399449	CD133+ cancer cells selected from cultured human pancreatic cancer cell lines KP-2 and SUIT-2 showed elevated anchorage-independent growth as compared to the CD133-population in the same cell lines, implicating that CD133 promotes cancer cell transformation, invasiveness, and metastasis.	('promotes', 'PosReg', (222, 230))	('elevated', 'PosReg', (101, 109))	('metastasis', 'CPA', (277, 287))	('CD133', 'Var', (216, 221))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (231, 237))	('cancer', 'Disease', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('pancreatic cancer', 'Disease', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('invasiveness', 'CPA', (259, 271))	('cancer', 'Disease', (60, 66))	('anchorage-independent growth', 'CPA', (110, 138))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (43, 48))
33662	30399449	In addition, CXCR4 was highly expressed in these CD133+ isolated cells and knockdown of CXCR4 by small interfering RNA diminished CD133-mediated cell migration and invasion.	('CXCR4', 'molecular_function', 'GO:0038147', ('13', '18'))	('rat', 'Species', '10116', (153, 156))	('diminished', 'NegReg', (119, 129))	('cell migration', 'biological_process', 'GO:0016477', ('145', '159'))	('small interfering', 'Var', (97, 114))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('CXCR4', 'molecular_function', 'GO:0038147', ('88', '93'))
33663	30399449	Similarly, as compared to the CD133+/CXCR4- cells isolated from a highly metastatic pancreatic cancer cell line L3.6pl, CD133+/CXCR4+ cells from the same parental cells were able to intravasate into the portal vein in a xenograft mouse model.	('mouse', 'Species', '10090', (230, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('CD133+/CXCR4+', 'Var', (120, 133))	('pancreatic cancer', 'Disease', (84, 101))	('CXCR4', 'molecular_function', 'GO:0038147', ('37', '42'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('intravasate into the portal vein', 'MPA', (182, 214))	('CXCR4', 'molecular_function', 'GO:0038147', ('127', '132'))
33665	30399449	Silencing of CD133 in Capan1M9 cells that have high levels of endogenous CD133 inhibits Capan1M9-induced lung and liver metastases in mice possibly through downregulation of genes that modulate epithelial-mesenchymal transition (EMT) process such as Slug and N-Cadherin.	('Capan1M9-induced', 'Gene', (88, 104))	('mice', 'Species', '10090', (134, 138))	('Slug', 'Gene', (250, 254))	('downregulation', 'NegReg', (156, 170))	('CD133', 'Gene', (73, 78))	('inhibits', 'NegReg', (79, 87))	('Cadherin', 'molecular_function', 'GO:0008014', ('261', '269'))	('Capan1M9', 'CellLine', 'CVCL:0A59', (88, 96))	('liver metastases', 'Disease', (114, 130))	('Capan1M9', 'CellLine', 'CVCL:0A59', (22, 30))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('194', '227'))	('Slug', 'Gene', '20583', (250, 254))	('liver metastases', 'Disease', 'MESH:D009362', (114, 130))	('EMT', 'biological_process', 'GO:0001837', ('229', '232'))	('Silencing', 'Var', (0, 9))	('CD133', 'Gene', (13, 18))
33667	30399449	It also has been shown that ectopically expressed CD133 induced EMT and more invasive cells of MIA PaCa-2 through activation of NF-kappaB.	('activation', 'PosReg', (114, 124))	('invasive cells of MIA PaCa-2', 'CPA', (77, 105))	('NF-kappaB', 'Protein', (128, 137))	('ectopically expressed', 'Var', (28, 49))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('114', '137'))	('induced', 'PosReg', (56, 63))	('CD133', 'Gene', (50, 55))	('EMT', 'biological_process', 'GO:0001837', ('64', '67'))	('more', 'PosReg', (72, 76))	('EMT', 'CPA', (64, 67))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))
33668	30399449	Furthermore, either silencing of PROM1 by shRNA technique or inhibition of NF-kappaB activation by introduction of an IKKbeta mutant or by a pharmacological BAY 11-7085 treatment, all of them abolished CD133 mediated invasiveness of MIA PaCa-2 cells.	('silencing', 'NegReg', (20, 29))	('abolished', 'NegReg', (192, 201))	('PROM1', 'Gene', (33, 38))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (157, 168))	('inhibition', 'NegReg', (61, 71))	('IKKbeta', 'Gene', '1147', (118, 125))	('IKKbeta', 'Gene', (118, 125))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (233, 243))	('PROM1', 'Gene', '8842', (33, 38))	('activation', 'PosReg', (85, 95))	('NF-kappaB', 'Protein', (75, 84))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('75', '95'))	('CD133 mediated invasiveness of MIA PaCa-2 cells', 'CPA', (202, 249))	('mutant', 'Var', (126, 132))
33673	30399449	Treating AsPC-1 cells with the EGFR inhibitor Gefitinib reversed the effect on cancer cell migration induced by ectopically expressed CD133.	('rat', 'Species', '10116', (94, 97))	('EGFR', 'Gene', '1956', (31, 35))	('AsPC-1', 'CellLine', 'CVCL:0152', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('EGFR', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('Gefitinib', 'Chemical', 'MESH:C419708', (46, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('CD133', 'Gene', (134, 139))	('cancer', 'Disease', (79, 85))	('ectopically expressed', 'Var', (112, 133))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))
33675	30399449	Of note, it has been shown that upon using the lineage tracing technique to track endogenous CD133+ cells in a transgenic mouse model during the development of colon cancer metastasis, CD133 is expressed in the colon cancer epithelium.	('colon cancer', 'Disease', 'MESH:D015179', (160, 172))	('colon cancer metastasis', 'Disease', (160, 183))	('colon cancer', 'Disease', (211, 223))	('colon cancer metastasis', 'Disease', 'MESH:D015179', (160, 183))	('CD133', 'Var', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('mouse', 'Species', '10090', (122, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (211, 223))	('colon cancer', 'Disease', 'MESH:D015179', (211, 223))
33695	30399449	Among them, colorectal cancer is the best reported cancer type for the presence of the CD133+/CD44+ population in the metastatic site liver at an early stage of the disease.	('colorectal cancer', 'Disease', (12, 29))	('rectal cancer', 'Phenotype', 'HP:0100743', (16, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CD133+/CD44+', 'Var', (87, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
33700	30399449	Overexpression of CD133 in a head and neck squamous cell carcinoma (HNSCC) cell line rendered the cells insensitive to 5-FU-or cisplatin-induced cell death.	('CD133', 'Gene', (18, 23))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (38, 66))	('neck squamous cell carcinoma', 'Disease', (38, 66))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (29, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('neck', 'cellular_component', 'GO:0044326', ('38', '42'))	('cell death', 'biological_process', 'GO:0008219', ('145', '155'))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))
33701	30399449	Furthermore, the CD133+ HNSCCs were arrested at the G0/G1 phase of the cell cycle in response to 5-FU and cisplatin treatment.	('CD133+', 'Var', (17, 23))	('G1 phase', 'biological_process', 'GO:0051318', ('55', '63'))	('cell cycle', 'biological_process', 'GO:0007049', ('71', '81'))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('HNSCCs', 'Disease', (24, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('HNSCCs', 'Disease', 'MESH:C535575', (24, 30))
33702	30399449	Similarly, ectopic expression of CD133 in rat C6 glioma cells increased the drug resistance of camptothecin and doxorubicin via upregulation of p-glycoprotein 1 (multidrug resistance protein 1/MDR1) transcription and ABC transporter activity.	('increased', 'PosReg', (62, 71))	('activity', 'MPA', (233, 241))	('upregulation', 'PosReg', (128, 140))	('transcription', 'MPA', (199, 212))	('CD133', 'Gene', (33, 38))	('MDR1', 'Gene', '24646', (193, 197))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('ABC transporter', 'molecular_function', 'GO:0140359', ('217', '232'))	('MDR1', 'Gene', (193, 197))	('p-glycoprotein 1', 'Gene', (144, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('ectopic expression', 'Var', (11, 29))	('glioma', 'Disease', (49, 55))	('multidrug resistance protein', 'molecular_function', 'GO:0008559', ('162', '190'))	('multidrug resistance protein 1', 'Gene', '24646', (162, 192))	('p-glycoprotein', 'molecular_function', 'GO:0008559', ('144', '158'))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('ABC', 'Enzyme', (217, 220))	('transcription', 'biological_process', 'GO:0006351', ('199', '212'))	('MDR', 'molecular_function', 'GO:0004745', ('193', '196'))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('drug resistance', 'Phenotype', 'HP:0020174', (167, 182))	('multidrug resistance protein 1', 'Gene', (162, 192))	('drug resistance', 'biological_process', 'GO:0009315', ('76', '91'))	('drug resistance', 'biological_process', 'GO:0042493', ('76', '91'))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('C6', 'CellLine', 'CVCL:X905', (46, 48))	('camptothecin', 'Chemical', 'MESH:D002166', (95, 107))	('p-glycoprotein 1', 'Gene', '24646', (144, 160))	('transporter activity', 'molecular_function', 'GO:0005215', ('221', '241'))	('rat', 'Species', '10116', (42, 45))
33704	30399449	In cultured human gastric cancer cells, knockdown of CD133 rendered cells more sensitive to 5-FU induced cell death.	('gastric cancer', 'Disease', (18, 32))	('more', 'PosReg', (74, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('CD133', 'Gene', (53, 58))	('knockdown', 'Var', (40, 49))	('sensitive to 5-FU induced', 'MPA', (79, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('human', 'Species', '9606', (12, 17))	('cell death', 'biological_process', 'GO:0008219', ('105', '115'))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
33706	30399449	Blockade of this pathway via the PI3K/Akt inhibitor LY294002 in CD133-expressed gastric cancer cells has the same effect as shCD133-expressed cells in response to 5-FU treatment.	('gastric cancer', 'Disease', (80, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('LY294002', 'Var', (52, 60))	('PI3', 'Gene', (33, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('5-FU', 'Chemical', 'MESH:D005472', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('LY294002', 'Chemical', 'MESH:C085911', (52, 60))	('PI3', 'Gene', '5266', (33, 36))
33708	30399449	Colorectal cancer cells that are CD133high/CD44high survived better than CD133low/CD44low cancer cells after exposure to a high dose of gamma irradiation.	('survived', 'CPA', (52, 60))	('better', 'PosReg', (61, 67))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('rectal cancer', 'Phenotype', 'HP:0100743', (4, 17))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('Colorectal cancer', 'Disease', (0, 17))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (90, 96))	('CD133high/CD44high', 'Var', (33, 51))
33709	30399449	In addition, Akt expression was higher in the CD133high/CD44high cells as compared to the CD133low/CD44low cancer cells.	('CD133high/CD44high', 'Var', (46, 64))	('higher', 'PosReg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('Akt', 'Pathway', (13, 16))
33712	30399449	Given that CD133 plays a pivotal role in regulating cancer metastasis and therapeutic resistance and that both of cancer metastasis and drug resistance are the major contributors to cancer death, targeting CD133 in cancer patients who have metastatic disease would be the best strategy to bring down the death toll of cancer.	('cancer', 'Disease', (318, 324))	('cancer metastasis', 'Disease', (52, 69))	('patients', 'Species', '9606', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('drug resistance', 'biological_process', 'GO:0009315', ('136', '151'))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('drug resistance', 'biological_process', 'GO:0042493', ('136', '151'))	('cancer', 'Disease', (215, 221))	('cancer metastasis', 'Disease', (114, 131))	('cancer', 'Disease', (182, 188))	('cancer death', 'Disease', 'MESH:D003643', (182, 194))	('cancer metastasis', 'Disease', 'MESH:D009362', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('CD133', 'Gene', (206, 211))	('drug resistance', 'Phenotype', 'HP:0020174', (136, 151))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer metastasis', 'Disease', 'MESH:D009362', (114, 131))	('cancer death', 'Disease', (182, 194))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('targeting', 'Var', (196, 205))	('rat', 'Species', '10116', (279, 282))	('cancer', 'Disease', (114, 120))
33720	30399449	The in vitro effect of CD133-MMAF conjugates was verified in Hep3B xenografted SCID mice that anti-CD133-MMAF treatment delayed tumor growth in vivo.	('SCID', 'Gene', (79, 83))	('anti-CD133-MMAF', 'Var', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('delayed', 'NegReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('SCID', 'Gene', '19090', (79, 83))	('Hep3B', 'CellLine', 'CVCL:0326', (61, 66))	('mice', 'Species', '10090', (84, 88))
33721	30399449	Another invention includes to conjugate anti-CD133 monoclonal antibody to nanoparticles that were loaded with anti-cancer drug paclitaxel.	('antibody', 'cellular_component', 'GO:0019814', ('62', '70'))	('cancer', 'Disease', (115, 121))	('antibody', 'molecular_function', 'GO:0003823', ('62', '70'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('anti-CD133', 'Var', (40, 50))	('antibody', 'cellular_component', 'GO:0042571', ('62', '70'))	('antibody', 'cellular_component', 'GO:0019815', ('62', '70'))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
33726	30399449	CART-CD133 treatment has been tested in CD133high glioblastoma stem cells in vitro and in an orthotopic tumor model in vivo.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CART-CD133', 'Gene', (0, 10))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('CD133high', 'Var', (40, 49))	('CART-CD133', 'Gene', '8842', (0, 10))	('tumor', 'Disease', (104, 109))	('glioblastoma', 'Disease', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
33739	30399449	It would be of most importance to evaluate if the blockade of CD133 alternatively results in selections for other cancer stem cell markers that could compensate the loss of CD133, and what the final outcome of cancer metastasis as well as drug resistance is in animal models capitulating human cancers.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('loss', 'Var', (165, 169))	('blockade', 'Var', (50, 58))	('human', 'Species', '9606', (288, 293))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancer', 'Disease', (294, 300))	('cancer metastasis', 'Disease', (210, 227))	('cancers', 'Disease', (294, 301))	('results in', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('drug resistance', 'biological_process', 'GO:0009315', ('239', '254'))	('CD133', 'Gene', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('drug resistance', 'biological_process', 'GO:0042493', ('239', '254'))	('CD133', 'Gene', (173, 178))	('cancer metastasis', 'Disease', 'MESH:D009362', (210, 227))	('drug resistance', 'Phenotype', 'HP:0020174', (239, 254))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (114, 120))
33742	30298562	Following retrospective analysis of whole 474 consecutive pathological N0M0 lung adenocarcinoma patients, the prognostic significance of EGFR mutation status was evaluated in limited 394 subjects.	('EGFR', 'Gene', (137, 141))	('N0M0', 'Var', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung adenocarcinoma', 'Disease', (76, 95))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('patients', 'Species', '9606', (96, 104))	('EGFR', 'Gene', '1956', (137, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))
33744	30298562	Following the exclusion of specific subtypes free from recurrence or EGFR mutation (adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive mucinous adenocarcinoma), the five-year RFI was obviously poorer in EGFR positive compared to negative cases (80.7% and 92.1%, respectively; HR 2.163, 95% CI 1.055-4.341; P = 0.035).	('adenocarcinoma in situ', 'Disease', (84, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('224', '228'))	('RFI', 'MPA', (196, 199))	('invasive adenocarcinoma', 'Disease', (118, 141))	('invasive mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (147, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('EGFR', 'Gene', '1956', (69, 73))	('mutation', 'Var', (74, 82))	('EGFR', 'Gene', (224, 228))	('invasive mucinous adenocarcinoma', 'Disease', (147, 179))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('positive', 'Var', (229, 237))	('adenocarcinoma in situ', 'Disease', 'MESH:D065311', (84, 106))	('poorer', 'NegReg', (214, 220))	('EGFR', 'Gene', '1956', (224, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('EGFR', 'Gene', (69, 73))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (118, 141))
33747	30298562	EGFR mutations are associated with recurrence in pN0M0 lung adenocarcinoma.	('associated', 'Reg', (19, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', (55, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('EGFR', 'Gene', '1956', (0, 4))
33749	30298562	EGFR mutations represent one of the most frequent genetic aberrations in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (73, 92))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('frequent', 'Reg', (41, 49))	('EGFR', 'Gene', '1956', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
33750	30298562	The frequency in Asia is reported at 40-60%.1, 2 Somatic mutations in EGFR are more likely to occur in Asian, female, and adenocarcinoma patients.1, 3 A number of studies have estimated the prognostic impact of EGFR mutation in resected non-small cell lung cancer (NSCLC) patients; however, most of them included several types of histology and advanced stage.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (237, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (241, 263))	('EGFR', 'Gene', '1956', (70, 74))	('cell lung cancer', 'Disease', 'MESH:D008175', (247, 263))	('EGFR', 'Gene', '1956', (211, 215))	('mutation', 'Var', (216, 224))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cell lung cancer', 'Disease', (247, 263))	('adenocarcinoma', 'Disease', (122, 136))	('patients', 'Species', '9606', (137, 145))	('NSCLC', 'Disease', 'MESH:D002289', (265, 270))	('patients', 'Species', '9606', (272, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))	('NSCLC', 'Disease', (265, 270))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('EGFR', 'Gene', (70, 74))	('EGFR', 'Gene', (211, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (265, 270))
33751	30298562	The prognostic significance of EGFR mutations as oncogenic driver mutations in resected pN0M0 lung adenocarcinoma is yet to be determined.	('EGFR', 'Gene', '1956', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung adenocarcinoma', 'Disease', (94, 113))	('EGFR', 'Gene', (31, 35))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('mutations', 'Var', (36, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))
33752	30298562	Herein, we evaluated the oncological consequences of EGFR mutations in pN0M0 lung adenocarcinoma.	('mutations', 'Var', (58, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('lung adenocarcinoma', 'Disease', (77, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
33753	30298562	In addition to overall survival (OS), the recurrence-free interval (RFI) was utilized to estimate the oncological impact of EGFR mutation on recurrence.	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('mutation', 'Var', (129, 137))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (124, 128))
33755	30298562	We performed a retrospective cohort study of consecutive patients with pN0M0 lung adenocarcinoma at a single institution.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('patients', 'Species', '9606', (57, 65))	('lung adenocarcinoma', 'Disease', (77, 96))	('pN0M0', 'Var', (71, 76))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
33760	30298562	The effects of EGFR mutation status on OS and RFI were initially estimated in all 394 tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (20, 28))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))
33761	30298562	Subsequently, OS and RFI were calculated for specific histological subtypes by considering the risk of recurrence and positive EGFR mutation status.	('EGFR', 'Gene', '1956', (127, 131))	('mutation', 'Var', (132, 140))	('EGFR', 'Gene', (127, 131))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))
33772	30298562	Overall survival and RFI were used to evaluate the oncological significance of EGFR mutation status.	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
33775	30298562	Univariate analyses were built with EGFR mutation status and clinicopathological factors regarding prognosis, and multivariate analysis was conducted using a Cox proportional hazards model with a backward stepwise procedure.	('EGFR', 'Gene', (36, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('mutation', 'Var', (41, 49))	('EGFR', 'Gene', '1956', (36, 40))
33783	30298562	EGFR mutation status was positive in 176 cases (44.7%).	('EGFR', 'Gene', (0, 4))	('positive', 'Reg', (25, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
33784	30298562	The frequency of EGFR mutation positivity was significantly higher in female patients; non-smokers; patients with larger tumors (median 2.0 cm [IQR 1.2 cm] vs. 1.6 cm [IQR 1.3 cm] for EGFR positive and negative cases, respectively); papillary predominant subtypes; and cases accompanied by a lepidic or micropapillary component.	('papillary', 'Disease', (233, 242))	('lepidic or micropapillary component', 'Disease', (292, 327))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('higher', 'PosReg', (60, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('184', '188'))	('EGFR', 'Gene', '1956', (184, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('lepidic or micropapillary component', 'Disease', 'MESH:C562869', (292, 327))	('positivity', 'Var', (31, 41))	('EGFR', 'Gene', (184, 188))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', '1956', (17, 21))	('mutation positivity', 'Var', (22, 41))	('EGFR', 'Gene', (17, 21))
33785	30298562	Conversely, EGFR mutation positive status was observed significantly less frequently in the acinar and solid predominant histological subtypes.	('mutation positive', 'Var', (17, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('EGFR', 'Gene', '1956', (12, 16))	('acinar', 'Disease', (92, 98))	('EGFR', 'Gene', (12, 16))	('less', 'NegReg', (69, 73))
33786	30298562	None of the IMA cases harbored an EGFR mutation (Table 2).	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('IMA', 'Disease', (12, 15))	('EGFR', 'Gene', '1956', (34, 38))
33787	30298562	The frequencies of EGFR mutations in different histological subtypes are summarized in Figure 2.	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))
33788	30298562	Among the EGFR mutation positive cases, the proportions with an exon 19 deletion and L858R mutation were 39.2% (n = 69) and 53.4% (n = 94), respectively (Table 1).	('EGFR', 'Gene', '1956', (10, 14))	('L858R', 'Var', (85, 90))	('exon 19 deletion', 'Var', (64, 80))	('EGFR', 'Gene', (10, 14))	('L858R', 'Mutation', 'rs121434568', (85, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))
33789	30298562	The overall five-year OS was 88.7% and 93.7% for the EGFR positive and negative cases, respectively (hazard ratio [HR] 1.630, 95% confidence interval [CI] 0.787-3.432; P = 0.2).	('EGFR', 'Gene', (53, 57))	('positive', 'Var', (58, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('EGFR', 'Gene', '1956', (53, 57))
33793	30298562	Univariate analysis after excluding AIS, MIA, and IMA cases identified age, pathological tumor size (cm), a highly malignant subtype (micropapillary/solid predominant adenocarcinoma), pleural/lymphatic/vascular invasion, and positive EGFR mutation status as significantly associated with shorter RFI.	('EGFR', 'Gene', '1956', (234, 238))	('mutation', 'Var', (239, 247))	('EGFR', 'Gene', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('234', '238'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('MIA', 'Disease', 'None', (41, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('MIA', 'Disease', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('pleural', 'Disease', 'MESH:D010995', (184, 191))	('pleural', 'Disease', (184, 191))	('shorter RFI', 'Disease', (288, 299))	('tumor', 'Disease', (89, 94))	('adenocarcinoma', 'Disease', (167, 181))
33794	30298562	Multivariate analysis confirmed that male sex (HR 0.273, 95% CI 0.087-0.860; P = 0.027), age (HR 1.078, 95% CI 1.032-1.125; P = 0.001), current or Ex-Smoking status (HR 3.056, 95% CI 1.087-8.590; P = 0.034), pleural invasion (HR 5.454, 95% CI 2.250-13.222; P < 0.001), and positive EGFR mutation status (HR 2.607, 95% CI 1.042-6.523; P = 0.041) were independently associated with poor RFI (Table 3).	('EGFR', 'Gene', '1956', (282, 286))	('poor RFI', 'Disease', (380, 388))	('mutation', 'Var', (287, 295))	('EGFR', 'molecular_function', 'GO:0005006', ('282', '286'))	('pleural invasion', 'Disease', 'MESH:D010995', (208, 224))	('EGFR', 'Gene', (282, 286))	('pleural invasion', 'Disease', (208, 224))
33795	30298562	EGFR mutations represent one of the major somatic mutations in lung adenocarcinoma and are a therapeutic target in advanced lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (63, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', (124, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('EGFR', 'Gene', '1956', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
33797	30298562	Although previous studies have shown that EGFR mutations are of significant prognostic value in lung adenocarcinoma, these studies included various histologic subtypes or pStage.12, 13, 14, 15, 16, 17, 18 Systematic meta-analyses have shown that EGFR mutation status is not a prognostic factor in patients with surgically resected NSCLC.11 Kobayashi et al.	('lung adenocarcinoma', 'Disease', (96, 115))	('EGFR', 'Gene', '1956', (42, 46))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (96, 115))	('patients', 'Species', '9606', (297, 305))	('EGFR', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('NSCLC', 'Disease', (331, 336))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('246', '250'))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('NSCLC', 'Disease', 'MESH:D002289', (331, 336))	('EGFR', 'Gene', '1956', (246, 250))	('EGFR', 'Gene', (246, 250))	('NSCLC', 'Phenotype', 'HP:0030358', (331, 336))
33798	30298562	demonstrated that positive EGFR mutation status correlates with growth in early-stage lung adenocarcinoma cases with a ground-glass component of >= 50%.19 This report supports the unfavorable effects of EGFR mutation status in early-stage lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', '1956', (203, 207))	('EGFR', 'Gene', (27, 31))	('mutation', 'Var', (208, 216))	('lung adenocarcinoma', 'Disease', (86, 105))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (239, 258))	('EGFR', 'molecular_function', 'GO:0005006', ('203', '207'))	('EGFR', 'Gene', (203, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('lung adenocarcinoma', 'Disease', (239, 258))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (239, 258))
33799	30298562	However, studies limited to stage I cases indicated better prognostic tendencies in patients with EGFR mutations20, 21, 22 which contrasts with our results.	('EGFR', 'Gene', (98, 102))	('mutations20', 'Var', (103, 114))	('patients', 'Species', '9606', (84, 92))	('better', 'PosReg', (52, 58))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
33801	30298562	Thus, EGFR mutation in stage I adenocarcinoma is likely to be AIS or MIA.	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('AIS', 'Disease', (62, 65))	('EGFR', 'Gene', (6, 10))	('MIA', 'Disease', 'None', (69, 72))	('I adenocarcinoma', 'Disease', (29, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('I adenocarcinoma', 'Disease', 'MESH:D000230', (29, 45))	('MIA', 'Disease', (69, 72))	('mutation', 'Var', (11, 19))	('EGFR', 'Gene', '1956', (6, 10))
33803	30298562	Without considering histological subtypes, comparing EGFR mutation positive to wild-type cases is akin to comparing noninvasive or preinvasive cases to invasive tumors.	('invasive tumors', 'Disease', (152, 167))	('mutation positive', 'Var', (58, 75))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('invasive tumors', 'Disease', 'MESH:D009369', (152, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))
33804	30298562	In a cohort with extremely high five-year OS of 98% and a low rate of EGFR mutations (20.2%),20 most cases harboring EGFR mutations might be AIS and MIA.	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (117, 121))	('AIS', 'Disease', (141, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('MIA', 'Disease', 'None', (149, 152))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (122, 131))	('MIA', 'Disease', (149, 152))
33808	30298562	Thus, the prognostic significance of EGFR mutations is underestimated unless AIS, MIA, and IMA are excluded.	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('MIA', 'Disease', 'None', (82, 85))	('MIA', 'Disease', (82, 85))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('AIS', 'Disease', (77, 80))	('mutations', 'Var', (42, 51))
33814	30298562	Additionally, OS is generally improved in EGFR mutation-positive cases after receiving EGFR-TKIs.13, 34 Previous studies concluded that EGFR mutation is a favorable prognostic indicator and suggest that OS is prolonged by EGFR-TKIs.14, 15, 16, 22 In summary, the distribution of EGFR mutation and potential curability varies considerably among sub-histologies.	('EGFR', 'Gene', (136, 140))	('EGFR', 'Gene', '1956', (42, 46))	('mutation', 'Var', (284, 292))	('EGFR', 'Gene', (279, 283))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', '1956', (279, 283))	('EGFR', 'molecular_function', 'GO:0005006', ('222', '226'))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('EGFR', 'Gene', (42, 46))	('EGFR', 'Gene', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('EGFR', 'Gene', '1956', (222, 226))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('279', '283'))	('EGFR', 'Gene', (222, 226))
33815	30298562	The therapeutic effect of TKIs must be excluded to precisely estimate the prognostic impact of EGFR mutation.	('mutation', 'Var', (100, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (95, 99))
33816	30298562	Thus, we report contradictory results on the prognostic impact of EGFR mutation compared to those in published literature.	('mutation', 'Var', (71, 79))	('EGFR', 'Gene', (66, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))	('EGFR', 'Gene', '1956', (66, 70))
33822	30298562	In conclusion, EGFR mutations are associated with recurrence in pN0M0 lung adenocarcinoma, particularly in types other than AIS, MIA, and IMA.	('associated with', 'Reg', (34, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('pN0M0', 'Gene', (64, 69))	('MIA', 'Disease', 'None', (129, 132))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('MIA', 'Disease', (129, 132))	('AIS', 'Disease', (124, 127))	('IMA', 'Disease', (138, 141))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('mutations', 'Var', (20, 29))	('lung adenocarcinoma', 'Disease', (70, 89))
33823	30298562	The ratio of EGFR mutation and the risk of recurrence vary among histological subtypes.	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))
33829	30214559	A total of 14 patients (23.7%) exhibited EGFR mutations, which were significantly associated with female sex (9/14, 64.3%), non-smoker status (8/14, 57.1%), BM in the frontal lobes (9/14, 64.3%) and papillary adenocarcinoma (5/14, 35.7%).	('EGFR', 'Gene', (41, 45))	('associated', 'Reg', (82, 92))	('mutations', 'Var', (46, 55))	('frontal lobes', 'Disease', 'MESH:D001927', (167, 180))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (199, 223))	('EGFR', 'Gene', '1956', (41, 45))	('frontal lobes', 'Disease', (167, 180))	('papillary adenocarcinoma', 'Disease', (199, 223))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('patients', 'Species', '9606', (14, 22))	('papillary adenocarcinoma', 'Disease', 'MESH:D000231', (199, 223))
33830	30214559	Statistical analysis revealed a significant association between non-smoker status and BM in the frontal lobes, and more favorable disease prognosis.	('frontal lobes', 'Disease', (96, 109))	('frontal lobes', 'Disease', 'MESH:D001927', (96, 109))	('non-smoker status', 'Var', (64, 81))
33837	30214559	In lung adenocarcinoma, mutations in the epidermal growth factor receptor (EGFR) gene have been identified as a driver mutation promoting tumor growth.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('tumor', 'Disease', (138, 143))	('epidermal growth factor receptor', 'Gene', (41, 73))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('epidermal growth factor receptor', 'Gene', '1956', (41, 73))	('promoting', 'PosReg', (128, 137))	('EGFR', 'Gene', '1956', (75, 79))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('41', '64'))	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', (75, 79))	('lung adenocarcinoma', 'Disease', (3, 22))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
33838	30214559	Therapies targeting mutant EGFR protein are associated with relatively high overall response rates, and have been established as standard-of-care treatments.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('protein', 'Protein', (32, 39))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('mutant', 'Var', (20, 26))
33844	30214559	Given evidence that the presence of EGFR mutations is a positive prognostic factor in patients with BM from lung adenocarcinoma, it is feasible that analysis of tissue from BM may be used to guide more aggressive and effective treatments for patients with EGFR mutation-positive NSCLC.	('mutations', 'Var', (41, 50))	('lung adenocarcinoma', 'Disease', (108, 127))	('patients', 'Species', '9606', (242, 250))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('NSCLC', 'Disease', (279, 284))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('EGFR', 'Gene', '1956', (36, 40))	('NSCLC', 'Disease', 'MESH:D002289', (279, 284))	('EGFR', 'Gene', '1956', (256, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('256', '260'))	('EGFR', 'Gene', (36, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('EGFR', 'Gene', (256, 260))	('patients', 'Species', '9606', (86, 94))
33846	30214559	In addition, an evaluation of EGFR mutations and their association with disease prognosis was assessed.	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
33857	30214559	The clinicopathological parameters considered in this study included patient age, sex, location of BM, histological subtype of BM, smoking status, Karnofsky performance score (KPS), number of BM, presence of extracranial metastasis (ECM), GPA, timing of diagnosis, tyrosine kinase inhibitor (TKI) treatment prior to diagnosis of BM, presence of RAS mutations or anaplastic lymphoma kinase (ALK) rearrangements and re-operation.	('anaplastic lymphoma kinase', 'Gene', (362, 388))	('presence', 'Reg', (333, 341))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (362, 381))	('rearrangements', 'Var', (395, 409))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('274', '290'))	('lymphoma', 'Phenotype', 'HP:0002665', (373, 381))	('ALK', 'Gene', '238', (390, 393))	('anaplastic lymphoma kinase', 'Gene', '238', (362, 388))	('patient', 'Species', '9606', (69, 76))	('mutations', 'Var', (349, 358))	('RAS', 'Protein', (345, 348))	('ALK', 'Gene', (390, 393))
33859	30214559	EGFR mutations (including G719X in exon 18, exon 19 deletion, T790M in exon 20, and L858R and L861Q in exon 21) and RAS mutations (G12C and G12A in exon 2 and Q61H in exon 3) were detected in matching formalin-fixed paraffin-embedded tissue samples using cycleave PCR (which was performed by SRL Inc., Tokyo, Japan, cobas  EGFR Mutation Test v2 kit and MEBGEN  RASKET kit according to the manufacture's protocol).	('EGFR', 'molecular_function', 'GO:0005006', ('323', '327'))	('G719X', 'Mutation', 'p.G719X', (26, 31))	('G12C', 'Var', (131, 135))	('G12A', 'Var', (140, 144))	('G12C', 'Mutation', 'c.12G>C', (131, 135))	('Q61H', 'Mutation', 'p.Q61H', (159, 163))	('T790M', 'Var', (62, 67))	('L861Q', 'Mutation', 'rs121913444', (94, 99))	('EGFR', 'Gene', '1956', (323, 327))	('L858R', 'Var', (84, 89))	('L861Q in', 'Var', (94, 102))	('paraffin', 'Chemical', 'MESH:D010232', (216, 224))	('EGFR', 'Gene', (0, 4))	('G12A', 'Mutation', 'c.12G>A', (140, 144))	('EGFR', 'Gene', (323, 327))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('T790M', 'Mutation', 'rs121434569', (62, 67))	('EGFR', 'Gene', '1956', (0, 4))	('L858R', 'Mutation', 'rs121434568', (84, 89))	('formalin', 'Chemical', 'MESH:D005557', (201, 209))
33861	30214559	To identify clinical features associated with EGFR mutations, categorical variables were compared using Wilcoxon signed-rank test or Fisher's exact test.	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', (46, 50))
33867	30214559	A total of 14 patients (23.7%) exhibited EGFR mutations (Table II), of which deletion of exon 19 was the most common genetic alteration (eight patients, 57.1%), followed by L858R mutation in exon 21 (five patients, 35.7%).	('EGFR', 'Gene', (41, 45))	('patients', 'Species', '9606', (205, 213))	('EGFR', 'Gene', '1956', (41, 45))	('patients', 'Species', '9606', (143, 151))	('deletion', 'Var', (77, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('exon 19', 'Gene', (89, 96))	('L858R', 'Var', (173, 178))	('patients', 'Species', '9606', (14, 22))	('L858R', 'Mutation', 'rs121434568', (173, 178))
33869	30214559	EGFR mutations occurred significantly more often in female compared with male patients (64.3 vs. 35.7%; P=0.0001).	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
33870	30214559	EGFR mutations also occurred significantly more frequently in non-smokers compared with current or ex-smokers (57.1 vs. 42.9%; P=0.04).	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('occurred', 'Reg', (20, 28))	('EGFR', 'Gene', '1956', (0, 4))
33871	30214559	BM within the frontal lobe were significantly more common compared with other locations in patients with EGFR mutations [64.3 (frontal lobe) vs. 21.4 (cerebellum) vs. 7.1% (posterior lobe); P=0.03].	('common', 'Reg', (51, 57))	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (110, 119))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('EGFR', 'Gene', (105, 109))
33872	30214559	The rate of surgery for tumor recurrence occurred significantly more often in patients with wild-type compared with mutated EGFR (37.8 vs. 7.1%; P=0.04).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('EGFR', 'Gene', '1956', (124, 128))	('tumor', 'Disease', (24, 29))	('wild-type', 'Var', (92, 101))	('patients', 'Species', '9606', (78, 86))	('EGFR', 'Gene', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('mutated', 'Var', (116, 123))
33873	30214559	The two groups did not significantly differ in GPA measures of age, KPS, number of BM, presence of ECMs, timing of diagnosis, and frequency of RAS mutation and ALK rearrangements.	('ALK', 'Gene', (160, 163))	('RAS', 'Protein', (143, 146))	('mutation', 'Var', (147, 155))	('ALK', 'Gene', '238', (160, 163))
33876	30214559	The sites at which ECMs occurred in the patients with EGFR mutation were similar to those in which ECMs occurred in patients with WT.	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (116, 124))	('EGFR', 'Gene', '1956', (54, 58))	('mutation', 'Var', (59, 67))	('EGFR', 'Gene', (54, 58))
33877	30214559	In patients with EGFR mutations, six patients had ECMs (one patient had multiple lesions).	('patient', 'Species', '9606', (60, 67))	('patient', 'Species', '9606', (37, 44))	('patients', 'Species', '9606', (37, 45))	('ECMs', 'Disease', (50, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('patient', 'Species', '9606', (3, 10))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
33883	30214559	A total of five patients (8.5%) received systemic chemotherapy only, while two patients (3.4%) with EGFR mutations were treated with the EGFR-TKI gefitinib prior to the diagnosis of BM.	('EGFR', 'Gene', (137, 141))	('EGFR', 'Gene', '1956', (100, 104))	('gefitinib', 'Chemical', 'MESH:D000077156', (146, 155))	('EGFR', 'Gene', (100, 104))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('mutations', 'Var', (105, 114))	('patients', 'Species', '9606', (79, 87))	('EGFR', 'Gene', '1956', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))
33886	30214559	EGFR mutations occurred most commonly in papillary adenocarcinoma (five patients, 35.7%), followed by acinar adenocarcinoma (four patients, 26.7%), solid adenocarcinoma (four patients, 26.7%) and micropapillary adenocarcinoma (one patient, 7.1%).	('patient', 'Species', '9606', (72, 79))	('patient', 'Species', '9606', (231, 238))	('papillary adenocarcinoma', 'Disease', 'MESH:D000231', (201, 225))	('solid adenocarcinoma', 'Disease', (148, 168))	('patient', 'Species', '9606', (175, 182))	('acinar adenocarcinoma', 'Disease', 'MESH:D018267', (102, 123))	('papillary adenocarcinoma', 'Disease', 'MESH:D000231', (41, 65))	('micropapillary adenocarcinoma', 'Disease', (196, 225))	('EGFR', 'Gene', (0, 4))	('solid adenocarcinoma', 'Disease', 'MESH:D000230', (148, 168))	('occurred', 'Reg', (15, 23))	('mutations', 'Var', (5, 14))	('papillary adenocarcinoma', 'Disease', (41, 65))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (201, 225))	('patients', 'Species', '9606', (130, 138))	('acinar adenocarcinoma', 'Disease', (102, 123))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (41, 65))	('patient', 'Species', '9606', (130, 137))	('patients', 'Species', '9606', (175, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('micropapillary adenocarcinoma', 'Disease', 'MESH:D000230', (196, 225))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (72, 80))
33887	30214559	No significant association was identified between the occurrence of an EGFR mutation and histological subtype.	('EGFR', 'Gene', '1956', (71, 75))	('mutation', 'Var', (76, 84))	('EGFR', 'Gene', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))
33897	30214559	The OS time was significantly increased in patients with EGFR mutations (median OS of 31.5 months vs. 15.6 months; P=0.02; Fig.	('OS time', 'MPA', (4, 11))	('OS', 'Chemical', '-', (4, 6))	('OS', 'Chemical', '-', (80, 82))	('patients', 'Species', '9606', (43, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', '1956', (57, 61))	('increased', 'PosReg', (30, 39))	('EGFR', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
33904	30214559	Previous studies have investigated the incidence of EGFR mutations in a large population of patients with lung cancer.	('EGFR', 'Gene', '1956', (52, 56))	('lung cancer', 'Disease', (106, 117))	('EGFR', 'Gene', (52, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (57, 66))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
33905	30214559	EGFR mutations have been detected in 30% of patients with adenocarcinoma, 38% of female patients, 47% of non-smokers and 32% of patients of East Asian origin in the patients with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (179, 198))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (88, 96))	('adenocarcinoma', 'Disease', (58, 72))	('mutations', 'Var', (5, 14))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (179, 198))	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('adenocarcinoma', 'Disease', (184, 198))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('patients', 'Species', '9606', (165, 173))	('adenocarcinoma', 'Disease', 'MESH:D000230', (184, 198))	('EGFR', 'Gene', '1956', (0, 4))	('detected', 'Reg', (25, 33))	('patients', 'Species', '9606', (128, 136))	('lung adenocarcinoma', 'Disease', (179, 198))
33906	30214559	It has also been reported to be easier to detect EGFR mutations in smaller primary tumors.	('EGFR', 'Gene', '1956', (49, 53))	('primary tumors', 'Disease', 'MESH:D009369', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('primary tumors', 'Disease', (75, 89))
33907	30214559	Deletion of exon 19 and L858R mutations in exon 21 account for ~85% of EGFR mutations and have been recognized as important markers in determining the appropriate treatment strategy for patients with advanced lung cancer.	('mutations', 'Var', (76, 85))	('lung cancer', 'Disease', (209, 220))	('L858R', 'Var', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('L858R', 'Mutation', 'rs121434568', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (186, 194))	('Deletion', 'Var', (0, 8))
33908	30214559	BM from lung cancer were detected at the time of diagnosis of the primary tumor in 8-23% of patients with EGFR mutations, and in 24% of patients with NSCLC during follow-up care.	('mutations', 'Var', (111, 120))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('primary tumor', 'Disease', (66, 79))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (136, 144))	('primary tumor', 'Disease', 'MESH:D009369', (66, 79))	('EGFR', 'Gene', '1956', (106, 110))	('lung cancer', 'Disease', (8, 19))	('NSCLC', 'Disease', (150, 155))	('EGFR', 'Gene', (106, 110))
33909	30214559	In patients with NSCLC in which EGFR mutations were present, 34.2% were identified to have developed BM 1 year after diagnosis, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years and 52.9% at 5 years in the USA.	('NSCLC', 'Disease', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EGFR', 'Gene', '1956', (32, 36))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (3, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))
33910	30214559	At the time of the initial diagnosis of primary lung adenocarcinoma, the incidence of EGFR mutation is reported to vary according to the site of BM.	('mutation', 'Var', (91, 99))	('primary lung adenocarcinoma', 'Disease', (40, 67))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('primary lung adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 67))	('EGFR', 'Gene', (86, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))
33911	30214559	Patients with lung adenocarcinoma with EGFR mutations have been suggested to have a higher incidence rate of BM compared with patients without mutations.	('lung adenocarcinoma', 'Disease', (14, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (44, 53))	('patients', 'Species', '9606', (126, 134))	('EGFR', 'Gene', '1956', (39, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('EGFR', 'Gene', (39, 43))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))
33913	30214559	Therefore, the association between the presence of EGFR mutations and BM is controversial.	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('mutations', 'Var', (56, 65))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
33914	30214559	Multiple BM (>=2) have been reported to occur more frequently in patients with EGFR mutations, but the size of the largest BM does not appear to be associated with the presence of EGFR mutations.	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))
33917	30214559	In the current study, 5/20 patients examined had EGFR mutations in the primary lung adenocarcinoma and BM.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('primary lung adenocarcinoma', 'Disease', (71, 98))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (27, 35))	('primary lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 98))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))
33918	30214559	Five patients had the same EGFR mutation in both sites (three patients had exon 19 deletions and one patient each had had L858R and L861Q substitutions in exon 21).	('exon', 'Var', (75, 79))	('L861Q', 'Mutation', 'rs121913444', (132, 137))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('L858R', 'Var', (122, 127))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('L858R', 'Mutation', 'rs121434568', (122, 127))	('patient', 'Species', '9606', (62, 69))	('deletions', 'Var', (83, 92))	('L861Q', 'Var', (132, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('patient', 'Species', '9606', (101, 108))	('patients', 'Species', '9606', (62, 70))
33919	30214559	In the present study, the frequency of EGFR mutations in patients with BM (23.7%) was lower compared with previously reported.	('patients', 'Species', '9606', (57, 65))	('lower', 'NegReg', (86, 91))	('mutations', 'Var', (44, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
33921	30214559	EGFR mutations in lung adenocarcinoma are most common in female patients and non-smokers, but the present study cohort included predominantly male patients (76.3% of all patients).	('patients', 'Species', '9606', (170, 178))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (64, 72))	('lung adenocarcinoma', 'Disease', (18, 37))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (18, 37))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (147, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (18, 37))	('EGFR', 'Gene', '1956', (0, 4))
33926	30214559	EGFR mutation have been reported to occur significantly more often in adenocarcinoma papillary predominant, compared with all other subtypes.	('adenocarcinoma papillary', 'Disease', 'MESH:D000231', (70, 94))	('EGFR', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('adenocarcinoma papillary', 'Disease', (70, 94))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
33931	30214559	Furthermore, this histopathological subtype was less likely to harbor EGFR mutations and occurred less frequently in never smokers.	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))
33935	30214559	However, wild type EGFR was significantly more common in patients with the solid predominant subtype.	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('patients', 'Species', '9606', (57, 65))	('EGFR', 'Gene', '1956', (19, 23))	('solid predominant', 'Disease', (75, 92))	('common', 'Reg', (47, 53))	('wild type', 'Var', (9, 18))	('EGFR', 'Gene', (19, 23))
33936	30214559	In recent years, TKIs targeting mutated EGFR proteins have been established as the standard treatment for NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('proteins', 'Protein', (45, 53))	('mutated', 'Var', (32, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('NSCLC', 'Disease', (106, 111))
33942	30214559	Excluding these two patients, there was no statistically significant difference in OS between patients with and without EGFR mutations (17.1 vs. 15.6 months).	('mutations', 'Var', (125, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('patients', 'Species', '9606', (94, 102))	('OS', 'Chemical', '-', (83, 85))	('patients', 'Species', '9606', (20, 28))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (120, 124))
33943	30214559	The presence of an EGFR mutation prolonged OS, but improved outcome may be due to the efficacy of treatment with TKIs.	('EGFR', 'Gene', (19, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('EGFR', 'Gene', '1956', (19, 23))	('OS', 'Chemical', '-', (43, 45))	('mutation', 'Var', (24, 32))	('prolonged', 'PosReg', (33, 42))
33944	30214559	In agreement with the current results, for patients with BM from lung adenocarcinoma, the presence of EGFR mutations has been associated with improved survival from the time of development of BM (15-25 vs. 7 months).	('mutations', 'Var', (107, 116))	('presence', 'Var', (90, 98))	('patients', 'Species', '9606', (43, 51))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('improved', 'PosReg', (142, 150))	('EGFR', 'Gene', (102, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('EGFR', 'Gene', '1956', (102, 106))	('survival', 'MPA', (151, 159))	('lung adenocarcinoma', 'Disease', (65, 84))
33946	30214559	To the best of our knowledge, no previous study has reported an association between EGFR mutation and the site of BM.	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('mutation', 'Var', (89, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))
33947	30214559	Thus, the findings in the present study of a significant association between EGFR mutations and BM in the frontal lobe is novel.	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('mutations', 'Var', (82, 91))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))
33950	30214559	However, the present study indicated that the presence of EGFR mutations, BM within the frontal lobe and non-smoker status are additional independent prognostic factors.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))
33958	30214559	Despite these limitations, to the best of our knowledge, this is the first report to investigate the histopathological subtypes of BM from lung adenocarcinoma, and the association between these subtypes, EGFR mutations and disease prognosis in a large patient cohort.	('patient', 'Species', '9606', (252, 259))	('association', 'Interaction', (168, 179))	('lung adenocarcinoma', 'Disease', (139, 158))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (139, 158))	('EGFR', 'Gene', '1956', (204, 208))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (139, 158))	('mutations', 'Var', (209, 218))	('EGFR', 'Gene', (204, 208))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))
33959	30214559	In the present study, univariate analysis was used to demonstrated that three factors, EGFR mutation, BM localized to the frontal lobes and non-smoker status, may be used as prognostic indicators.	('EGFR', 'Gene', '1956', (87, 91))	('mutation', 'Var', (92, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('frontal lobes', 'Disease', 'MESH:D001927', (122, 135))	('EGFR', 'Gene', (87, 91))	('frontal lobes', 'Disease', (122, 135))
34048	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))	('patients', 'Species', '9606', (259, 267))	('tumor', 'Disease', (65, 70))	('lung adenocarcinoma', 'Disease', (289, 308))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (289, 308))	('patient', 'Species', '9606', (121, 128))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('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))
34056	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))	('promoting', 'PosReg', (170, 179))	('aggravate', 'PosReg', (142, 151))	('tumor', 'Disease', (152, 157))	('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))
34066	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', 'molecular_function', 'GO:0004229', ('56', '61'))	('MMP-9', 'Gene', (56, 61))	('changes', 'Var', (21, 28))	('alter', 'Reg', (66, 71))	('MMP-2', 'Gene', (46, 51))	('MMP-2', 'molecular_function', 'GO:0004228', ('46', '51'))	('wound-healing', 'biological_process', 'GO:0042060', ('114', '127'))	('expression', 'MPA', (32, 42))
34074	29755687	KRAS, BRAF and NRAS mutations were found in 335 (46%), 78 (11%) and 32 (4%) samples, respectively.	('KRAS', 'Gene', '3845', (0, 4))	('NRAS', 'Gene', (15, 19))	('BRAF', 'Gene', '673', (6, 10))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', (6, 10))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (20, 29))	('found', 'Reg', (35, 40))
34075	29755687	Moreover, mutations and amplifications in potentially actionable genes were identified in 464 samples (64%), including mutations in PIK3CA (14%), ERBB2 (0.4%), AKT1 (0.6%), and MAP2K1 (0.1%), as well as amplifications of ERBB2 (0.3%) and EGFR (0.3%).	('MAP2K1', 'Gene', '5604', (177, 183))	('amplifications', 'Var', (203, 217))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))	('MAP2K1', 'Gene', (177, 183))	('MAP2K', 'molecular_function', 'GO:0004708', ('177', '182'))	('AKT1', 'Gene', '207', (160, 164))	('EGFR', 'Gene', '1956', (238, 242))	('EGFR', 'Gene', (238, 242))	('ERBB2', 'Gene', (146, 151))	('AKT1', 'Gene', (160, 164))	('ERBB2', 'Gene', '2064', (146, 151))	('PIK3CA', 'Gene', (132, 138))	('mutations', 'Var', (10, 19))	('mutations', 'Var', (119, 128))	('ERBB2', 'Gene', (221, 226))	('PIK3CA', 'Gene', '5290', (132, 138))	('ERBB2', 'Gene', '2064', (221, 226))
34082	29755687	Until recently, indications for standard-of-care molecular testing in colorectal carcinomas included testing for KRAS mutational status as a predictor of response to anti-EGFR agents.	('EGFR', 'Gene', (171, 175))	('EGFR', 'molecular_function', 'GO:0005006', ('171', '175'))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (70, 91))	('KRAS', 'Gene', (113, 117))	('mutational status', 'Var', (118, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('KRAS', 'Gene', '3845', (113, 117))	('EGFR', 'Gene', '1956', (171, 175))	('colorectal carcinomas', 'Disease', (70, 91))
34084	29755687	Indeed, not only is the benefit of anti-EGFR therapy confined to RAS wild type (wt) tumors, but treatment with anti-EGFR antibodies may even harm patients with a RAS mutation.	('EGFR', 'Gene', '1956', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('EGFR', 'Gene', (116, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('harm', 'NegReg', (141, 145))	('RAS', 'Gene', (162, 165))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (146, 154))	('mutation', 'Var', (166, 174))
34085	29755687	BRAF mutation is a strong negative prognostic biomarker and evidence is accumulating that patients with a BRAF mutant tumor do not benefit from anti-EGFR therapy.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mutant', 'Var', (111, 117))	('BRAF', 'Gene', '673', (106, 110))	('EGFR', 'Gene', '1956', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (106, 110))	('tumor', 'Disease', (118, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('EGFR', 'Gene', (149, 153))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (90, 98))
34087	29755687	International efforts to catalogue mutations for multiple forms of cancer, coupled with the successes of targeted agents in patients with molecularly defined tumors, have generated enthusiasm for incorporating genomic profiling into clinical cancer practice.	('tumors', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patients', 'Species', '9606', (124, 132))	('mutations', 'Var', (35, 44))
34095	29755687	The most frequent mutations were found in TP53 (62%) and KRAS (46%) (Table 2 and Figure 3).	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))	('mutations', 'Var', (18, 27))
34096	29755687	Of successfully sequenced cases, 563 potentially actionable mutations were identified in 464 patients (64%), including 343 KRAS mutations, 32 NRAS mutations, 78 BRAF mutations, 101 PIK3CA mutations, 4 AKT1 mutations, 3 ERBB2 mutations, 1 EGFR mutation, and 1 MAP2K1 mutation.	('mutations', 'Var', (147, 156))	('NRAS', 'Gene', '4893', (142, 146))	('PIK3CA', 'Gene', (181, 187))	('EGFR', 'Gene', '1956', (238, 242))	('KRAS', 'Gene', (123, 127))	('patients', 'Species', '9606', (93, 101))	('MAP2K1', 'Gene', '5604', (259, 265))	('mutations', 'Var', (166, 175))	('MAP2K1', 'Gene', (259, 265))	('mutations', 'Var', (128, 137))	('AKT1', 'Gene', '207', (201, 205))	('NRAS', 'Gene', (142, 146))	('ERBB2', 'Gene', (219, 224))	('PIK3CA', 'Gene', '5290', (181, 187))	('AKT1', 'Gene', (201, 205))	('EGFR', 'Gene', (238, 242))	('mutations', 'Var', (188, 197))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('ERBB2', 'Gene', '2064', (219, 224))	('MAP2K', 'molecular_function', 'GO:0004708', ('259', '264'))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', '3845', (123, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))
34097	29755687	The frequencies of these variants detected by NGS were consistent with frequencies reported in public databases (www.cbioportal.org; http://cancer.sanger.ac.uk/cosmic).	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('variants', 'Var', (25, 33))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
34099	29755687	Furthermore, around 50% of cases showed KRAS and/or NRAS mutations for each category of tumor cell content (27/54 in cases with <10% tumor cell content; 278/553 in those with 10-50% tumor cells; or 59/117 in cases with >50% tumor cells).	('NRAS', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('NRAS', 'Gene', '4893', (52, 56))	('KRAS', 'Gene', (40, 44))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (133, 138))	('KRAS', 'Gene', '3845', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
34100	29755687	Using coverage analysis, potential EGFR or ERBB2 amplifications were suggested for 2 and 2 patients, respectively.	('ERBB2', 'Gene', '2064', (43, 48))	('patients', 'Species', '9606', (91, 99))	('ERBB2', 'Gene', (43, 48))	('amplifications', 'Var', (49, 63))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))
34107	29755687	We are able to identify potentially actionable mutations for 464 patients, most of them carrying KRAS and/or NRAS mutations (365).	('KRAS', 'Gene', (97, 101))	('mutations', 'Var', (114, 123))	('NRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (97, 101))	('NRAS', 'Gene', '4893', (109, 113))	('patients', 'Species', '9606', (65, 73))
34108	29755687	According to international guidelines, the presence of a RAS mutation is a contraindication to anti-EGFR therapy.	('RAS', 'Gene', (57, 60))	('EGFR', 'Gene', '1956', (100, 104))	('mutation', 'Var', (61, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('EGFR', 'Gene', (100, 104))
34109	29755687	Nevertheless, the discovery of particular mutations in rare genes can cause a change in the treatment of the patient by including him/her in a clinical trial or medical need program.	('patient', 'Species', '9606', (109, 116))	('change', 'Reg', (78, 84))	('mutations', 'Var', (42, 51))	('cause', 'Reg', (70, 75))
34116	29755687	Briefly, 10 ng of DNA was amplified using the Colon and Lung Cancer panel (Ampliseq , Life Technologies) in order to sequence 1825 hotspot mutations in 22 genes (90 amplicons) including AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, TP53.	('FGFR2', 'Gene', (251, 256))	('MAP2K1', 'Gene', (271, 277))	('STK11', 'molecular_function', 'GO:0033868', ('319', '324'))	('FGFR', 'molecular_function', 'GO:0005007', ('244', '248'))	('ERBB4', 'Gene', (230, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('CTNNB1', 'Gene', (203, 209))	('ERBB2', 'Gene', (223, 228))	('Colon and Lung Cancer', 'Disease', 'MESH:D008175', (46, 67))	('TP53', 'Gene', '7157', (326, 330))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('FGFR2', 'Gene', '2263', (251, 256))	('Lung Cancer', 'Phenotype', 'HP:0100526', (56, 67))	('EGFR', 'Gene', (217, 221))	('PTEN', 'Gene', (306, 310))	('NRAS', 'Gene', '4893', (292, 296))	('PIK3CA', 'Gene', (298, 304))	('NOTCH1', 'Gene', (284, 290))	('AKT1', 'Gene', '207', (186, 190))	('KRAS', 'Gene', '3845', (265, 269))	('FGFR3', 'Gene', (258, 263))	('ERBB2', 'Gene', '2064', (223, 228))	('FGFR1', 'Gene', (244, 249))	('FBXW7', 'Gene', (237, 242))	('ALK', 'Gene', '238', (192, 195))	('DDR2', 'Gene', '4921', (211, 215))	('FGFR3', 'Gene', '2261', (258, 263))	('FGFR', 'molecular_function', 'GO:0005007', ('258', '262'))	('SMAD4', 'Gene', (312, 317))	('STK11', 'Gene', (319, 324))	('BRAF', 'Gene', (197, 201))	('KRAS', 'Gene', (265, 269))	('ALK', 'Gene', (192, 195))	('PTEN', 'Gene', '5728', (306, 310))	('NOTCH1', 'Gene', '4851', (284, 290))	('BRAF', 'Gene', '673', (197, 201))	('AKT1', 'Gene', (186, 190))	('CTNNB1', 'Gene', '1499', (203, 209))	('NRAS', 'Gene', (292, 296))	('FGFR', 'molecular_function', 'GO:0005007', ('251', '255'))	('TP53', 'Gene', (326, 330))	('EGFR', 'Gene', '1956', (217, 221))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (139, 148))	('FBXW7', 'Gene', '55294', (237, 242))	('DDR2', 'Gene', (211, 215))	('PIK3CA', 'Gene', '5290', (298, 304))	('STK11', 'Gene', '6794', (319, 324))	('MAP2K1', 'Gene', '5604', (271, 277))	('SMAD4', 'Gene', '4089', (312, 317))	('MAP2K', 'molecular_function', 'GO:0004708', ('271', '276'))	('FGFR1', 'Gene', '2260', (244, 249))	('ERBB4', 'Gene', '2066', (230, 235))
34127	29214456	A 66-year-old woman underwent thoracoscopic left lower lobectomy with lymph node dissection for pT1aN0M0 adenocarcinoma of the lung.	('adenocarcinoma of the lung', 'Disease', (105, 131))	('woman', 'Species', '9606', (14, 19))	('pT1aN0M0', 'Var', (96, 104))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (105, 131))
34169	28903410	We found that low RASSF6 expression corresponds to a poor prognosis in colorectal cancer patients, and low RASSF6 expression is distinctly associated with tumour progression.	('low', 'Var', (103, 106))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (25, 35))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('low', 'NegReg', (14, 17))	('patients', 'Species', '9606', (89, 97))	('associated', 'Reg', (139, 149))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('RASSF6', 'Gene', (18, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('tumour', 'Disease', (155, 161))
34170	28903410	Our in vitro analysis revealed that RASSF6 suppresses the proliferation and metastasis of DLD1 cells, and RASSF6 knockdown in HCT116 cells confirmed these observations.	('RASSF6', 'Gene', (36, 42))	('HCT116', 'CellLine', 'CVCL:0291', (126, 132))	('suppresses', 'NegReg', (43, 53))	('RASSF6', 'Gene', (106, 112))	('knockdown', 'Var', (113, 122))
34171	28903410	Our mechanistic investigation revealed that RASSF6 inhibits the expression of the classical target genes of Wnt signalling, as demonstrated by the reduced expression of TCF1, c-Jun, and c-Myc in RASSF6-overexpressing DLD1 stable cell lines.	('expression', 'MPA', (64, 74))	('signalling', 'biological_process', 'GO:0023052', ('112', '122'))	('inhibits', 'NegReg', (51, 59))	('c-Myc', 'Gene', '4609', (186, 191))	('c-Jun', 'Gene', '3725', (175, 180))	('expression', 'MPA', (155, 165))	('c-Myc', 'Gene', (186, 191))	('TCF1', 'Gene', (169, 173))	('c-Jun', 'Gene', (175, 180))	('RASSF6', 'Var', (44, 50))	('reduced', 'NegReg', (147, 154))	('TCF1', 'Gene', '6932', (169, 173))
34173	28903410	Additionally, rescue assays revealed that the activation of Wnt signalling by LiCl treatment impaired the inhibitory effect of RASSF6 on the proliferation and metastasis of colorectal cancer cells, which implies that RASSF6 suppresses the tumorigenicity of colorectal cancer cells at least in part through inhibiting Wnt signalling pathway.	('RASSF6', 'Var', (217, 223))	('impaired', 'NegReg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inhibiting', 'NegReg', (306, 316))	('Wnt signalling pathway', 'Pathway', (317, 339))	('colorectal cancer', 'Disease', (257, 274))	('inhibitory effect', 'MPA', (106, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('LiCl', 'Chemical', 'MESH:D018021', (78, 82))	('signalling pathway', 'biological_process', 'GO:0007165', ('321', '339'))	('tumor', 'Disease', (239, 244))	('suppresses', 'NegReg', (224, 234))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (257, 274))	('colorectal cancer', 'Disease', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('signalling', 'biological_process', 'GO:0023052', ('64', '74'))	('colorectal cancer', 'Disease', 'MESH:D015179', (257, 274))
34188	28903410	Despite a previous study indicating that RASSF6 inhibits cell growth and migration in HT29 and Lovo cell lines, further underlying mechanisms is needed to determine how RASSF6 suppress proliferation and metastasis in CRC, and to determine whether the expression level of RASSF6 correlates with the prognosis of CRC patients.	('proliferation', 'CPA', (185, 198))	('HT29', 'CellLine', 'CVCL:0320', (86, 90))	('RASSF6', 'Var', (41, 47))	('suppress', 'NegReg', (176, 184))	('inhibits', 'NegReg', (48, 56))	('CRC', 'Disease', (311, 314))	('CRC', 'Phenotype', 'HP:0003003', (217, 220))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('patients', 'Species', '9606', (315, 323))	('CRC', 'Phenotype', 'HP:0003003', (311, 314))	('CRC', 'Disease', (217, 220))	('RASSF6', 'Gene', (169, 175))
34190	28903410	Previous studies have demonstrated that the dysregulation of the Wnt pathway is involved in many types malignant tumours and is an important regulator of biological processes, such as cell growth, migration and EMT process.	('malignant tumours', 'Disease', (103, 120))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('cell growth', 'biological_process', 'GO:0016049', ('184', '195'))	('dysregulation', 'Var', (44, 57))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('EMT', 'biological_process', 'GO:0001837', ('211', '214'))	('Wnt pathway', 'Pathway', (65, 76))	('involved', 'Reg', (80, 88))	('malignant tumours', 'Disease', 'MESH:D009369', (103, 120))
34192	28903410	In the present study, we first determined the expression level of RASSF6 in eight CRC cell lines and in patient tissues, and we then investigated potential mechanisms to elucidate how RASSF6 inhibits CRC progression.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('CRC', 'Disease', (200, 203))	('RASSF6', 'Var', (184, 190))	('inhibits', 'NegReg', (191, 199))	('RASSF6', 'Gene', (66, 72))	('patient', 'Species', '9606', (104, 111))	('CRC', 'Phenotype', 'HP:0003003', (200, 203))
34223	28903410	Results showed that both the weight and volume of tumours were significantly decreased in the RASSF6 group compared with the Vector group (Figure 5A and 5B).	('volume of tumours', 'Disease', (40, 57))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('RASSF6', 'Var', (94, 100))	('volume of tumours', 'Disease', 'MESH:D009369', (40, 57))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('decreased', 'NegReg', (77, 86))
34239	28903410	Secondly, except for negative correlation between RASSF6 expression and advanced TNM stage, we also found that low RASSF6 expression was significantly associated with tumour size (p = 0.042), lymph node status (p < 0.001), and the presence of distant metastasis (p < 0.001, Table 1), which provided more powerful evidence that RASSF6 suppresses CRC proliferation and metastasis.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('expression', 'MPA', (122, 132))	('TNM', 'Gene', (81, 84))	('lymph node status', 'CPA', (192, 209))	('tumour', 'Disease', (167, 173))	('RASSF6', 'Var', (327, 333))	('distant metastasis', 'CPA', (243, 261))	('RASSF6', 'Gene', (115, 121))	('TNM', 'Gene', '10178', (81, 84))	('CRC', 'Phenotype', 'HP:0003003', (345, 348))	('CRC proliferation', 'CPA', (345, 362))	('low', 'NegReg', (111, 114))	('suppresses', 'NegReg', (334, 344))
34240	28903410	Addtionally, we first established both hepatic and lung metastasis models to demonstrate that RASSF6 inhibits metastasis of CRC cell lines in vivo to further confirm the role of RASSF6 in CRC (Figure 5E-5H), which has not been reported before.	('hepatic and lung metastasis', 'Disease', 'MESH:D009362', (39, 66))	('CRC', 'Phenotype', 'HP:0003003', (188, 191))	('metastasis of CRC cell lines', 'CPA', (110, 138))	('RASSF6', 'Var', (94, 100))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('CRC', 'Disease', (188, 191))	('inhibits', 'NegReg', (101, 109))
34241	28903410	To the best of our knowledge, our study first emphasized the role of RASSF6 in predicting the prognosis of CRC patients, discovered that RASSF6 suppresses EMT process, and inhibits tumorigenesis of CRC at least in part, through suppressing Wnt signaling pathway.	('tumor', 'Disease', (181, 186))	('EMT', 'biological_process', 'GO:0001837', ('155', '158'))	('inhibits', 'NegReg', (172, 180))	('CRC', 'Disease', (198, 201))	('Wnt signaling pathway', 'Pathway', (240, 261))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('suppresses', 'NegReg', (144, 154))	('EMT process', 'CPA', (155, 166))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('240', '261'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('suppressing', 'NegReg', (228, 239))	('RASSF6', 'Var', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))	('patients', 'Species', '9606', (111, 119))
34245	28903410	Moreover, to further validate whether RASSF6 indeed inhibits CRC tumorigenesis by modulating the Wnt pathway, we also performed rescue assays by treating cells with the Wnt activator LiCl.	('modulating', 'Reg', (82, 92))	('RASSF6', 'Var', (38, 44))	('tumor', 'Disease', (65, 70))	('inhibits', 'NegReg', (52, 60))	('CRC', 'Disease', (61, 64))	('LiCl', 'Chemical', 'MESH:D018021', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Wnt pathway', 'Pathway', (97, 108))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
34248	28903410	Dysregulated Wnt signalling is widely implicated in various malignancies, especially in colorectal cancer, and this leads to cell changes that influence a vast array of biological processes, including embryonic development, cell proliferation, cell migration, stem cell maintenance, and tumourigenesis.	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('signalling', 'biological_process', 'GO:0023052', ('17', '27'))	('cell migration', 'CPA', (244, 258))	('cell proliferation', 'biological_process', 'GO:0008283', ('224', '242'))	('colorectal cancer', 'Disease', (88, 105))	('cell proliferation', 'CPA', (224, 242))	('influence', 'Reg', (143, 152))	('Dysregulated', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('tumour', 'Disease', 'MESH:D009369', (287, 293))	('tumour', 'Disease', (287, 293))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('implicated', 'Reg', (38, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('leads to', 'Reg', (116, 124))	('malignancies', 'Disease', (60, 72))	('embryonic development', 'CPA', (201, 222))	('stem cell maintenance', 'CPA', (260, 281))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cell migration', 'biological_process', 'GO:0016477', ('244', '258'))
34249	28903410	Given that RASSF6 inhibiting Wnt signalling in CRC, we suspect that RASSF6 may also involve in other biological processes in CRC, such as stem cell maintenance, angiogenesis, and anti-tumour drug resistance, all of which require further investigation in future studies.	('drug resistance', 'biological_process', 'GO:0009315', ('191', '206'))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('RASSF6', 'Var', (11, 17))	('signalling', 'biological_process', 'GO:0023052', ('33', '43'))	('drug resistance', 'biological_process', 'GO:0042493', ('191', '206'))	('involve', 'Reg', (84, 91))	('RASSF6', 'Gene', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('angiogenesis', 'biological_process', 'GO:0001525', ('161', '173'))	('inhibiting', 'NegReg', (18, 28))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('drug resistance', 'Phenotype', 'HP:0020174', (191, 206))	('Wnt signalling', 'MPA', (29, 43))	('tumour', 'Disease', (184, 190))
34250	28903410	Additionally, the canonical target genes mediate the effects of Wnt signalling in normal and diseased cells, and RASSF6 overexpression led to a distinct reduction in the Wnt signalling target genes c-Myc, c-Jun, and TCF1, along with a decrease in cell growth and motility; however, the specific target genes that mediate the ability of RASSF6 to act as a tumour suppressor in CRC have not been elucidated.	('RASSF6', 'Gene', (113, 119))	('signalling', 'biological_process', 'GO:0023052', ('68', '78'))	('motility', 'CPA', (263, 271))	('cell growth', 'CPA', (247, 258))	('decrease', 'NegReg', (235, 243))	('CRC', 'Disease', (376, 379))	('TCF1', 'Gene', '6932', (216, 220))	('CRC', 'Phenotype', 'HP:0003003', (376, 379))	('signalling', 'biological_process', 'GO:0023052', ('174', '184'))	('c-Myc', 'Gene', (198, 203))	('overexpression', 'Var', (120, 134))	('c-Jun', 'Gene', '3725', (205, 210))	('TCF1', 'Gene', (216, 220))	('reduction', 'NegReg', (153, 162))	('c-Myc', 'Gene', '4609', (198, 203))	('c-Jun', 'Gene', (205, 210))	('tumour', 'Phenotype', 'HP:0002664', (355, 361))	('tumour', 'Disease', 'MESH:D009369', (355, 361))	('tumour', 'Disease', (355, 361))	('cell growth', 'biological_process', 'GO:0016049', ('247', '258'))
34252	28903410	For example, in melanoma, RASSF6 suppresses MAPK activation; whether RASSF6 also inhibits MAPK signalling in CRC, and whether Wnt is the primary mechanism that mediates the regulation of RASSF6 in CRC remains to be determined.	('inhibits', 'NegReg', (81, 89))	('suppresses', 'NegReg', (33, 43))	('MAPK', 'Gene', '5594', (90, 94))	('MAPK activation', 'biological_process', 'GO:0000187', ('44', '59'))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('90', '105'))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('melanoma', 'Disease', (16, 24))	('MAPK', 'Gene', (90, 94))	('MAPK', 'Gene', '5594', (44, 48))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('RASSF6', 'Var', (26, 32))	('MAPK', 'Gene', (44, 48))	('regulation', 'biological_process', 'GO:0065007', ('173', '183'))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
34319	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))
34345	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))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('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))
34346	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 suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('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))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('tumor', 'Disease', (136, 141))	('pathogenesis', 'biological_process', 'GO:0009405', ('109', '121'))
34350	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))
34377	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))
34394	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))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('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))
34395	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))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))
34397	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))
34413	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))
34434	27442668	According to clinical trials of anti-PD-1 antibodies, adverse events, such as interstitial pneumonia, endocrine system dysfunction, and liver damage that were different from those of cytotoxic chemotherapies, were reported.	('endocrine system dysfunction', 'Disease', 'MESH:D004700', (102, 130))	('endocrine system dysfunction', 'Disease', (102, 130))	('endocrine system dysfunction', 'Phenotype', 'HP:0000818', (102, 130))	('pneumonia', 'Phenotype', 'HP:0002090', (91, 100))	('liver damage', 'Disease', (136, 148))	('liver damage', 'Disease', 'MESH:D056486', (136, 148))	('interstitial pneumonia', 'Disease', (78, 100))	('antibodies', 'Var', (42, 52))	('interstitial pneumonia', 'Disease', 'MESH:D017563', (78, 100))	('anti-PD-1', 'Gene', (32, 41))
34451	27442668	As the patient had a nonmutated BRAF gene, the patient was started on intravenous administration of nivolumab (2 mg/kg, every 3 weeks) from September 2014.	('BRAF', 'Gene', '673', (32, 36))	('patient', 'Species', '9606', (47, 54))	('nonmutated', 'Var', (21, 31))	('patient', 'Species', '9606', (7, 14))	('BRAF', 'Gene', (32, 36))	('nivolumab', 'Chemical', 'MESH:D000077594', (100, 109))
34462	27442668	On close investigation, there were no findings of gastrointestinal bleeding on endoscopy, hemolytic anemia (haptoglobin 75 mg/dL, direct Coomb test negative), iron deficiency anemia (serum-iron 74 mug/dL, ferritin 1284 ng/mL), vitamin deficiency anemia (vitamin B12 329 pg/mL, folic acid 5.6 ng/mL), autoimmune disease (anti-nuclear antibody plus or minus, double-strand DNA negative), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), or infection.	('hemolytic anemia', 'Disease', (90, 106))	('Coomb test negative', 'Phenotype', 'HP:0004844', (137, 156))	('DIC', 'Phenotype', 'HP:0005521', (426, 429))	('infection', 'Disease', (478, 487))	('infection', 'Disease', 'MESH:D007239', (478, 487))	('anemia', 'Phenotype', 'HP:0001903', (246, 252))	('autoimmune disease', 'Disease', (300, 318))	('antibody', 'molecular_function', 'GO:0003823', ('333', '341'))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (50, 75))	('disseminated intravascular coagulation', 'Phenotype', 'HP:0005521', (386, 424))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (159, 181))	('autoimmune disease', 'Disease', 'MESH:D001327', (300, 318))	('thrombotic thrombocytopenic purpura', 'Disease', (432, 467))	('gastrointestinal bleeding', 'Disease', (50, 75))	('antibody', 'cellular_component', 'GO:0042571', ('333', '341'))	('thrombotic thrombocytopenic purpura', 'Disease', 'MESH:D011697', (432, 467))	('deficiency anemia', 'Disease', 'MESH:D000740', (235, 252))	('deficiency anemia', 'Disease', 'MESH:D000740', (164, 181))	('intravascular coagulation', 'Disease', (399, 424))	('autoimmune disease', 'Phenotype', 'HP:0002960', (300, 318))	('thrombotic thrombocytopenic purpura', 'Phenotype', 'HP:0001973', (432, 467))	('anemia', 'Phenotype', 'HP:0001903', (100, 106))	('antibody', 'cellular_component', 'GO:0019815', ('333', '341'))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (90, 106))	('DNA', 'cellular_component', 'GO:0005574', ('371', '374'))	('purpura', 'Phenotype', 'HP:0000979', (460, 467))	('iron deficiency anemia', 'Disease', (159, 181))	('hemolytic anemia', 'Disease', 'MESH:D000743', (90, 106))	('mug', 'molecular_function', 'GO:0043739', ('197', '200'))	('deficiency anemia', 'Disease', (235, 252))	('intravascular coagulation', 'Disease', 'MESH:D004211', (399, 424))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (159, 181))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (50, 75))	('anti-nuclear', 'Var', (320, 332))	('antibody', 'cellular_component', 'GO:0019814', ('333', '341'))	('coagulation', 'biological_process', 'GO:0050817', ('413', '424'))	('anemia', 'Phenotype', 'HP:0001903', (175, 181))
34476	27442668	Immune checkpoint inhibitors, anti-CTLA-4 antibody and anti-PD-1 antibodies, have shown good results for the treatment of advanced malignant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('CTLA-4', 'Gene', (35, 41))	('malignant melanoma', 'Phenotype', 'HP:0002861', (131, 149))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('anti-PD-1', 'Var', (55, 64))	('malignant melanoma', 'Disease', (131, 149))	('CTLA-4', 'Gene', '1493', (35, 41))	('malignant melanoma', 'Disease', 'MESH:D008545', (131, 149))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))
34508	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))
34533	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))
34573	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))
34577	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))
34715	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))	('DM', 'Disease', 'MESH:D009223', (34, 36))	('tumor', 'Disease', (86, 91))	('DM0', 'Chemical', '-', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('pPM0', 'Var', (100, 104))
34921	27301828	Here we examined protein and gene expression from the Cancer Genome and Proteome Atlases (TCGA and TCPA) to characterize proteins and protein-coding genes that are selectively upregulated in KRAS-mutant lung adenocarcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (203, 223))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (203, 223))	('KRAS-mutant', 'Var', (191, 202))	('Cancer', 'Disease', (54, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('TCPA', 'Chemical', '-', (99, 103))	('lung adenocarcinomas', 'Disease', (203, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('upregulated', 'PosReg', (176, 187))
34923	27301828	Co-occurring mutations in KRAS-mutants were associated with differential activation of PDK1 and PKC-alpha.	('activation', 'PosReg', (73, 83))	('KRAS-mutants', 'Gene', (26, 38))	('PKC', 'molecular_function', 'GO:0004697', ('96', '99'))	('PKC-alpha', 'Gene', (96, 105))	('PKC-alpha', 'Gene', '5578', (96, 105))	('PDK1', 'molecular_function', 'GO:0004740', ('87', '91'))	('PDK1', 'Gene', '5163', (87, 91))	('PDK1', 'Gene', (87, 91))	('mutations', 'Var', (13, 22))
34928	27301828	They also have identified pathways or processes further downstream from Ras proteins that are involved in malignant phenotypes induced by mutant RAS genes, including the NF-kappaB pathway, transcriptional activity of the oncogene YAP, generation of reactive oxygen species, and anabolic glucose metabolism.	('YAP', 'Gene', (230, 233))	('RAS genes', 'Gene', (145, 154))	('mutant', 'Var', (138, 144))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (249, 272))	('NF-kappaB', 'Gene', '4790', (170, 179))	('anabolic glucose metabolism', 'MPA', (278, 305))	('glucose', 'Chemical', 'MESH:D005947', (287, 294))	('YAP', 'Gene', '10413', (230, 233))	('glucose metabolism', 'biological_process', 'GO:0006006', ('287', '305'))	('involved', 'Reg', (94, 102))	('NF-kappaB', 'Gene', (170, 179))
34929	27301828	A third class of proposed oncogenic mediators of mutant RAS genes are induced secreted proteins including TGF-alpha, Vegf, IL-8, IL-6, CXCL1, and CCL5.	('CCL', 'molecular_function', 'GO:0044101', ('146', '149'))	('IL-8', 'Gene', '3576', (123, 127))	('mutant', 'Var', (49, 55))	('IL-6', 'Gene', (129, 133))	('CCL5', 'Gene', (146, 150))	('Vegf', 'Gene', '7422', (117, 121))	('IL-8', 'Gene', (123, 127))	('IL-6', 'molecular_function', 'GO:0005138', ('129', '133'))	('Vegf', 'Gene', (117, 121))	('IL-6', 'Gene', '3569', (129, 133))	('CCL5', 'Gene', '6352', (146, 150))	('IL-8', 'molecular_function', 'GO:0005153', ('123', '127'))	('CXCL1', 'Gene', '2919', (135, 140))	('RAS genes', 'Gene', (56, 65))	('CXCL1', 'Gene', (135, 140))
34930	27301828	Several members of these three classes of mediators of oncogenic Ras have been explored as potential therapeutic targets but as of yet there hasn't been a clinically successful treatment developed for cancers with mutant RAS genes.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('mutant', 'Var', (214, 220))	('RAS', 'Gene', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))
34931	27301828	The recent completion of large-scale human cancer sample characterizations such as the Cancer Genome Atlas (TCGA) and the Cancer Proteome Atlas (TCPA) has enabled an altogether different approach for discovery of protein targets that are upregulated by mutant RAS genes.	('Cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('TCPA', 'Chemical', '-', (145, 149))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (43, 49))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('Cancer Proteome Atlas', 'Disease', (122, 143))	('Cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('human', 'Species', '9606', (37, 42))	('upregulated', 'PosReg', (238, 249))	('RAS', 'Gene', (260, 263))	('mutant', 'Var', (253, 259))	('Cancer Proteome Atlas', 'Disease', 'MESH:D009369', (122, 143))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))
34932	27301828	This approach uses a direct comparison of tumor samples containing mutant RAS genes with either corresponding normal tissue samples or with tumor samples that contain wild-type RAS genes.	('tumor', 'Disease', (42, 47))	('RAS genes', 'Gene', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mutant', 'Var', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (140, 145))
34937	27301828	These three subtypes have both distinct RNA expression profiles and different patterns of co-occurring mutations in TP53, STK11, KEAP1, and others.	('STK11', 'molecular_function', 'GO:0033868', ('122', '127'))	('TP53', 'Gene', (116, 120))	('mutations', 'Var', (103, 112))	('STK11', 'Gene', (122, 127))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('STK11', 'Gene', '6794', (122, 127))	('KEAP1', 'Gene', '9817', (129, 134))	('TP53', 'Gene', '7157', (116, 120))	('KEAP1', 'Gene', (129, 134))
34938	27301828	In this study, we analyzed genomic and proteomic data from human lung adenocarcinomas to examine the strength and variability of mutant-KRAS activation of proteins and genes.	('human', 'Species', '9606', (59, 64))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (65, 85))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (65, 85))	('mutant-KRAS', 'Var', (129, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('lung adenocarcinomas', 'Disease', (65, 85))	('activation', 'PosReg', (141, 151))
34939	27301828	KRAS-mutants were compared to other lung adenocarcinoma samples and were also examined for the effects of commonly co-occurring mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (36, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('lung adenocarcinoma', 'Disease', (36, 55))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (36, 55))	('KRAS-mutants', 'Var', (0, 12))
34940	27301828	230 lung adenocarcinoma samples have been comprehensively characterized for mutations and gene expression by TCGA and these same samples have been characterized by reverse-phase protein array (RPPA) for their levels of 160 different proteins and modified proteins.	('lung adenocarcinoma', 'Disease', (4, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('mutations', 'Var', (76, 85))	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('TCGA', 'Gene', (109, 113))	('gene expression', 'MPA', (90, 105))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
34941	27301828	To determine the selective effects of mutational activation of KRAS on these proteins in lung adenocarcinomas, we compared KRAS-mutant tumors (n = 75) to other tumors with wild-type KRAS.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (89, 109))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('KRAS-mutant', 'Var', (123, 134))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (160, 166))	('lung adenocarcinomas', 'Disease', (89, 109))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (89, 109))	('mutational', 'Var', (38, 48))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
34942	27301828	We further divided tumors with wild-type KRAS into those with other mutations in components of the mitogenic RTK/RAF/MAPK pathway and those without, using the criteria found in the TCGA publication.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('RAF', 'Gene', '22882', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutations', 'Var', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('RAF', 'Gene', (113, 116))
34943	27301828	The other activating mutations in the RTK/RAF/MAPK pathway strongly tended toward mutual exclusivity and included missense or inframe deletion mutations in EGFR (n = 26), ERBB2 (n = 4), or RIT1 (n = 5); inactivating mutations in NF1 (n = 19); missense mutations in BRAF (n = 16), MAP2K1 (n = 2), HRAS (n = 1), or NRAS (n = 1); exon 14 skipping mutations in MET (n = 10), gene fusions involving ROS1 (n = 4), ALK (n = 3), or RET (n = 2); and focal high-level amplification of ERBB2 (n = 5), or MET (n = 5).	('inactivating mutations', 'Var', (203, 225))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('RAF', 'Gene', '22882', (42, 45))	('NF1', 'Gene', '4763', (229, 232))	('activating', 'PosReg', (10, 20))	('missense', 'Var', (114, 122))	('ROS1', 'Gene', '6098', (394, 398))	('ALK', 'Gene', '238', (408, 411))	('MET', 'Gene', (493, 496))	('RET', 'Gene', (424, 427))	('RAF', 'Gene', (42, 45))	('NF1', 'Gene', (229, 232))	('MET', 'Gene', (357, 360))	('ALK', 'Gene', (408, 411))	('EGFR', 'Gene', '1956', (156, 160))	('BRAF', 'Gene', '673', (265, 269))	('MAP2K', 'molecular_function', 'GO:0004708', ('280', '285'))	('ERBB2', 'Gene', (475, 480))	('RIT1', 'Gene', '6016', (189, 193))	('skipping', 'NegReg', (335, 343))	('HRAS', 'Gene', '3265', (296, 300))	('NRAS', 'Gene', '4893', (313, 317))	('ERBB2', 'Gene', (171, 176))	('ROS1', 'Gene', (394, 398))	('HRAS', 'Gene', (296, 300))	('RAF', 'Gene', '22882', (266, 269))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('ERBB2', 'Gene', '2064', (475, 480))	('mutations', 'Var', (21, 30))	('missense mutations', 'Var', (243, 261))	('MAP2K1', 'Gene', '5604', (280, 286))	('ERBB2', 'Gene', '2064', (171, 176))	('RET', 'Gene', '5979', (424, 427))	('exon', 'Var', (327, 331))	('MAP2K1', 'Gene', (280, 286))	('EGFR', 'Gene', (156, 160))	('RAF', 'Gene', (266, 269))	('RIT1', 'Gene', (189, 193))	('NRAS', 'Gene', (313, 317))	('BRAF', 'Gene', (265, 269))
34944	27301828	We performed pairwise analysis of the three tumor subsets: KRAS mutants, other RTK/RAF/MAPK mutants, and all others.	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('KRAS', 'Gene', (59, 63))	('RAF', 'Gene', '22882', (83, 86))	('RAF', 'Gene', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutants', 'Var', (64, 71))	('tumor', 'Disease', (44, 49))
34945	27301828	Of all the 160 measured modified proteins and native proteins, the top ranking change in KRAS-mutant tumors when compared to either group of wild-type KRAS tumors is activation of MEK1, as judged by increased levels detected by the anti-phospho-serine 218,222 MEK1 antibody used by TCPA (Fig.	('serine', 'Chemical', 'MESH:D012694', (245, 251))	('TCPA', 'Chemical', '-', (282, 286))	('antibody', 'cellular_component', 'GO:0019815', ('265', '273'))	('MEK1', 'Gene', '5604', (260, 264))	('KRAS tumors', 'Disease', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('antibody', 'cellular_component', 'GO:0019814', ('265', '273'))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('MEK1', 'Gene', (180, 184))	('MEK1', 'molecular_function', 'GO:0004708', ('260', '264'))	('MEK1', 'molecular_function', 'GO:0004708', ('180', '184'))	('antibody', 'molecular_function', 'GO:0003823', ('265', '273'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('MEK1', 'Gene', (260, 264))	('KRAS-mutant', 'Gene', (89, 100))	('KRAS-mutant', 'Var', (89, 100))	('antibody', 'cellular_component', 'GO:0042571', ('265', '273'))	('increased', 'PosReg', (199, 208))	('tumors', 'Disease', (156, 162))	('tumors', 'Disease', (101, 107))	('activation', 'PosReg', (166, 176))	('KRAS tumors', 'Disease', 'MESH:D009369', (151, 162))	('MEK1', 'Gene', '5604', (180, 184))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
34946	27301828	Also increased in both comparisons of KRAS-mutant tumors was activation of mTOR as determined by phosphorylation at serine 2448 (Fig.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('activation', 'PosReg', (61, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('KRAS-mutant', 'Var', (38, 49))	('increased', 'PosReg', (5, 14))	('phosphorylation at serine 2448', 'MPA', (97, 127))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('serine', 'Chemical', 'MESH:D012694', (116, 122))
34947	27301828	However, both PDK1 and AKT kinases, which might be expected to be upregulated in KRAS-mutant lung cancers due to Kras protein interaction with PI3-kinase, did not show any significant phosphorylation activation in KRAS-mutant tumors (Supplementary Table 1).	('Kras', 'Gene', (113, 117))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('PDK1', 'Gene', (14, 18))	('AKT', 'Gene', (23, 26))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interaction', 'Interaction', (126, 137))	('upregulated', 'PosReg', (66, 77))	('PDK1', 'molecular_function', 'GO:0004740', ('14', '18'))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('phosphorylation', 'biological_process', 'GO:0016310', ('184', '199'))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('AKT', 'Gene', '207', (23, 26))	('PDK1', 'Gene', '5163', (14, 18))	('KRAS-mutant', 'Gene', (81, 92))	('KRAS-mutant', 'Var', (81, 92))	('lung cancers', 'Disease', 'MESH:D008175', (93, 105))	('tumors', 'Disease', (226, 232))	('Kras', 'Gene', '3845', (113, 117))	('lung cancers', 'Disease', (93, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('lung cancers', 'Phenotype', 'HP:0100526', (93, 105))
34949	27301828	We did not observe any activation of NF-kappab in human KRAS-mutant lung adenocarcinomas; in fact, NF-kappab activation was significantly lower in KRAS-mutant tumors compared to other Raf/MAPK mutant tumors (Supplementary Table 1).	('NF-kappab activation', 'MPA', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('lower', 'NegReg', (138, 143))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('human', 'Species', '9606', (50, 55))	('Raf', 'Gene', (184, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (68, 88))	('KRAS-mutant', 'Var', (147, 158))	('NF-kappab activation', 'biological_process', 'GO:0051092', ('99', '119'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Raf', 'Gene', '22882', (184, 187))	('activation of NF-kappab', 'biological_process', 'GO:0051092', ('23', '46'))	('MAPK', 'molecular_function', 'GO:0004707', ('188', '192'))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (68, 88))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('lung adenocarcinomas', 'Disease', (68, 88))	('tumors', 'Disease', (200, 206))
34950	27301828	We next extended our comparative protein analysis to look within the group with other mutations in the RTK/RAF/MAPK pathway.	('mutations', 'Var', (86, 95))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('RAF', 'Gene', '22882', (107, 110))	('RAF', 'Gene', (107, 110))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))
34951	27301828	The subgroups with sufficiently large numbers for statistical analysis included EGFR mutants (n = 26), NF1 mutants (n = 19), MET mutants (n = 15), and BRAF mutants (n = 16).	('NF1', 'Gene', '4763', (103, 106))	('mutants', 'Var', (107, 114))	('BRAF', 'Gene', '673', (151, 155))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('mutants', 'Var', (156, 163))	('BRAF', 'Gene', (151, 155))	('mutants', 'Var', (85, 92))	('NF1', 'Gene', (103, 106))
34952	27301828	Notably, the phosphorylation activation of EGFR and HER2 proteins was significantly higher in EGFR mutants, but there was also increased phosphorylation of RET protein and decreased phosphorylation of HER3 and MET proteins (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('HER3', 'Gene', (201, 205))	('MET proteins', 'Protein', (210, 222))	('phosphorylation', 'MPA', (137, 152))	('mutants', 'Var', (99, 106))	('EGFR', 'Gene', (43, 47))	('higher', 'PosReg', (84, 90))	('HER2', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (94, 98))	('phosphorylation', 'MPA', (182, 197))	('phosphorylation activation', 'MPA', (13, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('HER3', 'Gene', '2065', (201, 205))	('RET', 'Gene', '5979', (156, 159))	('EGFR', 'Gene', '1956', (43, 47))	('HER2', 'Gene', '2064', (52, 56))	('decreased', 'NegReg', (172, 181))	('EGFR', 'Gene', (94, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('RET', 'Gene', (156, 159))	('increased', 'PosReg', (127, 136))	('phosphorylation', 'biological_process', 'GO:0016310', ('182', '197'))
34953	27301828	MET mutants on the other hand showed opposite effects, with significant increased phosphorylation of MET protein but decreased phosphorylation of EGFR, HER2, and RET (Fig.	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('increased', 'PosReg', (72, 81))	('mutants', 'Var', (4, 11))	('phosphorylation', 'MPA', (82, 97))	('HER2', 'Gene', (152, 156))	('phosphorylation', 'MPA', (127, 142))	('EGFR', 'Gene', '1956', (146, 150))	('HER2', 'Gene', '2064', (152, 156))	('decreased', 'NegReg', (117, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('EGFR', 'Gene', (146, 150))	('RET', 'Gene', '5979', (162, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('MET protein', 'Protein', (101, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('RET', 'Gene', (162, 165))
34954	27301828	NF1 mutants also showed decreased phosphorylation of EGFR, HER2, and RET proteins (Fig.	('decreased', 'NegReg', (24, 33))	('phosphorylation', 'MPA', (34, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('mutants', 'Var', (4, 11))	('RET', 'Gene', '5979', (69, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('RET', 'Gene', (69, 72))	('HER2', 'Gene', (59, 63))	('NF1', 'Gene', (0, 3))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (59, 63))	('NF1', 'Gene', '4763', (0, 3))
34955	27301828	We did not observe significant effects with these select phosphoproteins in BRAF mutants (Supplementary Table 2).	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutants', 'Var', (81, 88))
34956	27301828	We next examined the effects of co-occurring mutations in TP53, STK11, and KEAP1 on protein levels in mutant-KRAS tumors.	('KEAP1', 'Gene', (75, 80))	('mutations', 'Var', (45, 54))	('STK11', 'Gene', (64, 69))	('TP53', 'Gene', '7157', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('TP53', 'Gene', (58, 62))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('KRAS tumors', 'Disease', 'MESH:D009369', (109, 120))	('STK11', 'molecular_function', 'GO:0033868', ('64', '69'))	('KRAS tumors', 'Disease', (109, 120))	('STK11', 'Gene', '6794', (64, 69))	('KEAP1', 'Gene', '9817', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
34957	27301828	Using cBioPortal analysis of TCGA lung adenocarcinomas, we confirmed that mutations in TP53 and STK11 tend to be mutually exclusive, whereas mutations in KEAP1 and STK11 tend to co-occur.	('TP53', 'Gene', '7157', (87, 91))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (34, 54))	('STK11', 'molecular_function', 'GO:0033868', ('164', '169'))	('KEAP1', 'Gene', (154, 159))	('STK11', 'Gene', (164, 169))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (74, 83))	('STK11', 'Gene', (96, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (34, 53))	('STK11', 'Gene', '6794', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('KEAP1', 'Gene', '9817', (154, 159))	('STK11', 'molecular_function', 'GO:0033868', ('96', '101'))	('lung adenocarcinomas', 'Disease', (34, 54))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (34, 54))	('STK11', 'Gene', '6794', (96, 101))
34958	27301828	Amongst KRAS-mutant tumors, there were 22 tumors with mutations in TP53 but not STK11 or KEAP1, 20 tumors with mutations in STK11 but not in TP53, and 13 tumors with mutations in KEAP1 but not in TP53 (8 of these tumors also had mutations in STK11).	('TP53', 'Gene', (196, 200))	('STK11', 'Gene', '6794', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('TP53', 'Gene', (141, 145))	('STK11', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('KEAP1', 'Gene', '9817', (89, 94))	('STK11', 'Gene', (242, 247))	('mutations', 'Var', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (213, 219))	('KEAP1', 'Gene', (89, 94))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', '7157', (196, 200))	('TP53', 'Gene', (67, 71))	('STK11', 'Gene', '6794', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('STK11', 'Gene', '6794', (242, 247))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('TP53', 'Gene', '7157', (141, 145))	('STK11', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('STK11', 'molecular_function', 'GO:0033868', ('242', '247'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('KEAP1', 'Gene', '9817', (179, 184))	('tumors', 'Disease', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (154, 160))	('KRAS-mutant', 'Gene', (8, 19))	('KRAS-mutant', 'Var', (8, 19))	('KEAP1', 'Gene', (179, 184))	('tumors', 'Disease', (42, 48))	('STK11', 'molecular_function', 'GO:0033868', ('124', '129'))	('STK11', 'molecular_function', 'GO:0033868', ('80', '85'))	('TP53', 'Gene', '7157', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
34959	27301828	There was only one KRAS-mutant tumor with mutations in both TP53 and STK11 or KEAP1.	('KEAP1', 'Gene', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('STK11', 'Gene', (69, 74))	('TP53', 'Gene', '7157', (60, 64))	('KEAP1', 'Gene', '9817', (78, 83))	('STK11', 'molecular_function', 'GO:0033868', ('69', '74'))	('STK11', 'Gene', '6794', (69, 74))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
34960	27301828	Excluding this single sample, we divided KRAS-mutant tumors into three groups: those with TP53 mutations (n = 20), those with STK11 and/or KEAP1 mutations (n = 25), and those without any of these mutations (n = 27).	('STK11', 'Gene', (126, 131))	('TP53', 'Gene', '7157', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('KEAP1', 'Gene', '9817', (139, 144))	('STK11', 'Gene', '6794', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (95, 104))	('STK11', 'molecular_function', 'GO:0033868', ('126', '131'))	('KEAP1', 'Gene', (139, 144))	('tumors', 'Disease', (53, 59))
34962	27301828	The strongest effect of co-occurring TP53 mutations was seen with increased levels of Annexin I protein (Fig.	('increased', 'PosReg', (66, 75))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('TP53', 'Gene', '7157', (37, 41))	('levels of', 'MPA', (76, 85))	('TP53', 'Gene', (37, 41))	('Annexin I protein', 'Protein', (86, 103))	('mutations', 'Var', (42, 51))
34963	27301828	As expected, the group with mutations in the protein kinase gene STK11 had significantly lower levels of activation of its direct target, AMPK, than the other two groups (Fig.	('lower', 'NegReg', (89, 94))	('AMPK', 'molecular_function', 'GO:0050405', ('138', '142'))	('AMPK', 'MPA', (138, 142))	('activation of', 'MPA', (105, 118))	('STK11', 'molecular_function', 'GO:0033868', ('65', '70'))	('AMPK', 'molecular_function', 'GO:0004691', ('138', '142'))	('STK11', 'Gene', (65, 70))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('AMPK', 'molecular_function', 'GO:0047322', ('138', '142'))	('levels', 'MPA', (95, 101))	('STK11', 'Gene', '6794', (65, 70))	('mutations', 'Var', (28, 37))
34966	27301828	We ranked genes based on the average effect size when KRAS-mutant tumors were compared to tumors with other mutations in genes of the Raf/MAPK pathway, and when compared to tumors with no mutations in genes of the Raf/MAPK pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('218', '222'))	('MAPK', 'molecular_function', 'GO:0004707', ('138', '142'))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('KRAS-mutant', 'Var', (54, 65))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('Raf', 'Gene', (214, 217))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Raf', 'Gene', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', (90, 96))	('Raf', 'Gene', '22882', (214, 217))	('Raf', 'Gene', '22882', (134, 137))
34968	27301828	Also within this top-ranked group are several candidate transcriptional oncogenic effectors for mutant KRAS, including the receptor tyrosine kinase genes INSR and IGFR1; the receptor tyrosine phosphatase genes PTPRE and PTPRM; and genes encoding guanine-nucleotide exchange-factors that activate Rac/Rho/Cdc42 proteins DOCK5, DOCK1, DNMBP, and PLEKHG2; (Fig.	('PLEKHG2', 'Gene', (344, 351))	('DNMBP', 'Gene', (333, 338))	('IGFR1', 'Gene', '100132417', (163, 168))	('Cdc42', 'Gene', (304, 309))	('PTPRM', 'Gene', (220, 225))	('DOCK1', 'Gene', '1793', (326, 331))	('INSR', 'Gene', '3643', (154, 158))	('mutant', 'Var', (96, 102))	('PLEKHG2', 'Gene', '64857', (344, 351))	('guanine-nucleotide', 'Chemical', 'MESH:D006150', (246, 264))	('Cdc42', 'Gene', '998', (304, 309))	('DNMBP', 'Gene', '23268', (333, 338))	('IGFR1', 'Gene', (163, 168))	('DOCK5', 'Gene', '80005', (319, 324))	('INSR', 'Gene', (154, 158))	('PTPRM', 'Gene', '5797', (220, 225))	('KRAS', 'Gene', (103, 107))	('phosphatase', 'molecular_function', 'GO:0016791', ('192', '203'))	('DOCK5', 'Gene', (319, 324))	('DOCK1', 'Gene', (326, 331))	('PTPRE', 'Gene', (210, 215))
34970	27301828	Approximately 50% of the aforementioned genes that are selectively induced in KRAS-mutant lung adenocarcinomas were also significantly affected by co-occurring mutations in TP53, STK11, or KEAP1.	('KEAP1', 'Gene', '9817', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (90, 110))	('mutations', 'Var', (160, 169))	('STK11', 'Gene', (179, 184))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (90, 110))	('KEAP1', 'Gene', (189, 194))	('KRAS-mutant', 'Var', (78, 89))	('STK11', 'molecular_function', 'GO:0033868', ('179', '184'))	('STK11', 'Gene', '6794', (179, 184))	('induced', 'PosReg', (67, 74))	('TP53', 'Gene', '7157', (173, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('TP53', 'Gene', (173, 177))	('affected', 'Reg', (135, 143))	('lung adenocarcinomas', 'Disease', (90, 110))
34971	27301828	For the most part, co-occurring mutations in STK11 and/or KEAP1 were associated with significantly stronger expression of these genes.	('KEAP1', 'Gene', '9817', (58, 63))	('KEAP1', 'Gene', (58, 63))	('stronger', 'PosReg', (99, 107))	('mutations', 'Var', (32, 41))	('STK11', 'Gene', (45, 50))	('expression', 'MPA', (108, 118))	('STK11', 'molecular_function', 'GO:0033868', ('45', '50'))	('STK11', 'Gene', '6794', (45, 50))
34972	27301828	In only one case (DUSP6) was co-occurrence of mutant TP53 associated with stronger expression (Fig.	('DUSP6', 'Gene', '1848', (18, 23))	('associated', 'Reg', (58, 68))	('mutant', 'Var', (46, 52))	('TP53', 'Gene', '7157', (53, 57))	('expression', 'MPA', (83, 93))	('DUSP6', 'Gene', (18, 23))	('TP53', 'Gene', (53, 57))	('stronger', 'PosReg', (74, 82))
34975	27301828	These proteins include PI3-kinase (as judged by activation of AKT), AKT, and NF-kappaB, all of which have been proposed to be important mediators of mutant KRAS in lung adenocarcinomas.	('AKT', 'Gene', (62, 65))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (164, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('KRAS', 'Gene', (156, 160))	('NF-kappaB', 'Gene', (77, 86))	('NF-kappaB', 'Gene', '4790', (77, 86))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (164, 184))	('mutant', 'Var', (149, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (164, 183))	('AKT', 'Gene', '207', (68, 71))	('PI3-kinase', 'Enzyme', (23, 33))	('activation', 'PosReg', (48, 58))	('AKT', 'Gene', '207', (62, 65))	('lung adenocarcinomas', 'Disease', (164, 184))	('AKT', 'Gene', (68, 71))
34976	27301828	Since mTOR is the only component of the PI3-kinase pathway that was selectively activated in KRAS-mutant tumors, a greater therapeutic window could conceivably be achieved by combining Raf/MAPK inhibitors with highly selective mTOR inhibitors that do not inhibit PI3-kinase.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('KRAS-mutant', 'Gene', (93, 104))	('mTOR', 'Gene', '2475', (227, 231))	('KRAS-mutant', 'Var', (93, 104))	('Raf', 'Gene', '22882', (185, 188))	('mTOR', 'Gene', (227, 231))	('MAPK', 'molecular_function', 'GO:0004707', ('189', '193'))	('Raf', 'Gene', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PI3-kinase pathway', 'Pathway', (40, 58))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('mTOR', 'Gene', '2475', (6, 10))	('activated', 'PosReg', (80, 89))	('mTOR', 'Gene', (6, 10))
34980	27301828	However in this case, it would appear that loss of STK11 function is likely driving this decrease in activity, and that as such this would not represent a potential selective dependency in any of the KRAS-mutant subgroups.	('decrease', 'NegReg', (89, 97))	('activity', 'MPA', (101, 109))	('STK11', 'Gene', (51, 56))	('STK11', 'molecular_function', 'GO:0033868', ('51', '56'))	('loss', 'Var', (43, 47))	('STK11', 'Gene', '6794', (51, 56))
34984	27301828	A connection between mutant KRAS and IGF1R in lung adenocarcionoma has previously been documented.	('KRAS', 'Gene', (28, 32))	('IGF1R', 'Gene', (37, 42))	('mutant', 'Var', (21, 27))	('IGF1R', 'Gene', '3480', (37, 42))	('lung adenocarcionoma', 'Disease', 'MESH:D008171', (46, 66))	('lung adenocarcionoma', 'Disease', (46, 66))	('lung adenocarcionoma', 'Phenotype', 'HP:0030078', (46, 66))
34986	27301828	Thus the effect of mutational activation of KRAS on guanine-nucleotide exchange factors for small GTP-binding proteins is broader in lung adenocarcinoma than its biochemical activation of exchange factors that activate Ral proteins.	('GTP', 'Chemical', 'MESH:D006160', (98, 101))	('Ral', 'Gene', (219, 222))	('activation', 'PosReg', (30, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('mutational', 'Var', (19, 29))	('KRAS', 'Gene', (44, 48))	('lung adenocarcinoma', 'Disease', (133, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('guanine-nucleotide', 'Chemical', 'MESH:D006150', (52, 70))	('Ral', 'Gene', '5898', (219, 222))	('GTP-binding', 'molecular_function', 'GO:0005525', ('98', '109'))
34988	27301828	Finally, this set of upregulated genes includes a potential immunotherapy target for KRAS-mutant lung adenocarcinomas, the Kita-Kyushu lung cancer antigen 1, encoded by the CXorf61 gene.	('lung adenocarcinomas', 'Disease', (97, 117))	('CXorf61', 'Gene', '203413', (173, 180))	('Kita-Kyushu lung cancer antigen 1', 'Gene', '203413', (123, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (97, 117))	('Kita-Kyushu lung cancer antigen 1', 'Gene', (123, 156))	('upregulated', 'PosReg', (21, 32))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (97, 117))	('KRAS-mutant', 'Var', (85, 96))	('CXorf61', 'Gene', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
34993	27301828	We segregated samples using cBioPortal into three mutually exclusive groups: ones with KRAS missense mutations, ones with mutations in genes encoding other components of the RTK/RAF/MAPK pathway as delineated in the text, and other samples.	('KRAS', 'Gene', (87, 91))	('RAF', 'Gene', (178, 181))	('RAF', 'Gene', '22882', (178, 181))	('MAPK', 'molecular_function', 'GO:0004707', ('182', '186'))	('missense mutations', 'Var', (92, 110))
34994	27301828	Ranking with both effect size and t-test p-value generated top-ranked proteins and genes induced in KRAS mutants or Raf/MAPK pathway mutants (Fig.	('KRAS', 'Gene', (100, 104))	('Raf', 'Gene', '22882', (116, 119))	('induced', 'Reg', (89, 96))	('proteins', 'Protein', (70, 78))	('Raf', 'Gene', (116, 119))	('mutants', 'Var', (105, 112))	('MAPK', 'molecular_function', 'GO:0004707', ('120', '124'))	('mutants', 'Var', (133, 140))
34995	27301828	We used a similar approach to divide KRAS mutants into three groups depending on TP53, STK11, or KEAP1 status.	('mutants', 'Var', (42, 49))	('KEAP1', 'Gene', '9817', (97, 102))	('STK11', 'Gene', (87, 92))	('KEAP1', 'Gene', (97, 102))	('STK11', 'molecular_function', 'GO:0033868', ('87', '92'))	('TP53', 'Gene', '7157', (81, 85))	('STK11', 'Gene', '6794', (87, 92))	('TP53', 'Gene', (81, 85))
35109	33651168	As already mentioned, the content of 6Li in the MTS-N and MCP-N detectors causes an increase in measured neutron dose.	('MTS-N', 'Chemical', '-', (48, 53))	('MCP-N', 'Chemical', '-', (58, 63))	('MCP', 'molecular_function', 'GO:0004298', ('58', '61'))	('measured neutron dose', 'MPA', (96, 117))	('content', 'Var', (26, 33))	('increase', 'PosReg', (84, 92))
35133	33649539	Lung expression of genes putatively involved in SARS-CoV-2 infection is modulated in cis by germline variants Germline variants in genes involved in SARS-CoV-2 cell entry and in host innate immune responses to viruses may influence the susceptibility to infection.	('expression', 'MPA', (5, 15))	('in', 'Gene', '43565', (45, 47))	('susceptibility to infection', 'Phenotype', 'HP:0002719', (236, 263))	('infection', 'Disease', (254, 263))	('in', 'Gene', '43565', (36, 38))	('SARS-CoV-2', 'Species', '2697049', (149, 159))	('infection', 'Disease', 'MESH:D007239', (254, 263))	('susceptibility', 'MPA', (236, 250))	('in', 'Gene', '43565', (59, 61))	('modulated', 'Reg', (72, 81))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (48, 68))	('in', 'Gene', '43565', (115, 117))	('in', 'Gene', '43565', (146, 148))	('in', 'Gene', '43565', (137, 139))	('in', 'Gene', '43565', (82, 84))	('in', 'Gene', '43565', (183, 185))	('in', 'Gene', '43565', (128, 130))	('infection', 'Disease', (59, 68))	('in', 'Gene', '43565', (97, 99))	('infection', 'Disease', 'MESH:D007239', (59, 68))	('in', 'Gene', '43565', (222, 224))	('SARS-CoV-2 infection', 'Disease', (48, 68))	('variants', 'Var', (101, 109))	('in', 'Gene', '43565', (175, 177))	('in', 'Gene', '43565', (254, 256))	('SARS-CoV-2', 'Species', '2697049', (48, 58))
35134	33649539	This study used whole-genome analyses of lung tissue to identify polymorphisms acting as expression quantitative trait loci (eQTLs) for 60 genes of relevance to SARS-CoV-2 infection susceptibility.	('SARS-CoV-2 infection', 'Disease', (161, 181))	('polymorphisms', 'Var', (65, 78))	('in', 'Gene', '43565', (82, 84))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (161, 181))	('in', 'Gene', '43565', (172, 174))
35154	33649539	These results suggest that not only genetic variants affecting protein function but also those affecting gene expression modulate the response to viral infection.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('in', 'Gene', '43565', (101, 103))	('gene expression', 'biological_process', 'GO:0010467', ('105', '120'))	('in', 'Gene', '43565', (152, 154))	('viral infection', 'biological_process', 'GO:0016032', ('146', '161'))	('in', 'Gene', '43565', (68, 70))	('viral infection', 'Disease', 'MESH:D001102', (146, 161))	('viral infection', 'Disease', (146, 161))	('in', 'Gene', '43565', (59, 61))	('variants', 'Var', (44, 52))	('modulate', 'Reg', (121, 129))	('genetic variants', 'Var', (36, 52))
35155	33649539	For severe acute respiratory syndrome (SARS), caused by the SARS-CoV virus, the risk or severity of infection has been associated with polymorphisms in genes involved in inflammatory and immune responses or viral entry.	('severe acute respiratory syndrome', 'Disease', (4, 37))	('respiratory syndrome', 'Phenotype', 'HP:0011947', (17, 37))	('in', 'Gene', '43565', (167, 169))	('in', 'Gene', '43565', (170, 172))	('acute respiratory syndrome', 'Phenotype', 'HP:0011948', (11, 37))	('SARS-CoV', 'Species', '694009', (60, 68))	('infection', 'Disease', (100, 109))	('in', 'Gene', '43565', (158, 160))	('infection', 'Disease', 'MESH:D007239', (100, 109))	('in', 'Gene', '43565', (100, 102))	('polymorphisms', 'Var', (135, 148))	('in', 'Gene', '43565', (149, 151))	('severe acute respiratory syndrome', 'Disease', 'MESH:D045169', (4, 37))	('associated', 'Reg', (119, 129))
35159	33649539	According to molecular modeling studies, two coding variants may alter the binding affinity between ACE2 and the viral spike protein (protein S).	('in', 'Gene', '43565', (139, 141))	('spike', 'Gene', '43740568', (119, 124))	('ACE2', 'Gene', '59272', (100, 104))	('in', 'Gene', '43565', (130, 132))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('ACE2', 'Gene', (100, 104))	('variants', 'Var', (52, 60))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('alter', 'Reg', (65, 70))	('in', 'Gene', '43565', (79, 81))	('in', 'Gene', '43565', (48, 50))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('in', 'Gene', '43565', (86, 88))	('in', 'Gene', '43565', (28, 30))	('in', 'Gene', '43565', (6, 8))	('in', 'Gene', '43565', (76, 78))	('spike', 'Gene', (119, 124))
35167	33649539	As already observed for influenza, risk or severity of infection may also depend on noncoding variants that influence gene expression, for instance by modifying the binding sites for transcription factors or altering enhancer sequences.	('in', 'Gene', '43565', (139, 141))	('transcription', 'biological_process', 'GO:0006351', ('183', '196'))	('enhancer sequences', 'MPA', (217, 235))	('transcription', 'Protein', (183, 196))	('in', 'Gene', '43565', (166, 168))	('in', 'Gene', '43565', (108, 110))	('influenza', 'Species', '11320', (24, 33))	('in', 'Gene', '43565', (157, 159))	('in', 'Gene', '43565', (213, 215))	('binding', 'molecular_function', 'GO:0005488', ('165', '172'))	('variants', 'Var', (94, 102))	('infection', 'Disease', (55, 64))	('in', 'Gene', '43565', (24, 26))	('infection', 'Disease', 'MESH:D007239', (55, 64))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))	('in', 'Gene', '43565', (90, 92))	('in', 'Gene', '43565', (169, 171))	('in', 'Gene', '43565', (55, 57))
35168	33649539	These regulatory genetic variants are termed expression quantitative trait loci (eQTLs) because they alter gene expression in a quantitative manner.	('variants', 'Var', (25, 33))	('in', 'Gene', '43565', (123, 125))	('alter', 'Reg', (101, 106))	('gene expression', 'MPA', (107, 122))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))
35213	33649539	RAB14 gene had the most cis-eQTLs (n = 50) and the top significant association (FDR = 7.9 x 10-53, at rs56335605).	('RAB14', 'Gene', '51552', (0, 5))	('rs56335605', 'Var', (102, 112))	('RAB14', 'Gene', (0, 5))	('rs56335605', 'Mutation', 'rs56335605', (102, 112))	('cis-eQTLs', 'CPA', (24, 33))
35216	33649539	For six genes (i.e., ABO, APOBEC3D, BSG, CLEC4G, DPP4, and FURIN), transcript levels increased with an increasing number of minor alleles of their eQTL SNP (i.e., rs8176722, rs139331, rs117582572, rs115293707, rs13390563, and rs4932179, respectively).	('rs117582572', 'Var', (184, 195))	('FURIN', 'Gene', '5045', (59, 64))	('in', 'Gene', '43565', (85, 87))	('rs115293707', 'Mutation', 'rs115293707', (197, 208))	('rs8176722', 'Mutation', 'rs8176722', (163, 172))	('rs4932179', 'Var', (226, 235))	('rs115293707', 'Var', (197, 208))	('rs13390563', 'Var', (210, 220))	('rs139331', 'Mutation', 'rs139331', (174, 182))	('ABO', 'Gene', (21, 24))	('rs139331', 'Var', (174, 182))	('BSG', 'Gene', (36, 39))	('transcript levels', 'MPA', (67, 84))	('BSG', 'Gene', '682', (36, 39))	('rs4932179', 'Mutation', 'rs4932179', (226, 235))	('APOBEC3D', 'Gene', (26, 34))	('DPP4', 'Gene', '1803', (49, 53))	('rs117582572', 'Mutation', 'rs117582572', (184, 195))	('APOBEC', 'cellular_component', 'GO:0030895', ('26', '32'))	('in', 'Gene', '43565', (103, 105))	('rs8176722', 'Var', (163, 172))	('FURIN', 'Gene', (59, 64))	('ABO', 'Gene', '28', (21, 24))	('CLEC4G', 'Gene', '339390', (41, 47))	('CLEC4G', 'Gene', (41, 47))	('DPP4', 'Gene', (49, 53))	('in', 'Gene', '43565', (125, 127))	('rs13390563', 'Mutation', 'rs13390563', (210, 220))	('in', 'Gene', '43565', (110, 112))	('APOBEC3D', 'Gene', '140564', (26, 34))
35217	33649539	The other nine genes (i.e., ANPEP, AP2A2, APOBEC3G, DDX58I, FYCO1, RAB14, SERINC3, TRIM5, and ZCRB1) showed lower transcript levels with an increasing number of the minor allele of rs11635469, rs11605303, rs8177832, rs73479410, rs936939, rs56335605, rs36121075, rs59814799, rs1563419, respectively.	('ZCRB1', 'Gene', '85437', (94, 99))	('RAB14', 'Gene', '51552', (67, 72))	('in', 'Gene', '43565', (166, 168))	('APOBEC3G', 'Gene', '60489', (42, 50))	('rs59814799', 'Mutation', 'rs59814799', (262, 272))	('rs36121075', 'Mutation', 'rs36121075', (250, 260))	('in', 'Gene', '43565', (140, 142))	('ANPEP', 'Gene', '290', (28, 33))	('lower', 'NegReg', (108, 113))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('SERINC3', 'Gene', '10955', (74, 81))	('TRIM5', 'Gene', (83, 88))	('rs36121075', 'Var', (250, 260))	('rs936939', 'Var', (228, 236))	('AP2A2', 'Gene', '161', (35, 40))	('rs936939', 'Mutation', 'rs936939', (228, 236))	('rs11635469', 'Mutation', 'rs11635469', (181, 191))	('FYCO1', 'Gene', '79443', (60, 65))	('AP2A2', 'Gene', (35, 40))	('SERINC3', 'Gene', (74, 81))	('rs1563419', 'Var', (274, 283))	('in', 'Gene', '43565', (147, 149))	('in', 'Gene', '43565', (11, 13))	('ANPEP', 'Gene', (28, 33))	('APOBEC3G', 'Gene', (42, 50))	('rs73479410', 'Mutation', 'rs73479410', (216, 226))	('transcript levels', 'MPA', (114, 131))	('rs11635469', 'Var', (181, 191))	('TRIM5', 'Gene', '85363', (83, 88))	('RAB14', 'Gene', (67, 72))	('rs73479410', 'Var', (216, 226))	('FYCO1', 'Gene', (60, 65))	('AP2', 'cellular_component', 'GO:0005908', ('35', '38'))	('rs59814799', 'Var', (262, 272))	('rs1563419', 'Mutation', 'rs1563419', (274, 283))	('rs11605303', 'Var', (193, 203))	('rs11605303', 'Mutation', 'rs11605303', (193, 203))	('rs56335605', 'Var', (238, 248))	('DDX58', 'Gene', (52, 57))	('rs56335605', 'Mutation', 'rs56335605', (238, 248))	('rs8177832', 'Var', (205, 214))	('ZCRB1', 'Gene', (94, 99))	('rs8177832', 'Mutation', 'rs8177832', (205, 214))	('DDX58', 'Gene', '23586', (52, 57))
35221	33649539	One SNP, rs56335605 (the most significant eQTL associated with RAB14 levels), is located in the 3'UTR of its target gene.	('rs56335605', 'Var', (9, 19))	('UTR', 'Gene', '2837', (98, 101))	('in', 'Gene', '43565', (89, 91))	('RAB14', 'Gene', '51552', (63, 68))	('UTR', 'Gene', (98, 101))	('RAB14', 'Gene', (63, 68))	('rs56335605', 'Mutation', 'rs56335605', (9, 19))
35222	33649539	All but two of the 15 SNPs (i.e., rs8177832 and rs117582572) had MAF > 5% in our series, but MAFs varied widely in all populations examined.	('rs117582572', 'Mutation', 'rs117582572', (48, 59))	('in', 'Gene', '43565', (112, 114))	('in', 'Gene', '43565', (74, 76))	('rs8177832', 'Var', (34, 43))	('in', 'Gene', '43565', (135, 137))	('rs117582572', 'Var', (48, 59))	('rs8177832', 'Mutation', 'rs8177832', (34, 43))
35224	33649539	SNPs rs11635469 (in ANPEP) and rs11605303 (in AP2A2) were predicted to affect transcription factor binding sites.	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))	('transcription factor', 'MPA', (78, 98))	('rs11635469', 'Var', (5, 15))	('in', 'Gene', '43565', (43, 45))	('AP2A2', 'Gene', '161', (46, 51))	('SNPs rs11635469', 'Var', (0, 15))	('ANPEP', 'Gene', '290', (20, 25))	('in', 'Gene', '43565', (100, 102))	('affect', 'Reg', (71, 77))	('AP2', 'cellular_component', 'GO:0005908', ('46', '49'))	('rs11605303', 'Var', (31, 41))	('rs11605303', 'Mutation', 'rs11605303', (31, 41))	('in', 'Gene', '43565', (103, 105))	('in', 'Gene', '43565', (17, 19))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('78', '106'))	('ANPEP', 'Gene', (20, 25))	('AP2A2', 'Gene', (46, 51))	('rs11635469', 'Mutation', 'rs11635469', (5, 15))
35225	33649539	SNP rs8177832, on the other hand, is a missense variant of APOBEC3G gene located in an exonic splicing enhancer; it was predicted to be a benign non-synonymous SNP (according to Polyphen) and to affect splicing activity.	('APOBEC3G', 'Gene', (59, 67))	('rs8177832', 'Mutation', 'rs8177832', (4, 13))	('in', 'Gene', '43565', (207, 209))	('APOBEC3G', 'Gene', '60489', (59, 67))	('splicing', 'biological_process', 'GO:0045292', ('202', '210'))	('in', 'Gene', '43565', (99, 101))	('in', 'Gene', '43565', (81, 83))	('in', 'Gene', '43565', (171, 173))	('splicing', 'biological_process', 'GO:0045292', ('94', '102'))	('affect', 'Reg', (195, 201))	('APOBEC', 'cellular_component', 'GO:0030895', ('59', '65'))	('SNP', 'Var', (0, 3))
35226	33649539	Finally, SNP rs56335605 (in RAB14) was predicted (by miRanda) to slightly alter the binding of some miRNAs.	('alter', 'Reg', (74, 79))	('SNP rs56335605', 'Var', (9, 23))	('in', 'Gene', '43565', (1, 3))	('in', 'Gene', '43565', (85, 87))	('in', 'Gene', '43565', (88, 90))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('RAB14', 'Gene', '51552', (28, 33))	('rs56335605', 'Mutation', 'rs56335605', (13, 23))	('RAB14', 'Gene', (28, 33))	('in', 'Gene', '43565', (25, 27))
35232	33649539	SNP rs8177832 has been reported to be an APOBEC3G eQTL only in thyroid; however, the second most significant eQTL SNP of this gene (i.e., the intronic rs17537581) has been reported as a lung eQTL with the same effects of genotype as in our study: lower levels of APOBEC3G associated with an increasing number of minor alleles (GTEx data: rs17537581 normalized effect size, -0.30, P = 2.2 x 10-12).	('in', 'Gene', '43565', (142, 144))	('rs8177832', 'Mutation', 'rs8177832', (4, 13))	('APOBEC3G', 'Gene', '60489', (41, 49))	('rs17537581', 'Mutation', 'rs17537581', (151, 161))	('rs17537581', 'Var', (151, 161))	('APOBEC', 'cellular_component', 'GO:0030895', ('263', '269'))	('in', 'Gene', '43565', (60, 62))	('rs17537581', 'Mutation', 'rs17537581', (338, 348))	('in', 'Gene', '43565', (291, 293))	('in', 'Gene', '43565', (298, 300))	('APOBEC3G', 'Gene', (263, 271))	('rs17537581', 'Var', (338, 348))	('in', 'Gene', '43565', (233, 235))	('APOBEC3G', 'Gene', '60489', (263, 271))	('APOBEC3G', 'Gene', (41, 49))	('APOBEC', 'cellular_component', 'GO:0030895', ('41', '47'))	('in', 'Gene', '43565', (313, 315))
35233	33649539	SNP rs117582572 has been reported to be an BSG eQTL only in esophageal mucosa.	('in', 'Gene', '43565', (57, 59))	('BSG', 'Gene', (43, 46))	('rs117582572', 'Mutation', 'rs117582572', (4, 15))	('BSG', 'Gene', '682', (43, 46))	('SNP rs117582572', 'Var', (0, 15))
35234	33649539	The rs115293707 variant has been not yet reported as an eQTL of CLEC4G gene in lung tissue, but it has in 14 other tissues.	('CLEC4G', 'Gene', '339390', (64, 70))	('rs115293707', 'Mutation', 'rs115293707', (4, 15))	('CLEC4G', 'Gene', (64, 70))	('rs115293707', 'Var', (4, 15))	('in', 'Gene', '43565', (103, 105))	('in', 'Gene', '43565', (76, 78))
35236	33649539	On the contrary, the rs59814799 variant has already been reported as a TRIM5 eQTL in tibial nerve, skeletal muscle, and adipose tissue, but not in lung; in all the tissues, the highest levels of TRIM5 associated with the lowest number of minor alleles of rs59814799.	('in', 'Gene', '43565', (153, 155))	('TRIM5', 'Gene', '85363', (195, 200))	('variant', 'Var', (32, 39))	('rs59814799', 'Mutation', 'rs59814799', (255, 265))	('in', 'Gene', '43565', (239, 241))	('rs59814799', 'Mutation', 'rs59814799', (21, 31))	('TRIM5', 'Gene', (71, 76))	('in', 'Gene', '43565', (82, 84))	('in', 'Gene', '43565', (144, 146))	('TRIM5', 'Gene', '85363', (71, 76))	('TRIM5', 'Gene', (195, 200))	('rs59814799', 'Var', (255, 265))
35237	33649539	No DDX58 eQTLs have been previously identified in lung, and no associations between rs13390563 and DPP4 (or any other transcript) levels, in any tissue, have been reported, according to GTEx database.	('in', 'Gene', '43565', (138, 140))	('rs13390563', 'Mutation', 'rs13390563', (84, 94))	('DPP4', 'Gene', (99, 103))	('rs13390563', 'Var', (84, 94))	('in', 'Gene', '43565', (47, 49))	('DDX58', 'Gene', '23586', (3, 8))	('in', 'Gene', '43565', (179, 181))	('DPP4', 'Gene', '1803', (99, 103))	('DDX58', 'Gene', (3, 8))
35238	33649539	Also, rs36121075 and rs1563419 had not been previously associated with SERINC3 and ZCRB1 levels, respectively.	('rs1563419', 'Mutation', 'rs1563419', (21, 30))	('associated', 'Reg', (55, 65))	('rs36121075', 'Var', (6, 16))	('SERINC3', 'Gene', (71, 78))	('ZCRB1', 'Gene', (83, 88))	('SERINC3', 'Gene', '10955', (71, 78))	('rs1563419', 'Var', (21, 30))	('rs36121075', 'Mutation', 'rs36121075', (6, 16))	('ZCRB1', 'Gene', '85437', (83, 88))
35246	33649539	The main result of this study is the identification of cis-eQTLs in lung tissue for 15 putative SARS-CoV-2 infection-associated genes.	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (96, 116))	('SARS-CoV-2 infection', 'Disease', (96, 116))	('cis-eQTLs', 'Var', (55, 64))	('in', 'Gene', '43565', (6, 8))	('in', 'Gene', '43565', (65, 67))	('in', 'Gene', '43565', (107, 109))
35248	33649539	The genetic variants we found result in different levels of mRNA in different individuals, which is expected to result in different levels of the encoded proteins.	('result', 'Reg', (112, 118))	('in', 'Gene', '43565', (159, 161))	('levels', 'MPA', (132, 138))	('in', 'Gene', '43565', (37, 39))	('in', 'Gene', '43565', (78, 80))	('mRNA', 'MPA', (60, 64))	('variants', 'Var', (12, 20))	('in', 'Gene', '43565', (119, 121))	('in', 'Gene', '43565', (65, 67))
35269	33649539	Finally, we identified cis-eQTLs in two COVID-19 susceptibility loci.	('COVID-19', 'Disease', 'MESH:C000657245', (40, 48))	('cis-eQTLs', 'Var', (23, 32))	('in', 'Gene', '43565', (1, 3))	('COVID-19', 'Disease', (40, 48))	('in', 'Gene', '43565', (33, 35))
35272	33649539	Our data confirm previous reports on these eQTLs in lung, recorded in the GTEx database, and therefore support a role for these loci in susceptibility to severe COVID-19.	('in', 'Gene', '43565', (67, 69))	('COVID-19', 'Disease', 'MESH:C000657245', (161, 169))	('eQTLs', 'Var', (43, 48))	('in', 'Gene', '43565', (133, 135))	('COVID-19', 'Disease', (161, 169))	('in', 'Gene', '43565', (49, 51))
35275	33649539	Recently other loci and variants have been found to associate with COVID-19 susceptibility or severity.	('COVID-19', 'Disease', (67, 75))	('COVID-19', 'Disease', 'MESH:C000657245', (67, 75))	('variants', 'Var', (24, 32))
35376	33114182	In most cases, tumor cells carrying mutations in genes which belong to pathways targeted by the drug, gain selective advantage.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (15, 20))	('gain', 'PosReg', (102, 106))
35404	33114182	This may suggest that, despite the high diversity of mutations, the transcriptional programs of cancer cells converged on some specific signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('cancer', 'Disease', (96, 102))
35409	33114182	Several mechanisms of such de novo adaptation of tumors to the therapy are already well described: regulation of chemotherapeutic drug concentration in the cell, suppression of apoptotic pathways, modification of target proteins, or activation of alternative signaling cascades.	('signaling', 'biological_process', 'GO:0023052', ('259', '268'))	('modification', 'Var', (197, 209))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('suppression', 'NegReg', (162, 173))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('alternative signaling cascades', 'Pathway', (247, 277))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('apoptotic pathways', 'Pathway', (177, 195))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('proteins', 'Protein', (220, 228))
35416	33114182	Thus, in the course of tumor progression and subsequent therapy, additional mutations may occur providing the resistance of tumor cells to the drugs.	('mutations', 'Var', (76, 85))	('resistance', 'MPA', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (124, 129))	('occur', 'Reg', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
35417	33114182	Among chemotherapy-induced mutations, mutations in genes of the EGFR-dependent signaling pathway (EGFR, HER2, RAS) targeted by the drugs are common.	('mutations', 'Var', (27, 36))	('EGFR', 'Gene', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('RAS', 'Gene', (110, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('chemotherapy-induced', 'Disease', (6, 26))	('HER2', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (98, 102))	('HER2', 'Gene', '2064', (104, 108))
35418	33114182	Some of the most common examples are mutations in the BRCA1 and BRCA2 tumor suppressor genes.	('BRCA2', 'Gene', '675', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('mutations', 'Var', (37, 46))	('BRCA2', 'Gene', (64, 69))	('BRCA1', 'Gene', '672', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('BRCA1', 'Gene', (54, 59))
35419	33114182	Mutations in these genes lead not only to the enhanced probability of genomic instability but also to a greater sensitivity of tumor cells to DNA-damaging agents of the platinum group and inhibitors of poly(ADP-ribose) polymerase.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('sensitivity', 'MPA', (112, 123))	('tumor', 'Disease', (127, 132))	('poly(ADP-ribose) polymerase', 'Gene', '142', (202, 229))	('platinum', 'Chemical', 'MESH:D010984', (169, 177))	('genomic instability', 'MPA', (70, 89))	('Mutations', 'Var', (0, 9))	('poly(ADP-ribose) polymerase', 'Gene', (202, 229))	('enhanced', 'PosReg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
35420	33114182	Mutations in the TP53 gene induced by chemotherapy can lead to an acquisition of resistance to the drugs used.	('lead to', 'Reg', (55, 62))	('acquisition of resistance to the drugs used', 'MPA', (66, 109))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
35421	33114182	In addition to genetic aberrations, epigenetic changes may occur in tumor cells in response to therapy, for example, the silencing of key tumor suppressor genes mediates by DNA hypermethylation, histone modifications, and chromatin remodeling.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('histone', 'Var', (195, 202))	('chromatin remodeling', 'CPA', (222, 242))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('222', '242'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('chromatin', 'cellular_component', 'GO:0000785', ('222', '231'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('DNA hypermethylation', 'Var', (173, 193))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('173', '193'))	('silencing', 'NegReg', (121, 130))
35433	33114182	Knockdown of ZEB1 in breast cancer, non-small cell lung carcinoma, and osteosarcoma cell lines leads to an increase in the sensitivity to radiotherapy while its ectopic expression in cell models of breast cancer decreases the sensitivity.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (36, 65))	('ZEB1', 'Gene', (13, 17))	('non-small cell lung carcinoma', 'Disease', (36, 65))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (40, 65))	('breast cancer', 'Disease', (198, 211))	('sensitivity to radiotherapy', 'MPA', (123, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('increase', 'PosReg', (107, 115))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (36, 65))	('breast cancer', 'Disease', (21, 34))	('ZEB1', 'Gene', '6935', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('ectopic expression', 'Var', (161, 179))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('decreases', 'NegReg', (212, 221))	('osteosarcoma', 'Disease', (71, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))
35460	33114182	For example, cisplatin causes replicative stress, which activates the phosphokinases ATR, CHK1, and WEE1, thereby preventing further course of the cell cycle and leading to the arrest of tumor cells in the S phase.	('activates', 'PosReg', (56, 65))	('WEE1', 'Gene', '7465', (100, 104))	('cell cycle', 'biological_process', 'GO:0007049', ('147', '157'))	('preventing', 'NegReg', (114, 124))	('ATR', 'Gene', '545', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('arrest of tumor', 'Disease', 'MESH:D006323', (177, 192))	('ATR', 'Gene', (85, 88))	('phosphokinases', 'Enzyme', (70, 84))	('cisplatin', 'Var', (13, 22))	('S phase', 'biological_process', 'GO:0051320', ('206', '213'))	('CHK1', 'Gene', (90, 94))	('arrest of tumor', 'Disease', (177, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('leading to', 'Reg', (162, 172))	('WEE1', 'Gene', (100, 104))	('course of the cell cycle', 'CPA', (133, 157))	('CHK1', 'Gene', '1111', (90, 94))
35483	33114182	For example, cisplatin leads to a decrease in the level of miR-199a-5p in hepatocellular carcinoma cells, which, as a result, stimulates the activation of autophagy and promotes the proliferation of tumor cells.	('tumor', 'Disease', (199, 204))	('promotes', 'PosReg', (169, 177))	('proliferation', 'CPA', (182, 195))	('autophagy', 'biological_process', 'GO:0006914', ('155', '164'))	('autophagy', 'CPA', (155, 164))	('stimulates', 'PosReg', (126, 136))	('decrease', 'NegReg', (34, 42))	('cisplatin', 'Var', (13, 22))	('autophagy', 'biological_process', 'GO:0016236', ('155', '164'))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('hepatocellular carcinoma', 'Disease', (74, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('level', 'MPA', (50, 55))	('activation', 'PosReg', (141, 151))
35516	33114182	Components of the spliceosome; PGE2; survivin; MDR1, HMGB1; several microRNAs (miR-21, miR-155, and miR-194-5p, and lincRNA-VLDLR have been proposed as the main participants that trigger the acquisition of therapy resistance by tumor cells (Figure 2).	('lincRNA-VLDLR', 'Gene', '401491', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('miR-21', 'Gene', (79, 85))	('miR-155', 'Gene', (87, 94))	('HMGB1', 'Gene', (53, 58))	('HMGB1', 'Gene', '3146', (53, 58))	('therapy resistance', 'CPA', (206, 224))	('miR-155', 'Gene', '406947', (87, 94))	('MDR1', 'Gene', '5243', (47, 51))	('participants', 'Species', '9606', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('lincRNA-VLDLR', 'Gene', (116, 129))	('miR-21', 'Gene', '406991', (79, 85))	('MDR', 'molecular_function', 'GO:0004745', ('47', '50'))	('miR-194-5p', 'Var', (100, 110))	('MDR1', 'Gene', (47, 51))	('PGE2', 'Chemical', 'MESH:D015232', (31, 35))	('tumor', 'Disease', (228, 233))	('spliceosome', 'cellular_component', 'GO:0005681', ('18', '29'))
35534	33114182	Communication between CAFs and tumor cells promotes the formation of a therapy-resistant phenotype in the latter.	('CAFs', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Communication', 'Var', (0, 13))	('tumor', 'Disease', (31, 36))	('CAFs', 'Gene', '6899', (22, 26))	('formation', 'MPA', (56, 65))	('therapy-resistant phenotype', 'MPA', (71, 98))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
35537	33114182	After entering recipient tumor cells, miRNA-106b or miR-522 reduce cancer cells' sensitivity to the chemotherapy by targeting antiproliferative and pro-apoptotic protein TP53INP1 and arachidonate lipoxygenase (ALOX15), leading to a decrease in the accumulation of lipid peroxides in cells and inhibition of ferroptosis.	('TP53INP1 and arachidonate lipoxygenase', 'Gene', '94241', (170, 208))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('inhibition', 'NegReg', (293, 303))	('lipid peroxides', 'Chemical', 'MESH:D008054', (264, 279))	('reduce', 'NegReg', (60, 66))	('tumor', 'Disease', (25, 30))	('ferroptosis', 'biological_process', 'GO:0097707', ('307', '318'))	('ferroptosis', 'CPA', (307, 318))	('miRNA-106b', 'Var', (38, 48))	('-106b', 'Chemical', '-', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('ALOX15', 'Gene', '246', (210, 216))	('miR-522', 'Gene', (52, 59))	('decrease', 'NegReg', (232, 240))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('accumulation of lipid peroxides', 'MPA', (248, 279))	('miR-522', 'Gene', '574495', (52, 59))	('cancer', 'Disease', (67, 73))	('ALOX15', 'Gene', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('sensitivity to the chemotherapy', 'MPA', (81, 112))
35539	33114182	Similarly, miR-92a-3p activates the Wnt/beta-catenin pathway and directly inhibits pro-apoptotic proteins FBXW7 and MOAP1.	('MOAP1', 'Gene', (116, 121))	('FBXW7', 'Gene', '55294', (106, 111))	('FBXW7', 'Gene', (106, 111))	('beta-catenin', 'Gene', (40, 52))	('activates', 'PosReg', (22, 31))	('inhibits', 'NegReg', (74, 82))	('beta-catenin', 'Gene', '1499', (40, 52))	('miR-92a-3p', 'Chemical', '-', (11, 21))	('pro-apoptotic proteins', 'MPA', (83, 105))	('MOAP1', 'Gene', '64112', (116, 121))	('miR-92a-3p', 'Var', (11, 21))
35554	33114182	A similar mechanism has been demonstrated for gastric cancer: TGF-beta1 secreted by MSCs activates SMAD2/3 and thereby induces the expression of lncRNA MACC1-AS1 in tumor cells, which promotes fatty acid oxidation-dependent stemness and chemoresistance through antagonizing miR-145- 5p.	('induces', 'Reg', (119, 126))	('SMAD2/3', 'Gene', '4087;4088', (99, 106))	('MSCs', 'molecular_function', 'GO:0043854', ('84', '88'))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('gastric cancer', 'Disease', (46, 60))	('miR-145', 'Gene', '406937', (274, 281))	('AS1', 'Gene', '5729', (158, 161))	('antagonizing', 'Var', (261, 273))	('fatty acid', 'Chemical', 'MESH:D005227', (193, 203))	('MACC1', 'Gene', (152, 157))	('TGF-beta1', 'Gene', (62, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('miR-145', 'Gene', (274, 281))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('193', '213'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('promotes', 'PosReg', (184, 192))	('tumor', 'Disease', (165, 170))	('TGF-beta1', 'Gene', '7040', (62, 71))	('expression', 'MPA', (131, 141))	('fatty', 'CPA', (193, 198))	('SMAD2/3', 'Gene', (99, 106))	('activates', 'PosReg', (89, 98))	('AS1', 'Gene', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('chemoresistance', 'CPA', (237, 252))	('MACC1', 'Gene', '346389', (152, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))
35577	32977434	Our review shows that there are promising results with beta blockers, statins and metformin, whereas data concerning antidepressants and antibacterial antibiotics seem to show a potentially harmful effect.	('metformin', 'Var', (82, 91))	('beta', 'Var', (55, 59))	('metformin', 'Chemical', 'MESH:D008687', (82, 91))
35635	32977434	Focusing on 1511 patients with colorectal cancer treated with ARB/ACEi vs. 7291 colorectal cancer controls treated with other antihypertensive drugs, there was no increase for cancer-specific mortality (OR: 0.82, 95% CI: 0.64-1.07 and OR: 0.78, 95% CI: 0.66-0.92 respectively for ARB and ACEi).	('ARB/ACEi', 'Chemical', '-', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('mortality', 'Disease', 'MESH:D003643', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('hypertensive', 'Disease', (130, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('colorectal cancer', 'Disease', (80, 97))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('ARB/ACEi', 'Var', (62, 70))	('colorectal cancer', 'Disease', (31, 48))	('patients', 'Species', '9606', (17, 25))	('mortality', 'Disease', (192, 201))	('hypertensive', 'Disease', 'MESH:D006973', (130, 142))	('cancer', 'Disease', (91, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancer', 'Disease', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (176, 182))	('rectal cancer', 'Phenotype', 'HP:0100743', (35, 48))
35656	32977434	Risk-benefit assessment concerning use of non-aspirin-NSAIDs (NA-NSAIDs) for colorectal cancer prevention is still unknown: clinically relevant protective effects of NA-NSAIDs use have been found in women (19% relative risk reduction), distal colon cancer (22% relative risk reduction) and white people (risk reduction from 31% to 41%).	('people', 'Species', '9606', (296, 302))	('colorectal cancer', 'Disease', (77, 94))	('distal colon cancer', 'Disease', 'MESH:D015179', (236, 255))	('colon cancer', 'Phenotype', 'HP:0003003', (243, 255))	('rectal cancer', 'Phenotype', 'HP:0100743', (81, 94))	('distal colon cancer', 'Disease', (236, 255))	('NA-NSAIDs', 'Var', (166, 175))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('women', 'Species', '9606', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('aspirin', 'Chemical', 'MESH:D001241', (46, 53))	('reduction', 'NegReg', (275, 284))
35660	32977434	The study showed that, in vitro, ASA significantly enhances the cisplatin-mediated inhibition of cell proliferation, migration and invasion and induces apoptosis in colon cancer cells.	('ASA', 'Var', (33, 36))	('invasion', 'CPA', (131, 139))	('inhibition', 'NegReg', (83, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))	('induces', 'Reg', (144, 151))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('83', '115'))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('enhances', 'PosReg', (51, 59))	('colon cancer', 'Disease', (165, 177))	('apoptosis', 'CPA', (152, 161))	('cisplatin-mediated', 'MPA', (64, 82))	('ASA', 'Chemical', 'MESH:D001241', (33, 36))
35661	32977434	The combined treatment of aspirin and cisplatin suppresses the expression of the antiapoptotic protein Bcl-2 and the EMT-related proteins, upregulates the levels of the cleaved PARP and Bax, blocks the PI3K/AKT and RAF-MEK-ERK signalling pathways, and inhibits the binding activity of NF-kappaB to the COX-2 promoter.	('ERK', 'Gene', '2048', (223, 226))	('COX-2', 'Gene', (302, 307))	('Bcl-2', 'Gene', '596', (103, 108))	('Bax', 'Gene', (186, 189))	('upregulates', 'PosReg', (139, 150))	('RAF', 'Gene', '22882', (215, 218))	('binding', 'molecular_function', 'GO:0005488', ('265', '272'))	('Bax', 'Gene', '581', (186, 189))	('COX-2', 'Gene', '4513', (302, 307))	('EMT', 'biological_process', 'GO:0001837', ('117', '120'))	('AKT', 'Gene', '207', (207, 210))	('binding', 'Interaction', (265, 272))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('MEK', 'Gene', '5609', (219, 222))	('cisplatin', 'Var', (38, 47))	('suppresses', 'NegReg', (48, 58))	('RAF', 'Gene', (215, 218))	('inhibits', 'NegReg', (252, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('NF-kappaB', 'Gene', (285, 294))	('levels', 'MPA', (155, 161))	('antiapoptotic protein', 'MPA', (81, 102))	('aspirin', 'Chemical', 'MESH:D001241', (26, 33))	('signalling', 'biological_process', 'GO:0023052', ('227', '237'))	('MEK', 'Gene', (219, 222))	('PARP', 'Gene', '142', (177, 181))	('expression', 'MPA', (63, 73))	('NF-kappaB', 'Gene', '4790', (285, 294))	('blocks', 'NegReg', (191, 197))	('PARP', 'Gene', (177, 181))	('cleaved', 'MPA', (169, 176))	('ERK', 'Gene', (223, 226))	('Bcl-2', 'Gene', (103, 108))	('ERK', 'molecular_function', 'GO:0004707', ('223', '226'))	('AKT', 'Gene', (207, 210))	('PI3K', 'molecular_function', 'GO:0016303', ('202', '206'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('103', '108'))
35663	32977434	When it comes to patients who have already developed colorectal cancer, data concerning clinical usefulness of NSAIDs are rarer; use of aspirin seems to improve survival particularly in patients with colorectal cancer harbouring PIK3CA mutations.	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('rectal cancer', 'Phenotype', 'HP:0100743', (57, 70))	('PIK3CA', 'Gene', '5290', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('rectal cancer', 'Phenotype', 'HP:0100743', (204, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('mutations', 'Var', (236, 245))	('improve', 'PosReg', (153, 160))	('patients', 'Species', '9606', (17, 25))	('colorectal cancer', 'Disease', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('survival', 'MPA', (161, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('aspirin', 'Chemical', 'MESH:D001241', (136, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('PIK3CA', 'Gene', (229, 235))	('patients', 'Species', '9606', (186, 194))	('colorectal cancer', 'Disease', (53, 70))
35672	32977434	There are currently ongoing clinical trials (mostly focused on colon cancer patients harbouring PIK3CA mutations) that will look into this matter in detail.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (63, 75))	('colon cancer', 'Disease', 'MESH:D015179', (63, 75))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('colon cancer', 'Disease', (63, 75))
35676	32977434	The study showed that antibiotic use was associated with an 18% relative risk increase of cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('antibiotic', 'Var', (22, 32))	('increase', 'PosReg', (78, 86))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
35704	32977434	have shown that, in human HT29 and HCT116 colon carcinoma cells, TCAs reduce cell viability in a concentration-dependent manner and cause apoptotic cell death through either a non-mitochondrial or a mitochondrial pathway.	('mitochondrial pathway', 'Pathway', (199, 220))	('human', 'Species', '9606', (20, 25))	('TCAs', 'Var', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('colon carcinoma', 'Disease', (42, 57))	('TCAs', 'Chemical', 'MESH:D014238', (65, 69))	('HCT116', 'CellLine', 'CVCL:0291', (35, 41))	('reduce', 'NegReg', (70, 76))	('colon carcinoma', 'Disease', 'MESH:D003110', (42, 57))	('HT29', 'CellLine', 'CVCL:0320', (26, 30))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('138', '158'))	('death', 'Disease', 'MESH:D003643', (153, 158))	('death', 'Disease', (153, 158))	('cell viability', 'CPA', (77, 91))	('cause', 'Reg', (132, 137))	('non-mitochondrial', 'Pathway', (176, 193))
35732	32977434	Conversely, multiple epidemiological studies have demonstrated an association between metformin and reduced cancer incidence and mortality.	('mortality', 'Disease', 'MESH:D003643', (129, 138))	('reduced', 'NegReg', (100, 107))	('mortality', 'Disease', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('metformin', 'Var', (86, 95))	('metformin', 'Chemical', 'MESH:D008687', (86, 95))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
35735	32977434	On the whole, metformin can induce anticancer activity through two main routes: a direct mechanism resulting from the inhibition of mitochondrial complex I and consequent suppression of adenosine triphosphate (ATP) production in prenoplastic and neoplastic cells and an indirect mechanism related to metformin insulin-lowering activity, which may slow tumour development in hyperinsulinemic patients.	('insulin', 'Gene', (310, 317))	('hyperinsulinemic', 'Disease', (374, 390))	('adenosine', 'Chemical', 'MESH:D000241', (186, 195))	('mitochondrial complex I', 'Enzyme', (132, 155))	('insulin', 'molecular_function', 'GO:0016088', ('310', '317'))	('cancer', 'Disease', (39, 45))	('inhibition', 'NegReg', (118, 128))	('ATP', 'Chemical', 'MESH:D000255', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (352, 358))	('tumour', 'Disease', 'MESH:D009369', (352, 358))	('insulin', 'Gene', '3630', (379, 386))	('tumour', 'Disease', (352, 358))	('insulin', 'Gene', '3630', (310, 317))	('patients', 'Species', '9606', (391, 399))	('hyperinsulinemic', 'Disease', 'MESH:D044903', (374, 390))	('suppression', 'NegReg', (171, 182))	('complex I', 'cellular_component', 'GO:0030964', ('146', '155'))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('metformin', 'Var', (14, 23))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('slow', 'NegReg', (347, 351))	('metformin', 'Chemical', 'MESH:D008687', (300, 309))	('insulin', 'Gene', (379, 386))
35745	32977434	To conclude, metformin use might be associated with improved survival for patients with colorectal cancer, but its impact in patients with mCRC has still not been proven.	('colorectal cancer', 'Disease', (88, 105))	('metformin', 'Var', (13, 22))	('patients', 'Species', '9606', (74, 82))	('improved', 'PosReg', (52, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('rectal cancer', 'Phenotype', 'HP:0100743', (92, 105))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('survival', 'MPA', (61, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (125, 133))
35772	32977434	Indeed, the newest addition is the one represented by B-raf inhibitors for patients harbouring B-raf V600E mutations and we could still argue that it is still based on inhibition of a crucial target of RAS-RAF-MEK-ERK pathway.	('RAF', 'Gene', '22882', (206, 209))	('V600E mutations', 'Var', (101, 116))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('B-raf', 'Gene', '673', (54, 59))	('RAF', 'Gene', (206, 209))	('B-raf', 'Gene', (95, 100))	('B-raf', 'Gene', (54, 59))	('B-raf', 'Gene', '673', (95, 100))	('MEK', 'Gene', (210, 213))	('patients', 'Species', '9606', (75, 83))	('MEK', 'Gene', '5609', (210, 213))	('ERK', 'Gene', (214, 217))	('ERK', 'Gene', '2048', (214, 217))	('ERK', 'molecular_function', 'GO:0004707', ('214', '217'))
35786	32977434	Despite these differences, survival outcomes for patients who received beta blockers were still better compared to other drugs or to patients who did not receive any antihypertensive medication, independently from age of colorectal cancer diagnosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('rectal cancer', 'Phenotype', 'HP:0100743', (225, 238))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (166, 193))	('patients', 'Species', '9606', (133, 141))	('better', 'PosReg', (96, 102))	('hypertensive', 'Disease', 'MESH:D006973', (170, 182))	('beta', 'Var', (71, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patients', 'Species', '9606', (49, 57))	('hypertensive', 'Disease', (170, 182))	('colorectal cancer', 'Disease', (221, 238))	('survival outcomes', 'CPA', (27, 44))
35837	32423432	Personality has been associated with depressive symptoms in chronic illnesses and reduced emotional HRQoL in heart failure patients.	('depressive symptoms', 'Disease', (37, 56))	('depressive symptoms', 'Phenotype', 'HP:0000716', (37, 56))	('depressive symptoms', 'Disease', 'MESH:D000275', (37, 56))	('patients', 'Species', '9606', (123, 131))	('heart failure', 'Phenotype', 'HP:0001635', (109, 122))	('emotional HRQoL in heart failure', 'Disease', 'MESH:D006333', (90, 122))	('emotional HRQoL in heart failure', 'Disease', (90, 122))	('Personality', 'Var', (0, 11))	('reduced', 'NegReg', (82, 89))
35847	32423432	In addition, we estimated neuroticism and trait anxiety to be associated with decreased HRQoL and QoL scores.	('anxiety', 'Disease', (48, 55))	('anxiety', 'Phenotype', 'HP:0000739', (48, 55))	('neuroticism', 'Var', (26, 37))	('decreased HRQoL and QoL', 'Disease', 'MESH:D002303', (78, 101))	('anxiety', 'Disease', 'MESH:D001007', (48, 55))
35993	32214837	Association of XRCC1, XRCC2 and XRCC3 Gene Polymorphism with Esophageal Cancer Risk The X-ray repair cross-complementing (XRCC) gene polymorphisms influence esophageal carcinogenesis by altering the DNA repair capacity.	('DNA repair capacity', 'MPA', (199, 218))	('esophageal carcinogenesis', 'Disease', (157, 182))	('Esophageal Cancer', 'Disease', (61, 78))	('XRCC3', 'Gene', (32, 37))	('polymorphisms', 'Var', (133, 146))	('XRCC2', 'Gene', (22, 27))	('XRCC3', 'Gene', '7517', (32, 37))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('XRCC1', 'Gene', '7515', (15, 20))	('altering', 'Reg', (186, 194))	('influence', 'Reg', (147, 156))	('men', 'Species', '9606', (113, 116))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (61, 78))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('DNA repair', 'biological_process', 'GO:0006281', ('199', '209'))	('XRCC2', 'Gene', '7516', (22, 27))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (157, 182))	('XRCC1', 'Gene', (15, 20))
35994	32214837	The present study was designed to screen five single nucleotide polymorphisms (SNPs) of XRCC genes for their susceptibility to esophageal cancer (EC) risk.	('susceptibility', 'Reg', (109, 123))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('XRCC genes', 'Gene', (88, 98))	('single nucleotide polymorphisms', 'Var', (46, 77))
35997	32214837	For XRCC1 p.Arg399Gln, a decreased risk for EC was associated with the AA genotype [OR (95% CI): 0.53 (0.3-0.95), p=0.03] even after adjusting for various covariates [OR (95% CI): 0.49 (0.26-0.9), p=0.024] and with the recessive model [OR (95% CI): 0.49 (0.27-0.8), p=0.016].	('p.Arg399Gln', 'Var', (10, 21))	('p.Arg399Gln', 'Mutation', 'rs25487', (10, 21))	('XRCC1', 'Gene', (4, 9))	('decreased', 'NegReg', (25, 34))
35999	32214837	The two XRCC1 polymorphisms, p.Arg399Gln and p.Arg194Trp were in slight LD among EC patients (D=0.845, r2=0.042).	('XRCC1 p', 'Gene', '7515', (8, 15))	('p.Arg399Gln', 'Var', (29, 40))	('p.Arg399Gln', 'Mutation', 'rs25487', (29, 40))	('patients', 'Species', '9606', (84, 92))	('p.Arg194Trp', 'Mutation', 'rs1799782', (45, 56))	('p.Arg194Trp', 'Var', (45, 56))	('XRCC1 p', 'Gene', (8, 15))
36000	32214837	XRCC2 and XRCC3 polymorphisms were not associated with EC risk.	('polymorphisms', 'Var', (16, 29))	('XRCC2', 'Gene', '7516', (0, 5))	('XRCC2', 'Gene', (0, 5))	('XRCC3', 'Gene', (10, 15))	('XRCC3', 'Gene', '7517', (10, 15))
36001	32214837	XRCC1 p.Arg399Gln plays a protective role in the development of the EC.	('p.Arg399Gln', 'Mutation', 'rs25487', (6, 17))	('XRCC1', 'Gene', (0, 5))	('men', 'Species', '9606', (56, 59))	('p.Arg399Gln', 'Var', (6, 17))
36002	32214837	The study is the first report from India, providing baseline data about genetic polymorphisms in DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall EC risk.	('XRCC3', 'Gene', '7517', (131, 136))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('DNA repair', 'biological_process', 'GO:0006281', ('97', '107'))	('modulating', 'Reg', (137, 147))	('XRCC1', 'Gene', '7515', (114, 119))	('XRCC2', 'Gene', '7516', (121, 126))	('polymorphisms', 'Var', (80, 93))	('XRCC2', 'Gene', (121, 126))	('XRCC3', 'Gene', (131, 136))	('XRCC1', 'Gene', (114, 119))
36007	32214837	XRCC1 protein as a part of Base excision repair (BER) pathway plays an efficient role in repairing DNA single-strand breaks.	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('XRCC1 p', 'Gene', (0, 7))	('XRCC1 p', 'Gene', '7515', (0, 7))	('BER', 'biological_process', 'GO:0006284', ('49', '52'))	('DNA', 'Var', (99, 102))	('repairing', 'MPA', (89, 98))	('Base excision repair', 'biological_process', 'GO:0006284', ('27', '47'))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))
36009	32214837	Two XRCC1 polymorphisms, p.Arg194Trp (exon 6) and p. Arg280His (exon 9) affect the function of the protein.	('Arg280His', 'Var', (53, 62))	('affect', 'Reg', (72, 78))	('p.Arg194Trp', 'Mutation', 'rs1799782', (25, 36))	('p.Arg194Trp', 'Var', (25, 36))	('XRCC1 p', 'Gene', (4, 11))	('XRCC1 p', 'Gene', '7515', (4, 11))	('Arg280His', 'SUBSTITUTION', 'None', (53, 62))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('function of the protein', 'MPA', (83, 106))
36010	32214837	XRCC1 p.Arg399Gln polymorphism in exon 10 has been associated with breast, lung and head and neck cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('XRCC1', 'Gene', (0, 5))	('neck cancers', 'Disease', (93, 105))	('head and neck cancer', 'Disease', 'MESH:D006258', (84, 104))	('neck', 'cellular_component', 'GO:0044326', ('93', '97'))	('p.Arg399Gln', 'Var', (6, 17))	('associated', 'Reg', (51, 61))	('p.Arg399Gln', 'Mutation', 'rs25487', (6, 17))	('neck cancers', 'Disease', 'MESH:D006258', (93, 105))	('breast', 'Disease', (67, 73))	('head and neck cancer', 'Phenotype', 'HP:0012288', (84, 104))	('lung', 'Disease', (75, 79))	('head and neck cancers', 'Phenotype', 'HP:0012288', (84, 105))
36012	32214837	XRCC2 p.Arg188His polymorphism located in exon3 has been associated with cancers like pancreatic, ovarian, oral and upper aerodigestive tract cancers.	('upper aerodigestive tract cancers', 'Disease', (116, 149))	('cancers', 'Disease', (73, 80))	('pancreatic', 'Disease', (86, 96))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('XRCC2', 'Gene', '7516', (0, 5))	('cancers', 'Disease', (142, 149))	('upper aerodigestive tract cancers', 'Disease', 'MESH:D006258', (116, 149))	('p.Arg188His', 'Mutation', 'rs3218536', (6, 17))	('p.Arg188His', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('XRCC2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('pancreatic', 'Disease', 'MESH:D010195', (86, 96))	('ovarian', 'Disease', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('associated', 'Reg', (57, 67))
36014	32214837	Variation in expression of XRCC3 has been reported in various cancers, like gastric, breast, lung, skin and colorectal.	('colorectal', 'Disease', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'MPA', (13, 23))	('breast', 'Disease', (85, 91))	('reported', 'Reg', (42, 50))	('lung', 'Disease', (93, 97))	('XRCC3', 'Gene', (27, 32))	('skin', 'Disease', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('gastric', 'Disease', (76, 83))	('XRCC3', 'Gene', '7517', (27, 32))	('Variation', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
36015	32214837	The most common polymorphism in XRCC3 p.Thr241Met in exon 7 can influence the ability to repair DNA.	('XRCC3', 'Gene', (32, 37))	('p.Thr241Met', 'Var', (38, 49))	('ability', 'MPA', (78, 85))	('XRCC3', 'Gene', '7517', (32, 37))	('influence', 'Reg', (64, 73))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('p.Thr241Met', 'Mutation', 'rs861539', (38, 49))
36016	32214837	Allelic variants of XRCC1, XRCC2, and XRCC3 are associated with risk of different types of cancer among different populations all over the world.	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (91, 97))	('Allelic variants', 'Var', (0, 16))	('XRCC1', 'Gene', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('XRCC2', 'Gene', '7516', (27, 32))	('XRCC3', 'Gene', (38, 43))	('XRCC2', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XRCC3', 'Gene', '7517', (38, 43))	('XRCC1', 'Gene', '7515', (20, 25))
36019	32214837	Therefore, the present study was carried out to explore the role of five polymorphisms of XRCC genes; XRCC1 (p.Arg399Gln, p.Arg194Trp, p.Arg280His), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met) in the risk of EC in the population of Punjab, India.	('p.Arg280His', 'Var', (135, 146))	('p.Arg399Gln', 'Var', (109, 120))	('XRCC3', 'Gene', (173, 178))	('p.Arg399Gln', 'Mutation', 'rs25487', (109, 120))	('XRCC3', 'Gene', '7517', (173, 178))	('p.Arg280His', 'Mutation', 'rs25489', (135, 146))	('p.Arg194Trp', 'Mutation', 'rs1799782', (122, 133))	('XRCC1', 'Gene', (102, 107))	('p.Arg194Trp', 'Var', (122, 133))	('p.Thr241Met', 'Mutation', 'rs861539', (180, 191))	('XRCC genes', 'Gene', (90, 100))	('p.Arg188His', 'Mutation', 'rs3218536', (156, 167))	('p.Arg188His', 'Var', (156, 167))	('XRCC1', 'Gene', '7515', (102, 107))	('p.Thr241Met', 'Var', (180, 191))	('XRCC2', 'Gene', '7516', (149, 154))	('XRCC2', 'Gene', (149, 154))
36024	32214837	Previously published primer sequences for XRCC1 p.Arg399Gln, XRCC1 p.Arg194Trp, XRCC1 p.Arg280His, XRCC2 p.Arg188His and XRCC3 p.Thr241Met polymorphisms were used to amplify the target region.	('XRCC1', 'Gene', (61, 66))	('p.Arg194Trp', 'Mutation', 'rs1799782', (67, 78))	('p.Thr241Met', 'Var', (127, 138))	('XRCC2', 'Gene', '7516', (99, 104))	('XRCC2', 'Gene', (99, 104))	('XRCC1', 'Gene', (42, 47))	('XRCC3', 'Gene', '7517', (121, 126))	('p.Arg399Gln', 'Var', (48, 59))	('p.Arg280His', 'Var', (86, 97))	('p.Arg399Gln', 'Mutation', 'rs25487', (48, 59))	('p.Arg194Trp', 'Var', (67, 78))	('p.Thr241Met', 'Mutation', 'rs861539', (127, 138))	('p.Arg188His', 'Var', (105, 116))	('XRCC1', 'Gene', (80, 85))	('p.Arg280His', 'Mutation', 'rs25489', (86, 97))	('XRCC3', 'Gene', (121, 126))	('p.Arg188His', 'Mutation', 'rs3218536', (105, 116))
36031	32214837	In the present study 5 polymorphisms; XRCC1 (p.Arg399Gln, p.Arg280His, p.Arg194Trp), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met) were studied for the association with risk of esophageal cancer (EC).	('p.Thr241Met', 'Var', (116, 127))	('XRCC2', 'Gene', '7516', (85, 90))	('XRCC1', 'Gene', (38, 43))	('p.Arg399Gln', 'Var', (45, 56))	('XRCC3', 'Gene', '7517', (109, 114))	('p.Arg280His', 'Mutation', 'rs25489', (58, 69))	('p.Arg194Trp', 'Mutation', 'rs1799782', (71, 82))	('p.Arg188His', 'Mutation', 'rs3218536', (92, 103))	('p.Arg188His', 'Var', (92, 103))	('p.Arg194Trp', 'Var', (71, 82))	('XRCC1', 'Gene', '7515', (38, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('XRCC2', 'Gene', (85, 90))	('XRCC3', 'Gene', (109, 114))	('p.Thr241Met', 'Mutation', 'rs861539', (116, 127))	('esophageal cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('p.Arg280His', 'Var', (58, 69))	('p.Arg399Gln', 'Mutation', 'rs25487', (45, 56))
36032	32214837	For XRCC1 p.Arg280His polymorphism, A allele was associated with an increased risk of EC (OR=1.60, 95% CI= 1.02-2.52, p=0.04).	('XRCC1', 'Gene', (4, 9))	('p.Arg280His', 'Var', (10, 21))	('p.Arg280His', 'Mutation', 'rs25489', (10, 21))
36038	32214837	No significant difference in allele (p=0.54) and genotype (p=0.52) frequencies of XRCC1 p.Arg194Trp polymorphism was observed.	('p.Arg194Trp', 'Var', (88, 99))	('XRCC1', 'Gene', (82, 87))	('p.Arg194Trp', 'Mutation', 'rs1799782', (88, 99))
36039	32214837	No association with EC risk was observed for XRCC2 p.Arg188His and XRCC3 p.Thr241Met polymorphism (p=0.53) in the subjects.	('p.Thr241Met', 'Mutation', 'rs861539', (73, 84))	('XRCC3', 'Gene', (67, 72))	('XRCC3', 'Gene', '7517', (67, 72))	('p.Arg188His', 'Mutation', 'rs3218536', (51, 62))	('p.Thr241Met', 'Var', (73, 84))	('p.Arg188His', 'Var', (51, 62))	('XRCC2', 'Gene', '7516', (45, 50))	('XRCC2', 'Gene', (45, 50))
36040	32214837	Genetic model analysis of XRCC1 p.Arg399Gln and XRCC3p.Thr241Met (Table 6) revealed a decreased risk of EC under the recessive model AA vs GG+GA (OR=0.55, 95% CI=0.32-0.95, p=0.027) for XRCC1p.Arg399Gln polymorphism which became more significant after adjustment with binomial logistic regression (OR=0.49, 95% CI=0.27-0.88, p=0.016).	('p.Arg399Gln', 'Mutation', 'rs25487', (191, 202))	('men', 'Species', '9606', (258, 261))	('XRCC1', 'Gene', (26, 31))	('p.Thr241Met', 'Mutation', 'rs861539', (53, 64))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (32, 43))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (191, 202))	('decreased', 'NegReg', (86, 95))	('p.Arg399Gln', 'Var', (32, 43))	('p.Arg399Gln', 'Var', (191, 202))	('p.Arg399Gln', 'Mutation', 'rs25487', (32, 43))
36041	32214837	For p.Thr241Met polymorphism no genotype combination was associated with EC.	('p.Thr241Met', 'Mutation', 'rs861539', (4, 15))	('p.Thr241Met', 'Var', (4, 15))	('associated', 'Reg', (57, 67))
36043	32214837	Based on the measures of linkage disequilibrium (LD), the two polymorphisms of XRCC1gene, p.Arg399Gln and p.Arg194Trp, were in slight LD among EC patients (D=0.845, r2=0.042) (Figure 1A).	('XRCC1', 'Gene', '7515', (79, 84))	('p.Arg194Trp', 'Var', (106, 117))	('p.Arg194Trp', 'Mutation', 'rs1799782', (106, 117))	('XRCC1', 'Gene', (79, 84))	('p.Arg399Gln', 'Var', (90, 101))	('p.Arg399Gln', 'Mutation', 'rs25487', (90, 101))	('patients', 'Species', '9606', (146, 154))
36044	32214837	The haplotype GGT (p.Arg399Gln, p.Arg280His, and p.Arg194Trp) was predominant in EC cases as compared to controls, but the difference was statistically non-significant (p=0.1).	('p.Arg280His', 'Var', (32, 43))	('p.Arg399Gln', 'Mutation', 'rs25487', (19, 30))	('p.Arg280His', 'Mutation', 'rs25489', (32, 43))	('p.Arg194Trp', 'Mutation', 'rs1799782', (49, 60))	('p.Arg194Trp', 'Var', (49, 60))	('p.Arg399Gln', 'Var', (19, 30))
36046	32214837	The combinations comprising the AA genotype (p.Arg399Gln) occurred significantly more often in controls than patients, with AA-CC-CC combination associated with significantly decreased risk of EC (OR=0.5, 95% CI=0.29-0.91, p=0.020).	('p.Arg399Gln', 'Mutation', 'rs25487', (45, 56))	('patients', 'Species', '9606', (109, 117))	('decreased', 'NegReg', (175, 184))	('p.Arg399Gln', 'Var', (45, 56))
36047	32214837	According to MDR analysis, the best MDR model included all the five studied polymorphisms XRCC1 (p.Arg399Gln, p.Arg194Trp, p.Arg280His), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met).	('p.Arg188His', 'Var', (144, 155))	('XRCC1', 'Gene', '7515', (90, 95))	('p.Arg280His', 'Var', (123, 134))	('p.Thr241Met', 'Var', (168, 179))	('XRCC3', 'Gene', (161, 166))	('p.Arg194Trp', 'Var', (110, 121))	('p.Arg280His', 'Mutation', 'rs25489', (123, 134))	('XRCC2', 'Gene', (137, 142))	('p.Arg194Trp', 'Mutation', 'rs1799782', (110, 121))	('XRCC3', 'Gene', '7517', (161, 166))	('XRCC2', 'Gene', '7516', (137, 142))	('MDR', 'molecular_function', 'GO:0004745', ('36', '39'))	('MDR', 'molecular_function', 'GO:0004745', ('13', '16'))	('p.Thr241Met', 'Mutation', 'rs861539', (168, 179))	('XRCC1', 'Gene', (90, 95))	('p.Arg399Gln', 'Var', (97, 108))	('p.Arg399Gln', 'Mutation', 'rs25487', (97, 108))	('p.Arg188His', 'Mutation', 'rs3218536', (144, 155))
36050	32214837	In India, the inter-individual differences in susceptibility to cancer due to the genetic polymorphisms in XRCC1 previously found.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('XRCC1 p', 'Gene', (107, 114))	('susceptibility', 'MPA', (46, 60))	('polymorphisms', 'Var', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('XRCC1 p', 'Gene', '7515', (107, 114))
36051	32214837	As DNA-repair gene polymorphisms play a very important role in carcinogenesis, we carried out this case-control study to evaluate whether XRCC1 (p.Arg399Gln, p.Arg194Trp and p.Arg280His), XRCC2 (p.Arg188His), and XRCC3 (p.Thr241Met) gene polymorphisms modulate the risk of esophageal cancer.	('XRCC2', 'Gene', '7516', (188, 193))	('modulate', 'Reg', (252, 260))	('p.Arg399Gln', 'Mutation', 'rs25487', (145, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('p.Arg194Trp', 'Mutation', 'rs1799782', (158, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (273, 290))	('p.Arg188His', 'Mutation', 'rs3218536', (195, 206))	('p.Arg188His', 'Var', (195, 206))	('DNA-repair', 'biological_process', 'GO:0006281', ('3', '13'))	('p.Arg280His', 'Var', (174, 185))	('XRCC3', 'Gene', (213, 218))	('XRCC1', 'Gene', (138, 143))	('p.Arg399Gln', 'Var', (145, 156))	('p.Thr241Met', 'Mutation', 'rs861539', (220, 231))	('esophageal cancer', 'Disease', (273, 290))	('p.Arg194Trp', 'Var', (158, 169))	('p.Arg280His', 'Mutation', 'rs25489', (174, 185))	('XRCC2', 'Gene', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('XRCC1', 'Gene', '7515', (138, 143))	('p.Thr241Met', 'Var', (220, 231))	('XRCC3', 'Gene', '7517', (213, 218))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))	('carcinogenesis', 'Disease', (63, 77))
36054	32214837	Very few studies relating the XRCC1 Arg399Gln polymorphism with esophageal cancer risk are available from which only one is from India.	('XRCC1', 'Gene', (30, 35))	('esophageal cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('XRCC1', 'Gene', '7515', (30, 35))	('Arg399Gln', 'Var', (36, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('Arg399Gln', 'SUBSTITUTION', 'None', (36, 45))
36055	32214837	Among previous reports from North India on EC; a study of Chandigarh region found association with a decreased risk of XRCC1 p.Arg399Gln, another study from Uttar Pradesh also reported Arg/Gln (p=0.03, OR= 0.62) and Gln/Gln (p=0.003, OR=0.37) genotype to be associated with a decreased risk of gall bladder cancer; a study from Kashmir on colorectal cancer also reported a protective role of AA genotype.	('colorectal cancer', 'Phenotype', 'HP:0003003', (339, 356))	('Gln', 'Chemical', 'MESH:D005973', (189, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (339, 356))	('Arg', 'Chemical', 'MESH:D001120', (185, 188))	('colorectal cancer', 'Disease', (339, 356))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('decreased', 'NegReg', (101, 110))	('XRCC1', 'Gene', (119, 124))	('Arg', 'Chemical', 'MESH:D001120', (127, 130))	('gall bladder cancer', 'Disease', (294, 313))	('Gln', 'Chemical', 'MESH:D005973', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('bladder cancer', 'Phenotype', 'HP:0009725', (299, 313))	('gall bladder cancer', 'Disease', 'MESH:D005706', (294, 313))	('p.Arg399Gln', 'Var', (125, 136))	('Gln', 'Chemical', 'MESH:D005973', (216, 219))	('p.Arg399Gln', 'Mutation', 'rs25487', (125, 136))	('Gln', 'Chemical', 'MESH:D005973', (220, 223))
36057	32214837	Contrary to the results of the present study, some previous studies from North India have reported an increased risk with AA genotype of XRCC1p.Arg399Gln polymorphism in lung cancer, head and neck cancer, colorectal cancer and prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('head and neck cancer', 'Disease', 'MESH:D006258', (183, 203))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (142, 153))	('lung cancer', 'Disease', (170, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('head and neck cancer', 'Phenotype', 'HP:0012288', (183, 203))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('neck', 'cellular_component', 'GO:0044326', ('192', '196'))	('prostate cancer', 'Disease', (227, 242))	('colorectal cancer', 'Disease', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('p.Arg399Gln', 'Var', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
36059	32214837	However, few studies from South India reported no association of XRCC1p.Arg399Gln polymorphism with any of cancer (Table 1).	('p.Arg399Gln', 'SUBSTITUTION', 'None', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p.Arg399Gln', 'Var', (70, 81))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('association', 'Interaction', (50, 61))	('cancer', 'Disease', (107, 113))
36060	32214837	Results of the present study on XRCC1 p.Arg399Gln polymorphism is in agreement with the studies from different parts of the globe like esophageal cancer in Han Chinese, colorectal adenocarcinoma in Norwegian population, gallbladder cancer, and non-melanoma skin cancers.	('gallbladder cancer', 'Disease', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('men', 'Species', '9606', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (244, 269))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (169, 194))	('skin cancer', 'Phenotype', 'HP:0008069', (257, 268))	('bladder cancer', 'Phenotype', 'HP:0009725', (224, 238))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('non-melanoma skin cancers', 'Disease', (244, 269))	('gallbladder cancer', 'Disease', 'MESH:D005706', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('p.Arg399Gln', 'Mutation', 'rs25487', (38, 49))	('skin cancers', 'Phenotype', 'HP:0008069', (257, 269))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('p.Arg399Gln', 'Var', (38, 49))	('esophageal cancer', 'Disease', (135, 152))	('colorectal adenocarcinoma', 'Disease', (169, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('XRCC1', 'Gene', (32, 37))
36061	32214837	In contrast, some previous studies have reported the association of Arg399Gln polymorphism with an increased risk of esophageal, stomach and oral cancers, colorectal cancers in Korean, Egyptian and Japanese populations, lung cancer and breast cancer.	('oral cancers', 'Disease', (141, 153))	('oral cancers', 'Disease', 'MESH:D009062', (141, 153))	('esophageal', 'Disease', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('association', 'Reg', (53, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('lung cancer', 'Disease', (220, 231))	('stomach', 'Disease', (129, 136))	('colorectal cancers', 'Disease', (155, 173))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('Arg399Gln', 'SUBSTITUTION', 'None', (68, 77))	('colorectal cancers', 'Disease', 'MESH:D015179', (155, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('Arg399Gln', 'Var', (68, 77))
36062	32214837	However, three studies did not find any association between p.Arg399Gln polymorphism and cancer of the esophagus, gall bladder and breast.	('gall bladder', 'Disease', 'MESH:D005705', (114, 126))	('p.Arg399Gln', 'Var', (60, 71))	('p.Arg399Gln', 'Mutation', 'rs25487', (60, 71))	('gall bladder', 'Disease', (114, 126))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('breast', 'Disease', (131, 137))	('cancer', 'Disease', (89, 95))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (89, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
36064	32214837	Among international studies, no association of XRCC1 p.Arg194Trp has been reported with EC risk in the population of North Carolina, gastric cancer in Korean population and breast cancer in Caucasian women.	('women', 'Species', '9606', (200, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('XRCC1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('gastric cancer', 'Disease', (133, 147))	('p.Arg194Trp', 'Var', (53, 64))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('p.Arg194Trp', 'Mutation', 'rs1799782', (53, 64))	('breast cancer', 'Disease', (173, 186))
36065	32214837	On the contrary, Trp allele has been reported to be associated with an increased risk of gastric cancer in the Chinese population.	('associated', 'Reg', (52, 62))	('Trp', 'Gene', (17, 20))	('Trp', 'Chemical', 'MESH:D014364', (17, 20))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (71, 103))	('allele', 'Var', (21, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
36067	32214837	In the present study, we observed a lower risk of esophageal cancer associated with p.Arg399Gln polymorphism of XRCC1.	('p.Arg399Gln', 'Var', (84, 95))	('p.Arg399Gln', 'Mutation', 'rs25487', (84, 95))	('XRCC1', 'Gene', (112, 117))	('XRCC1', 'Gene', '7515', (112, 117))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
36068	32214837	A relationship between polymorphism in XRCC1Arg399Gln and increased rate of apoptosis has been reported in patients of ulcerative colitis and in schizophrenia patients.	('ulcerative colitis', 'Disease', (119, 137))	('schizophrenia', 'Disease', 'MESH:D012559', (145, 158))	('colitis', 'Phenotype', 'HP:0002583', (130, 137))	('increased', 'PosReg', (58, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('patients', 'Species', '9606', (159, 167))	('schizophrenia', 'Phenotype', 'HP:0100753', (145, 158))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (119, 137))	('polymorphism', 'Var', (23, 35))	('apoptosis', 'CPA', (76, 85))	('XRCC1Arg399Gln', 'Gene', (39, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('patients', 'Species', '9606', (107, 115))	('schizophrenia', 'Disease', (145, 158))	('ulcerative colitis', 'Disease', 'MESH:D003093', (119, 137))	('rate', 'MPA', (68, 72))
36069	32214837	The increased rates of the apoptosis results into the elimination of potential premalignant cells and hence, the XRCC1 Gln399 may play a protective role in esophageal cancer risk.	('rates', 'MPA', (14, 19))	('XRCC1', 'Gene', (113, 118))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))	('Gln399', 'Var', (119, 125))	('esophageal cancer', 'Disease', (156, 173))	('apoptosis', 'CPA', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Gln399', 'Chemical', '-', (119, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('XRCC1', 'Gene', '7515', (113, 118))
36070	32214837	The A allele of XRCC1p.Arg280His was associated with an increased risk of esophageal cancer in the present study.	('esophageal cancer', 'Disease', (74, 91))	('p.Arg280His', 'SUBSTITUTION', 'None', (21, 32))	('p.Arg280His', 'Var', (21, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
36072	32214837	From the North Indian population, p.Arg280His has been associated with an increased risk of hepatocellular carcinoma but no association has been reported with SCC head and neck.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('p.Arg280His', 'Var', (34, 45))	('SCC', 'Gene', (159, 162))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('p.Arg280His', 'Mutation', 'rs25489', (34, 45))	('neck', 'cellular_component', 'GO:0044326', ('172', '176'))	('SCC', 'Gene', '6317', (159, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 116))
36074	32214837	A meta-analysis within the Asian population has reported an association of p.Arg280His polymorphism with bladder cancer risk.	('p.Arg280His', 'Var', (75, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p.Arg280His', 'Mutation', 'rs25489', (75, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('association', 'Interaction', (60, 71))
36077	32214837	A study on the Chinese population reported no association between p.Arg280His polymorphism and ESCC.	('SCC', 'Gene', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('SCC', 'Gene', '6317', (96, 99))	('p.Arg280His', 'Mutation', 'rs25489', (66, 77))	('p.Arg280His', 'Var', (66, 77))
36079	32214837	No association of XRCC2 p.Arg188His with EC has been observed in the present study, which is the first report from India for esophageal cancer risk.	('p.Arg188His', 'Mutation', 'rs3218536', (24, 35))	('p.Arg188His', 'Var', (24, 35))	('XRCC2', 'Gene', '7516', (18, 23))	('esophageal cancer', 'Disease', (125, 142))	('XRCC2', 'Gene', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
36080	32214837	In previous reports from India, no association of XRCC2 p.Arg188His polymorphism was reported with nasopharyngeal carcinoma whereas another study found an association of GA genotype with increased risk of SCC head and neck.	('XRCC2', 'Gene', '7516', (50, 55))	('XRCC2', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (99, 123))	('neck', 'cellular_component', 'GO:0044326', ('218', '222'))	('SCC', 'Gene', (205, 208))	('p.Arg188His', 'Mutation', 'rs3218536', (56, 67))	('p.Arg188His', 'Var', (56, 67))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (99, 123))	('SCC', 'Phenotype', 'HP:0002860', (205, 208))	('nasopharyngeal carcinoma', 'Disease', (99, 123))	('SCC', 'Gene', '6317', (205, 208))
36081	32214837	The contradictory reports from different parts of the world have shown that XRCC2 p.Arg188His polymorphism was associated with a significantly increased risk of pharyngeal cancer and breast cancer but not with bladder cancer, colorectal adenoma, skin cancer, thyroid cancer and breast cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (210, 224))	('bladder cancer', 'Disease', (210, 224))	('skin cancer', 'Disease', 'MESH:D012878', (246, 257))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('associated', 'Reg', (111, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (210, 224))	('breast cancer', 'Disease', (278, 291))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('thyroid cancer', 'Disease', 'MESH:D013964', (259, 273))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('XRCC2', 'Gene', '7516', (76, 81))	('breast cancer', 'Disease', (183, 196))	('cancer', 'Disease', (190, 196))	('colorectal adenoma', 'Disease', 'MESH:D015179', (226, 244))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('thyroid cancer', 'Phenotype', 'HP:0002890', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', (285, 291))	('skin cancer', 'Disease', (246, 257))	('p.Arg188His', 'Mutation', 'rs3218536', (82, 93))	('cancer', 'Disease', (267, 273))	('p.Arg188His', 'Var', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (161, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (251, 257))	('skin cancer', 'Phenotype', 'HP:0008069', (246, 257))	('XRCC2', 'Gene', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (218, 224))	('thyroid cancer', 'Disease', (259, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal adenoma', 'Disease', (226, 244))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
36083	32214837	XRCC3 gene mainly repairs using the HR pathway and in vitro studies revealed high sensitivity to DNA damaging agents in cells with XRCC3 gene knockouts.	('knockouts', 'Var', (142, 151))	('XRCC3', 'Gene', '7517', (131, 136))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('XRCC3', 'Gene', (0, 5))	('XRCC3', 'Gene', '7517', (0, 5))	('XRCC3', 'Gene', (131, 136))	('sensitivity to DNA damaging agents', 'MPA', (82, 116))
36084	32214837	No association of XRCC3 p.Thr241Met polymorphism with esophageal cancer has been observed in the present study.	('p.Thr241Met', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('XRCC3', 'Gene', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('XRCC3', 'Gene', '7517', (18, 23))	('p.Thr241Met', 'Mutation', 'rs861539', (24, 35))
36087	32214837	For XRCC3 p.Thr241Met polymorphism, no association was reported with gastric cancer in Italian population and with colorectal cancer in the West Algerian population but an association with an increased risk was reported for lung cancer in an Italian population, oral SCC in Thai population, and gastric cancer in the Chinese population.	('SCC', 'Gene', '6317', (267, 270))	('XRCC3', 'Gene', '7517', (4, 9))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (295, 309))	('SCC', 'Gene', (267, 270))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('p.Thr241Met', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (69, 83))	('XRCC3', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('SCC', 'Phenotype', 'HP:0002860', (267, 270))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('lung cancer', 'Disease', (224, 235))	('gastric cancer', 'Disease', (295, 309))	('colorectal cancer', 'Disease', (115, 132))	('p.Thr241Met', 'Mutation', 'rs861539', (10, 21))
36089	32214837	The haplotype analysis in the present study shows an association of haplotype GGT of XRCC1 gene (Arg399-Arg280-194Trp of p.Arg399Gln, p.Arg280His, and p.Arg194Trp polymorphisms) with a risk of EC, however, the association was not statistically significant (Table 7).	('p.Arg280His', 'Mutation', 'rs25489', (134, 145))	('p.Arg194Trp', 'Mutation', 'rs1799782', (151, 162))	('p.Arg280His', 'Var', (134, 145))	('XRCC1', 'Gene', (85, 90))	('p.Arg194Trp', 'Var', (151, 162))	('Arg399-Arg280-194Trp', 'Var', (97, 117))	('p.Arg399Gln', 'Var', (121, 132))	('p.Arg399Gln', 'Mutation', 'rs25487', (121, 132))	('Arg399-Arg280-194Trp', 'Mutation', 'p.R,R399,280-194W', (97, 117))	('association', 'Interaction', (53, 64))	('XRCC1', 'Gene', '7515', (85, 90))
36091	32214837	However, a study from West Bengal (East India) reported CAG haplotype (Arg194-His280-Arg399) to have reduced risk against gastric cancer.	('His280', 'Chemical', '-', (78, 84))	('Arg194', 'Chemical', '-', (71, 77))	('Arg194-His280-Arg399', 'Var', (71, 91))	('gastric cancer', 'Disease', (122, 136))	('reduced', 'NegReg', (101, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('Arg399', 'Chemical', '-', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
36092	32214837	A study from Uttar Pradesh (North India) reported CGA and CAG haplotype of XRCC1 (Arg194-His280-Arg399) to be associated with prostate cancer and haplotype CGA to be associated with bladder cancer.	('CGA', 'Gene', '1113', (156, 159))	('CGA', 'Gene', (50, 53))	('CGA', 'Gene', '1113', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (110, 120))	('Arg194', 'Chemical', '-', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('associated', 'Reg', (166, 176))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('bladder cancer', 'Disease', (182, 196))	('XRCC1', 'Gene', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('Arg399', 'Chemical', '-', (96, 102))	('His280', 'Chemical', '-', (89, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('CGA', 'Gene', (156, 159))	('Arg194-His280-Arg399', 'Var', (82, 102))	('prostate cancer', 'Disease', (126, 141))	('XRCC1', 'Gene', '7515', (75, 80))
36094	32214837	The XRCC1 codon 399 Arg/Arg genotype has been associated with increased risk of acute radiation dermatitis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.	('Arg', 'Chemical', 'MESH:D001120', (20, 23))	('patients', 'Species', '9606', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Arg', 'Chemical', 'MESH:D001120', (24, 27))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (110, 134))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (110, 134))	('XRCC1', 'Gene', (4, 9))	('nasopharyngeal carcinoma', 'Disease', (110, 134))	('dermatitis', 'Phenotype', 'HP:0011123', (96, 106))	('radiation dermatitis', 'Disease', 'MESH:D004194', (86, 106))	('radiation dermatitis', 'Disease', (86, 106))	('codon 399 Arg/Arg', 'Var', (10, 27))	('XRCC1', 'Gene', '7515', (4, 9))
36096	32214837	The present study indicates a protective role of the XRCC1 p.Arg399Gln towards the development of EC.	('p.Arg399Gln', 'Mutation', 'rs25487', (59, 70))	('XRCC1', 'Gene', (53, 58))	('p.Arg399Gln', 'Var', (59, 70))	('men', 'Species', '9606', (90, 93))
36098	32214837	The present study being the first report from India, providing baseline data about five genetic polymorphisms in three DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall esophageal cancer susceptibility in ethnic Punjabi Indian subjects.	('XRCC3', 'Gene', (153, 158))	('esophageal cancer', 'Disease', (178, 195))	('XRCC3', 'Gene', '7517', (153, 158))	('DNA repair', 'biological_process', 'GO:0006281', ('119', '129'))	('XRCC1', 'Gene', (136, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('modulating', 'Reg', (159, 169))	('XRCC2', 'Gene', '7516', (143, 148))	('XRCC2', 'Gene', (143, 148))	('polymorphisms', 'Var', (96, 109))	('XRCC1', 'Gene', '7515', (136, 141))
36102	32214837	The results suggest a role of XRCC gene polymorphisms in esophageal cancer risk and a need to confirm our findings with higher sample size in different ethnic groups inhabiting different geographical areas of India.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('polymorphisms', 'Var', (40, 53))	('XRCC gene', 'Gene', (30, 39))	('esophageal cancer', 'Disease', (57, 74))	('role', 'Reg', (22, 26))
36128	31861811	Some chemotherapeutic agents were shown to be able to induce all these features, such as mitoxantrone, doxorubicin, epirubicin, bleomycin or cyclophosphamide.	('cyclophosphamide', 'Disease', (141, 157))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (141, 157))	('bleomycin', 'Disease', (128, 137))	('doxorubicin', 'MPA', (103, 114))	('bleomycin', 'Chemical', 'MESH:D001761', (128, 137))	('mitoxantrone', 'Var', (89, 101))	('epirubicin', 'Chemical', 'MESH:D015251', (116, 126))	('mitoxantrone', 'Chemical', 'MESH:D008942', (89, 101))	('epirubicin', 'Disease', (116, 126))	('doxorubicin', 'Chemical', 'MESH:D004317', (103, 114))
36134	31861811	Cleaved Bap31 entails Bax and Bak oligomerization, leading to the disruption of mitochondrial permeability, resulting in cytochrome c release in the cytosol.	('Bax', 'Gene', (22, 25))	('Cleaved', 'Var', (0, 7))	('Bap31', 'Gene', (8, 13))	('disruption of mitochondrial permeability', 'MPA', (66, 106))	('Bak', 'Gene', (30, 33))	('Bap31', 'Gene', '27061', (8, 13))	('cytochrome c', 'molecular_function', 'GO:0045155', ('121', '133'))	('Bax', 'Gene', '12028', (22, 25))	('cytosol', 'cellular_component', 'GO:0005829', ('149', '156'))	('cytochrome c release in the cytosol', 'MPA', (121, 156))	('Bak', 'Gene', '12018', (30, 33))	('leading to', 'Reg', (51, 61))	('cytochrome c', 'molecular_function', 'GO:0009461', ('121', '133'))
36221	31861811	Worth noting, cisplatin has numerous acute and late side effects such as nausea, vomiting, nephrotoxicity, myelosuppression (thrombocytopenia, leucopenia, anemia) and peripheral sensory neuropathy (ototoxicity), which will limit treatment dosage.	('peripheral sensory neuropathy', 'Disease', (167, 196))	('ototoxicity', 'Disease', 'MESH:D006311', (198, 209))	('vomiting', 'Phenotype', 'HP:0002013', (81, 89))	('vomiting', 'Disease', (81, 89))	('nausea', 'Phenotype', 'HP:0002018', (73, 79))	('anemia', 'Disease', 'MESH:D000740', (155, 161))	('ototoxicity', 'Disease', (198, 209))	('peripheral sensory neuropathy', 'Disease', 'MESH:D010523', (167, 196))	('cisplatin', 'Var', (14, 23))	('leucopenia', 'Disease', (143, 153))	('nausea', 'Disease', (73, 79))	('thrombocytopenia', 'Disease', (125, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('leucopenia', 'Disease', 'MESH:C536227', (143, 153))	('anemia', 'Phenotype', 'HP:0001903', (155, 161))	('neuropathy', 'Phenotype', 'HP:0009830', (186, 196))	('nausea', 'Disease', 'MESH:D009325', (73, 79))	('anemia', 'Disease', (155, 161))	('nephrotoxicity, myelosuppression', 'Disease', 'MESH:D007674', (91, 123))	('thrombocytopenia', 'Disease', 'MESH:D013921', (125, 141))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (125, 141))	('vomiting', 'Disease', 'MESH:D014839', (81, 89))	('peripheral sensory neuropathy', 'Phenotype', 'HP:0000763', (167, 196))
36242	31861811	Overexpression of these transporters significantly increases oxaliplatin cellular accumulation (with no effect on cisplatin and carboplatin).	('oxaliplatin cellular accumulation', 'MPA', (61, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('increases', 'PosReg', (51, 60))	('carboplatin', 'Chemical', 'MESH:D016190', (128, 139))	('Overexpression', 'Var', (0, 14))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (61, 72))
36264	31861811	Nevertheless, in metastatic colon cancer patients treated with oxaliplatin-based chemotherapy, the presence of a mutated TLR4 allele is correlated with a significant decrease in progression-free and overall survival.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (63, 74))	('TLR4', 'Gene', (121, 125))	('patients', 'Species', '9606', (41, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('mutated', 'Var', (113, 120))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('presence', 'Var', (99, 107))	('decrease', 'NegReg', (166, 174))	('colon cancer', 'Disease', (28, 40))
36265	31861811	Additionally, oxaliplatin has been shown to induce CXCL10 secretion by melanoma cells, another ICD feature.	('CXCL10', 'Gene', (51, 57))	('induce', 'PosReg', (44, 50))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (14, 25))	('oxaliplatin', 'Var', (14, 25))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('CXCL10', 'Gene', '15945', (51, 57))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('secretion', 'biological_process', 'GO:0046903', ('58', '67'))
36268	31861811	In CT26 cells, cisplatin can induce HMGB1 and ATP release, but not CRT exposure.	('HMGB1', 'Gene', (36, 41))	('cisplatin', 'Var', (15, 24))	('CT26', 'CellLine', 'CVCL:7254', (3, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('HMGB1', 'Gene', '15289', (36, 41))	('ATP', 'Gene', '51761', (46, 49))	('induce', 'PosReg', (29, 35))	('ATP', 'Gene', (46, 49))
36269	31861811	In EG7 cells and U2OS cells, cisplatin is able to induce ATP release, but not CRT exposure.	('ATP', 'Gene', (57, 60))	('ATP', 'Gene', '51761', (57, 60))	('cisplatin', 'Var', (29, 38))	('U2OS', 'CellLine', 'CVCL:0042', (17, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('EG7', 'CellLine', 'CVCL:S390', (3, 6))
36293	31861811	In a murine peritoneal carcinomatosis model (injection of CT26 cells in the peritoneal cavity), oxaliplatin in hypotonic conditions decreased the appearance of tumor nodules and increased mice survival.	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (12, 37))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (96, 107))	('mice', 'Species', '10090', (188, 192))	('hypotonic conditions decreased', 'Disease', 'MESH:D009123', (111, 141))	('hypotonic conditions decreased', 'Disease', (111, 141))	('peritoneal carcinomatosis', 'Disease', (12, 37))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('murine', 'Species', '10090', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('oxaliplatin', 'Var', (96, 107))	('CT26', 'CellLine', 'CVCL:7254', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mice survival', 'CPA', (188, 201))	('tumor', 'Disease', (160, 165))	('increased', 'PosReg', (178, 187))
36308	31861811	Macrophages pre-treated with cisplatin become active, as shown by their capacity to produce NO and pro-inflammatory cytokines and to express TLRs.	('TLR', 'Gene', (141, 144))	('cisplatin', 'Var', (29, 38))	('express', 'Reg', (133, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('TLR', 'Gene', '142980;7099;21898', (141, 144))	('pre', 'molecular_function', 'GO:0003904', ('12', '15'))
36314	31861811	In a murine lung cancer model, cisplatin increased intra-tumoral APCs and the expression of co-stimulatory molecules, then leading to IFNgamma and TNFalpha production by CD8+ T cells.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('increased', 'PosReg', (41, 50))	('expression', 'MPA', (78, 88))	('CD8', 'Gene', '925', (170, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('murine', 'Species', '10090', (5, 11))	('cisplatin', 'Var', (31, 40))	('TNFalpha', 'Gene', '21926', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('leading to', 'Reg', (123, 133))	('lung cancer', 'Disease', (12, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('tumor', 'Disease', (57, 62))	('CD8', 'Gene', (170, 173))	('IFNgamma', 'MPA', (134, 142))	('TNFalpha', 'Gene', (147, 155))
36330	31861811	Although the real effect of oxaliplatin is not known, FOLFOX also enhances PD-L1 expression in tumor cells from patients.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (28, 39))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD-L1', 'Protein', (75, 80))	('FOLFOX', 'Chemical', '-', (54, 60))	('FOLFOX', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('enhances', 'PosReg', (66, 74))	('tumor', 'Disease', (95, 100))
36336	31861811	Its association with anti-PD-L1/PD-1 was shown to slow down tumor growth and to improve survival without any significant effect on cisplatin-induced toxicities, or on the number and the function of tumor-infiltrating immune cells.	('survival', 'CPA', (88, 96))	('improve', 'PosReg', (80, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('anti-PD-L1/PD-1', 'Var', (21, 36))	('toxicities', 'Disease', (149, 159))	('association', 'Interaction', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('slow down', 'NegReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('toxicities', 'Disease', 'MESH:D064420', (149, 159))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (60, 65))
36342	31861811	This increase in PD-L1 expression was also correlated with a more important antitumor effect of cisplatin combined with anti-PD-L1 in a murine lung carcinoma model.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('murine', 'Species', '10090', (136, 142))	('tumor', 'Disease', (80, 85))	('increase', 'PosReg', (5, 13))	('lung carcinoma', 'Disease', (143, 157))	('lung carcinoma', 'Disease', 'MESH:D008175', (143, 157))	('PD-L1', 'Gene', (17, 22))	('anti-PD-L1', 'Var', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('expression', 'MPA', (23, 33))
36361	31847917	Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors.	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('mutational', 'Var', (186, 196))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))
36363	31847917	Because this technology produces genome-wide somatic mutation profiles within a reasonable timeframe and at a reasonable cost, many research groups, particularly International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), have produced population-scale whole-exome sequencing (WES) and whole-genome sequencing (WGS) datasets from most common cancer types.	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('mutation', 'Var', (53, 61))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Cancer', 'Disease', (216, 222))	('Cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('Cancer', 'Disease', 'MESH:D009369', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (364, 370))
36366	31847917	Sometimes, mutation calls are contaminated by experimental artifacts that accumulate during tissue handling and sequencing procedures, such as preparation of tissues into formalin-fixed paraffin-embedded (FFPE) samples, 8-oxoG-mediated errors, chimeric reads, and others.	('chimeric reads', 'Var', (244, 258))	('8-oxoG-mediated', 'MPA', (220, 235))	('paraffin', 'Chemical', 'MESH:D010232', (186, 194))	('formalin', 'Chemical', 'MESH:D005557', (171, 179))	('mutation', 'Var', (11, 19))
36367	31847917	In a routine genotyping of KRAS mutations in metastatic colorectal cancer patients, 53 (4.7%) out of 1130 FFPE samples had KRAS mutations that were validated as artifacts due to DNA fragmentation.	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('178', '195'))	('KRAS', 'Gene', '3845', (27, 31))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('mutations', 'Var', (128, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (123, 127))
36368	31847917	In another study validating the detection of the T790M mutation in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) patients, up to 48.5% of T790M mutations were FFPE-related artifacts.	('epidermal growth factor receptor', 'Gene', '1956', (71, 103))	('T790M', 'Mutation', 'rs121434569', (179, 184))	('T790M', 'Var', (49, 54))	('EGFR', 'Gene', (105, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('71', '94'))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('EGFR', 'Gene', '1956', (105, 109))	('patients', 'Species', '9606', (154, 162))	('non-small cell lung cancer', 'Disease', (119, 145))	('T790M', 'Mutation', 'rs121434569', (49, 54))	('NSCLC', 'Disease', (147, 152))	('T790M mutations', 'Var', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('epidermal growth factor receptor', 'Gene', (71, 103))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))
36369	31847917	Moreover, in a clinical trial that investigated the efficacy of the tyrosine kinase inhibitor (TKI) erlotinib in NSCLC patients, previously unidentified EGFR mutations were reported.	('erlotinib', 'Chemical', 'MESH:D000069347', (100, 109))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('77', '93'))	('patients', 'Species', '9606', (119, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('EGFR', 'Gene', '1956', (153, 157))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('NSCLC', 'Disease', (113, 118))	('mutations', 'Var', (158, 167))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
36370	31847917	The study concluded a lack of survival benefits in using erlotinib for patients with EGFR mutations and no clinical evidence to distinguish EGFR-mutant and wild-type patients for administration of the TKI.	('EGFR', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('EGFR', 'Gene', (140, 144))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('erlotinib', 'Chemical', 'MESH:D000069347', (57, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('140', '144'))	('EGFR', 'Gene', '1956', (85, 89))	('patients', 'Species', '9606', (166, 174))	('EGFR', 'Gene', '1956', (140, 144))
36373	31847917	Recently, the Pan-cancer Analysis of Whole Genomes (PCAWG) consortium generated 65 single-base substitution (SBS) mutational signatures from over 4600 whole cancer genomes and 19,000 cancer exomes; these signatures have been incorporated as version 3 into the v89 release of Catalog of Somatic Mutations in Cancer (COSMIC).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('Pan', 'Gene', '51816', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Disease', (157, 163))	('Cancer', 'Disease', (307, 313))	('single-base', 'Var', (83, 94))	('Pan', 'Gene', (14, 17))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('Cancer', 'Disease', 'MESH:D009369', (307, 313))
36374	31847917	For example, one of the signatures, termed SBS7, features preferential C>T mutations, whereas SBS4, a mutational spectrum of tobacco smoke exposure, is characterized by C>A mutations with a strong transcriptional strand bias.	('S7', 'Gene', '6264', (45, 47))	('preferential', 'PosReg', (58, 70))	('mutations', 'Var', (75, 84))	('tobacco', 'Species', '4097', (125, 132))	('C>T mutations', 'Var', (71, 84))
36375	31847917	In fact, the single nucleotide substitutions observed in these artifactual signatures were shown to be enriched in false positive variant calls by a previous investigation on the reliability of WES in breast cancer samples.	('false', 'biological_process', 'GO:0071878', ('115', '120'))	('variant', 'Var', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('false', 'biological_process', 'GO:0071877', ('115', '120'))	('breast cancer', 'Disease', (201, 214))	('single nucleotide substitutions', 'Var', (13, 44))
36379	31847917	In particular, 18 signatures associated with sequencing artifacts are exploited: SBS27, SBS43, SBS45, SBS46, SBS47, SBS48, SBS49, SBS50, SBS51, SBS52, SBS53, SBS54, SBS55, SBS56, SBS57, SBS58, SBS59, and SBS60 (Additional file 2: Figures S5 and S6).	('SBS27', 'Var', (81, 86))	('SBS49', 'Var', (123, 128))	('SBS56', 'Var', (172, 177))	('SBS58', 'Var', (186, 191))	('SBS43', 'Chemical', '-', (88, 93))	('SBS59', 'Var', (193, 198))	('SBS54', 'Var', (158, 163))	('SBS48', 'Var', (116, 121))	('SBS57', 'Var', (179, 184))	('SBS52', 'Var', (144, 149))	('SBS50', 'Var', (130, 135))	('SBS45', 'Var', (95, 100))	('SBS43', 'Var', (88, 93))	('SBS60', 'Var', (204, 209))	('SBS53', 'Var', (151, 156))	('SBS55', 'Var', (165, 170))	('SBS47', 'Var', (109, 114))	('SBS46', 'Var', (102, 107))	('SBS51', 'Var', (137, 142))
36383	31847917	Therefore, M = Mh + Ml, where:  We define the reference mutational signatures as follows:  Note that  represents the probability of the mechanism i (e.g., ultraviolet radiation) to cause a mutation type of j (e.g., cytosine to thymine transition at dipyrimidines) in the COSMIC mutational signatures (65 signatures in version 3).	('cytosine', 'Chemical', 'MESH:D003596', (215, 223))	('cause', 'Reg', (181, 186))	('mutation', 'Var', (189, 197))	('thymine', 'Chemical', 'MESH:D013941', (227, 234))	('dipyrimidines', 'Chemical', '-', (249, 262))
36386	31847917	For the evaluation of FIREVAT variant refinement performance, we used three datasets: the MC3 dataset, TCGA Genomic Data Commons (GDC) dataset, and multi-region WES of breast cancer dataset (Additional file 1: Note S3).	('MC3', 'Gene', (90, 93))	('MC3', 'Gene', '4159', (90, 93))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', (168, 181))	('variant', 'Var', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('GDC', 'Chemical', '-', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
36391	31847917	To establish ground truth, we herein describe how we determined real somatic and artifactual mutations in the MC3 dataset.	('MC3', 'Gene', '4159', (110, 113))	('MC3', 'Gene', (110, 113))	('mutations', 'Var', (93, 102))
36392	31847917	We further selected variants that were validated and statistically powered in either WGS or targeted sequencing in terms of read evidence according to the MC3 definition ("mutval_targeted_status" = "validated_powered" or "mutval_wgs_status" = "validated_powered").	('MC3', 'Gene', (155, 158))	('variants', 'Var', (20, 28))	('MC3', 'Gene', '4159', (155, 158))
36399	31847917	To evaluate the FIREVAT variant refinement performance on the multi-region WES breast cancer samples, we downloaded the supplementary tables from the original manuscript for technical and biological replicates.	('WES breast cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('WES breast cancer', 'Disease', 'MESH:D001943', (75, 92))	('variant', 'Var', (24, 31))
36414	31847917	The second dataset utilized for evaluation of FIREVAT variant refinement performance was the multi-region WES dataset, where breast cancer samples were sequenced multiple times by biological and technical replicates.	('variant', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
36416	31847917	The increase in precision resulting from FIREVAT refinement was also observed in the ICGC-TCGA-DREAM Somatic Mutation Calling Challenge dataset and in additional benchmarking studies.	('DREAM', 'Gene', (95, 100))	('refinement', 'Var', (49, 59))	('precision', 'MPA', (16, 25))	('DREAM', 'Gene', '30818', (95, 100))	('increase', 'PosReg', (4, 12))
36418	31847917	However, a substantial fraction of mutations was attributed to sequencing error signatures such as SBS45 (median weight = 28.4%), SBS43 (median weight = 14.9%), and SBS50 (median weight = 14.7%) (Fig.	('SBS50', 'Var', (165, 170))	('SBS45', 'Gene', (99, 104))	('SBS43', 'Var', (130, 135))	('SBS43', 'Chemical', '-', (130, 135))	('mutations', 'Var', (35, 44))
36430	31847917	For example, in the TCGA-LAML cohort, the artifactual mutations favored regions of repeated adenine sequences (3 bases upstream and 7 bases downstream).	('mutations', 'Var', (54, 63))	('adenine', 'Chemical', 'MESH:D000225', (92, 99))	('favored', 'PosReg', (64, 71))
36433	31847917	In the multi-region WES dataset (SRP070662), SBS51 was detected in 20 (83.3%) out of 24 samples with a median weight of 21.1%, while the first base immediately upstream or downstream of the variant position was commonly guanine.	('guanine', 'Chemical', 'MESH:D006147', (220, 227))	('SRP', 'cellular_component', 'GO:0005786', ('33', '36'))	('variant', 'Var', (190, 197))	('SBS51', 'Gene', (45, 50))	('guanine', 'Var', (220, 227))
36435	31847917	Post-processing of variant calling is an indispensable step in the conventional cancer genomics analysis pipeline that ensures retention of high-quality real somatic variants and removal of artifactual variants.	('retention', 'biological_process', 'GO:0051235', ('127', '136'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('variant', 'Var', (19, 26))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
36450	31847917	In conclusion, we have developed a publicly available software toolkit that efficiently removes artifactual variants in cancer samples using mutational signatures.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('variants', 'Var', (108, 116))
36539	31593773	5B), there were so few junctions formed and subsequently masked by the program with Epac inhibition leading to overall similarities in lacunarity within the collagen I coating group and an overall decrease in junction end points that distort the quantification within the collagen I group.	('lacunarity', 'MPA', (135, 145))	('distort', 'Reg', (234, 241))	('collagen', 'molecular_function', 'GO:0005202', ('272', '280'))	('inhibition', 'Var', (89, 99))	('Epac', 'Gene', '223864', (84, 88))	('junction end points', 'MPA', (209, 228))	('Epac', 'Gene', (84, 88))	('decrease', 'NegReg', (197, 205))	('collagen', 'molecular_function', 'GO:0005202', ('157', '165'))
36546	31593773	The connection between integrin ECM binding and Epac activation by GPCRs suggests crosstalk between the two, which has also been seen in several other systems.	('Epac', 'Gene', '223864', (48, 52))	('integrin ECM', 'Protein', (23, 35))	('activation', 'PosReg', (53, 63))	('Epac', 'Gene', (48, 52))	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('GPCRs', 'Var', (67, 72))	('binding', 'Interaction', (36, 43))	('crosstalk', 'Interaction', (82, 91))
36571	31593773	Epac inhibition abolished laminin-mediated barrier resistance, as observed by TEER and ZO-1 immunofluorescent staining.	('Epac', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('laminin-mediated barrier resistance', 'CPA', (26, 61))	('ZO-1', 'Gene', '21872', (87, 91))	('ZO-1', 'Gene', (87, 91))	('Epac', 'Gene', '223864', (0, 4))	('abolished', 'NegReg', (16, 25))
36585	31720204	Sequential EGFR mutation and ALK rearrangement in adenocarcinoma lung, with rare metastasis to bilateral breast, ovary and endometrium With the advent of targeted therapies there was a paradigm shift in the treatment of metastatic adenocarcinoma of lung.	('ALK', 'Gene', (29, 32))	('mutation', 'Var', (16, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('adenocarcinoma of lung', 'Disease', 'MESH:C538231', (231, 253))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('adenocarcinoma of lung', 'Disease', (231, 253))	('adenocarcinoma lung', 'Disease', (50, 69))	('adenocarcinoma lung', 'Disease', 'MESH:C538231', (50, 69))	('ALK', 'Gene', '238', (29, 32))
36587	31720204	Oncogenic driver mutations in non-small cell lung cancer are commonly EGFR (Epidermal Growth Factor Receptor) gene mutation and ALK (Anaplastic Lymphoma Kinase) gene rearrangement, which are mutually exclusive.	('Epidermal Growth Factor Receptor', 'Gene', '1956', (76, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (34, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutation', 'Var', (115, 123))	('Lymphoma Kinase', 'Disease', (144, 159))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (30, 56))	('Anaplastic Lymphoma', 'Phenotype', 'HP:0012193', (133, 152))	('EGFR', 'Gene', '1956', (70, 74))	('Lymphoma Kinase', 'Disease', 'MESH:D058495', (144, 159))	('Lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('ALK', 'Gene', '238', (128, 131))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (30, 56))	('ALK', 'Gene', (128, 131))	('Epidermal Growth Factor Receptor', 'Gene', (76, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('EGFR', 'Gene', (70, 74))	('non-small cell lung cancer', 'Disease', (30, 56))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('76', '99'))
36589	31720204	Here, we present a case with EGFR mutation and ALK gene rearrangement which was expressed sequentially and with metastasis to rarest sites bilateral breast, ovaries and endometrium.	('ALK', 'Gene', (47, 50))	('ovaries', 'Disease', (157, 164))	('mutation', 'Var', (34, 42))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('ALK', 'Gene', '238', (47, 50))	('ovaries', 'Disease', 'MESH:D010051', (157, 164))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))
36593	31720204	Approximately 60-64% of patients with metastatic NSCLC have EGFR (epidermal growth factor receptor) mutation or ALK (anaplastic lymphoma kinase) rearrangement.	('ALK', 'Gene', (112, 115))	('NSCLC', 'Disease', (49, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('epidermal growth factor receptor', 'Gene', (66, 98))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('rearrangement', 'Var', (145, 158))	('mutation', 'Var', (100, 108))	('lymphoma', 'Disease', (128, 136))	('EGFR', 'Gene', '1956', (60, 64))	('lymphoma', 'Disease', 'MESH:D008223', (128, 136))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (117, 136))	('patients', 'Species', '9606', (24, 32))	('epidermal growth factor receptor', 'Gene', '1956', (66, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('ALK', 'Gene', '238', (112, 115))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('66', '89'))	('EGFR', 'Gene', (60, 64))
36594	31720204	ALK rearrangement can be seen in about 1-1.5% of EGFR mutated NSCLS.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('ALK', 'Gene', (0, 3))	('mutated', 'Var', (54, 61))	('NSCLS', 'Disease', (62, 67))	('ALK', 'Gene', '238', (0, 3))
36595	31720204	Here we present a case report of a young lady who had upfront metastatic adenocarcinoma of lung, both EGFR mutation and ALK rearrangement, with rare sites of distant metastasis to bilateral breast, ovary and endometrium, with 5 years survival.	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ALK', 'Gene', (120, 123))	('adenocarcinoma of lung', 'Disease', (73, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('ALK', 'Gene', '238', (120, 123))	('EGFR', 'Gene', '1956', (102, 106))	('mutation', 'Var', (107, 115))	('EGFR', 'Gene', (102, 106))	('adenocarcinoma of lung', 'Disease', 'MESH:C538231', (73, 95))
36605	31720204	Mutation analysis by DNA sequencing showed mutation in exon 19 and exon 20 in EGFR gene Fig.	('exon 20', 'Var', (67, 74))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))	('mutation in exon 19', 'Var', (43, 62))
36619	31720204	Discovery of driver mutation has started a new era of targeted treatment in metastatic adenocarcinoma lung.	('adenocarcinoma lung', 'Disease', 'MESH:C538231', (87, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutation', 'Var', (20, 28))	('adenocarcinoma lung', 'Disease', (87, 106))
36622	31720204	Molecular studies have shown several oncogenic driver mutations in NSCLC: EGFR mutation, ALK rearrangement, c-ros (ROS1) oncogene 1, rearranged during transfection (RET, mesenchymal-to-epithelial transition (MET), human epidermal growth factor receptor 2 (HER2).	('HER2', 'Gene', '2064', (256, 260))	('ROS1', 'Gene', '6098', (115, 119))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (54, 63))	('ALK', 'Gene', '238', (89, 92))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('human epidermal growth factor receptor 2', 'Gene', (214, 254))	('RET', 'Gene', '5979', (165, 168))	('ALK', 'Gene', (89, 92))	('HER2', 'Gene', (256, 260))	('EGFR', 'Gene', '1956', (74, 78))	('mutation', 'Var', (79, 87))	('ROS1', 'Gene', (115, 119))	('NSCLC', 'Disease', (67, 72))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('220', '243'))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('RET', 'Gene', (165, 168))	('mesenchymal-to-epithelial transition', 'biological_process', 'GO:0060231', ('170', '206'))	('human epidermal growth factor receptor 2', 'Gene', '2064', (214, 254))
36623	31720204	The major mutations are seen in KRAS (25%), EGFR (17%), anaplastic lymphoma kinase (ALK) (7%), MET (3%), HER-2 (2%), ROS1 (2%), BRAF (2%), RET (2%).	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('ALK', 'Gene', '238', (84, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('MET', 'Gene', (95, 98))	('RET', 'Gene', (139, 142))	('EGFR', 'Gene', (44, 48))	('ALK', 'Gene', (84, 87))	('KRAS', 'Gene', '3845', (32, 36))	('ROS1', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (44, 48))	('lymphoma', 'Disease', (67, 75))	('lymphoma', 'Disease', 'MESH:D008223', (67, 75))	('KRAS', 'Gene', (32, 36))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (56, 75))	('HER-2', 'Gene', '2064', (105, 110))	('HER-2', 'Gene', (105, 110))	('RET', 'Gene', '5979', (139, 142))	('mutations', 'Var', (10, 19))	('BRAF', 'Gene', '673', (128, 132))	('ROS1', 'Gene', '6098', (117, 121))	('BRAF', 'Gene', (128, 132))
36624	31720204	The targeted therapies have shown to improve PFS and response rate in metastatic NSCLC and is used in first line treatment if mutation is present.	('targeted', 'Var', (4, 12))	('improve', 'PosReg', (37, 44))	('response rate', 'CPA', (53, 66))	('PFS', 'MPA', (45, 48))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
36625	31720204	Approximately 10-15% of Caucasian and 30-62% of Asian population has EGFR mutation.	('EGFR', 'Gene', '1956', (69, 73))	('mutation', 'Var', (74, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('EGFR', 'Gene', (69, 73))
36627	31720204	EGFR mutation is usually seen in females, younger age group with no history of smoking.	('EGFR', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))	('seen', 'Reg', (25, 29))
36630	31720204	In the Iressa Pan-Asia Study (IPAS) trial, gefitinib showed improved PFS when compared with standard doublet chemotherapy.	('gefitinib', 'Var', (43, 52))	('gefitinib', 'Chemical', 'MESH:C419708', (43, 52))	('PFS', 'MPA', (69, 72))	('improved', 'PosReg', (60, 68))
36631	31720204	Erlotinib has also shown increased PFS when compared with standard chemotherapy in OPTIMAL and EURTAC trials.	('Erlotinib', 'Var', (0, 9))	('PFS', 'MPA', (35, 38))	('increased', 'PosReg', (25, 34))	('Erlotinib', 'Chemical', 'MESH:C400278', (0, 9))
36635	31720204	Osimertinib was initially approved for patients who developed T790M resistance mutation, later expanded for EGFR deletion 19 or L858R mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('Osimertinib', 'Chemical', 'None', (0, 11))	('L858R', 'Mutation', 'p.L858R', (128, 133))	('deletion 19', 'Var', (113, 124))	('L858R', 'Var', (128, 133))	('T790M', 'Var', (62, 67))	('T790M', 'Mutation', 'p.T790M', (62, 67))
36637	31720204	Translocation of ALK and Echinoderm Microtubule-Associated Protein-Like 4 (EML4) from an inversion of the short arm of chromosome 2 and results in fusion protein EML4-ALKgene.	('ALK', 'Gene', '238', (17, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('EML4', 'Gene', (75, 79))	('Translocation', 'Var', (0, 13))	('ALK', 'Gene', (167, 170))	('ALK', 'Gene', (17, 20))	('Echinoderm Microtubule-Associated Protein-Like 4', 'Gene', (25, 73))	('results in', 'Reg', (136, 146))	('EML4', 'Gene', '27436', (75, 79))	('EML4', 'Gene', (162, 166))	('short arm', 'Phenotype', 'HP:0009824', (106, 115))	('Microtubule', 'cellular_component', 'GO:0005874', ('36', '47'))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('Echinoderm Microtubule-Associated Protein-Like 4', 'Gene', '27436', (25, 73))	('ALK', 'Gene', '238', (167, 170))	('EML4', 'Gene', '27436', (162, 166))
36641	31720204	In PROFILE study, crizotinib had better median PFS and objective response rate than chemotherapy.	('crizotinib', 'Var', (18, 28))	('PFS', 'MPA', (47, 50))	('objective response', 'CPA', (55, 73))	('crizotinib', 'Chemical', 'MESH:C551994', (18, 28))
36648	31720204	Co-existence of EGFR mutation ALK rearrangement is seen only in 1-1.5% of patients.	('ALK', 'Gene', (30, 33))	('patients', 'Species', '9606', (74, 82))	('mutation', 'Var', (21, 29))	('ALK', 'Gene', '238', (30, 33))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('EGFR', 'Gene', (16, 20))
36651	31720204	The most common co-mutations occurring de novo with EGFR were PIK3CA, KRAS, ALK and BRAF mutations.	('BRAF', 'Gene', '673', (84, 88))	('EGFR', 'Gene', '1956', (52, 56))	('ALK', 'Gene', '238', (76, 79))	('KRAS', 'Gene', (70, 74))	('PIK3CA', 'Gene', (62, 68))	('EGFR', 'Gene', (52, 56))	('BRAF', 'Gene', (84, 88))	('KRAS', 'Gene', '3845', (70, 74))	('mutations', 'Var', (89, 98))	('PIK3CA', 'Gene', '5290', (62, 68))	('ALK', 'Gene', (76, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
36653	31720204	in which only 0.75% of patients (three of 399) with EGFR mutations also harbored ALK rearrangement.	('ALK', 'Gene', (81, 84))	('EGFR', 'Gene', '1956', (52, 56))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('ALK', 'Gene', '238', (81, 84))	('harbored', 'Reg', (72, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
36656	31720204	Patients, who have EGFR mutation, usually do not undergo ALK testing since they are mutually exclusive.	('ALK', 'Gene', (57, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('EGFR', 'Gene', '1956', (19, 23))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (24, 32))	('EGFR', 'Gene', (19, 23))	('ALK', 'Gene', '238', (57, 60))
36658	31720204	Further studies help us in sequencing the treatment for patients with both EGFR mutation and ALK rearrangement.	('patients', 'Species', '9606', (56, 64))	('ALK', 'Gene', '238', (93, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('ALK', 'Gene', (93, 96))	('mutation', 'Var', (80, 88))	('EGFR', 'Gene', (75, 79))
36659	31720204	Here in our case report, a young lady who presented with upfront metastatic adenocarcinoma of lung, having both EGFR mutation and ALK rearrangement.	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('adenocarcinoma of lung', 'Disease', (76, 98))	('ALK', 'Gene', (130, 133))	('adenocarcinoma of lung', 'Disease', 'MESH:C538231', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('EGFR', 'Gene', '1956', (112, 116))	('mutation', 'Var', (117, 125))	('ALK', 'Gene', '238', (130, 133))
36662	31208370	EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs).	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))	('tyrosine kinase', 'Gene', '7294', (278, 293))	('lung cancer', 'Disease', (79, 90))	('EGFR', 'Gene', (273, 277))	('Epidermal growth factor receptor', 'Gene', '1956', (91, 123))	('osimertinib', 'Chemical', 'MESH:C000603933', (49, 60))	('EGFR', 'Gene', (143, 147))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('EGFR', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('EGFR', 'Gene', (199, 203))	('mutations', 'Var', (156, 165))	('mutations', 'Var', (204, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('273', '277'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('EGFR', 'Gene', '1956', (273, 277))	('Epidermal growth factor receptor', 'Gene', (91, 123))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('91', '114'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (143, 147))	('tyrosine kinase', 'Gene', (278, 293))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (199, 203))
36666	31208370	The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed.	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', '1956', (45, 49))	('mutations', 'Var', (59, 68))
36668	31208370	EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (59, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', (71, 76))	('mutant', 'Var', (64, 70))	('EGFR', 'Gene', '1956', (59, 63))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
36669	31208370	The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%).	('A767_V769dup', 'Var', (48, 60))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('A767_V769dup', 'Mutation', 'p.767,769dupV', (48, 60))
36674	31208370	This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients.	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Disease', (103, 108))	('EGFR', 'Gene', '1956', (56, 60))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('EGFR', 'Gene', (56, 60))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('mutations', 'Var', (68, 77))
36675	31208370	Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.	('NSCLC', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (99, 103))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('EGFR', 'Gene', (185, 189))	('mutant', 'Var', (111, 117))	('patients', 'Species', '9606', (133, 141))	('osimertinib', 'Chemical', 'MESH:C000603933', (159, 170))	('osimertinib', 'Chemical', 'MESH:C000603933', (76, 87))	('patients', 'Species', '9606', (206, 214))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', '1956', (185, 189))
36677	31208370	Epidermal growth factor receptor (EGFR) mutation is the first identified targetable driver mutation that was reported in about 17 and 50% of lung adenocarcinoma in Caucasians and Asians, respectively.	('mutation', 'Var', (40, 48))	('lung adenocarcinoma', 'Disease', (141, 160))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('EGFR', 'Gene', '1956', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
36678	31208370	The most common cluster of mutations in EGFR gene include inframe deletions around the LeuArgGluAla motif (residues 746-750) of exon 19, and the Leu858Arg (L858R) point mutation in exon 21, each accounting for about 45% of all EGFR mutations.	('L858R', 'Mutation', 'rs121434568', (156, 161))	('Leu858Arg', 'SUBSTITUTION', 'None', (145, 154))	('EGFR', 'Gene', '1956', (227, 231))	('Leu858Arg', 'Var', (145, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('227', '231'))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', (227, 231))	('LeuArgGluAla motif', 'Disease', (87, 105))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('LeuArgGluAla motif', 'Disease', 'None', (87, 105))	('residues 746-750', 'Var', (107, 123))
36679	31208370	These mutations are termed classic EGFR mutations and are more common in tumors in women, Asians, never smokers, and those with adenocarcinoma.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('common', 'Reg', (63, 69))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('EGFR', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumors', 'Disease', (73, 79))	('adenocarcinoma', 'Disease', (128, 142))	('women', 'Species', '9606', (83, 88))	('mutations', 'Var', (6, 15))
36680	31208370	The frequency and distribution of EGFR mutations in patients with different ethnic backgrounds also differ.	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('mutations', 'Var', (39, 48))	('EGFR', 'Gene', '1956', (34, 38))	('patients', 'Species', '9606', (52, 60))
36681	31208370	Patients with classic EGFR mutations generally have profound radiographic and clinical response to monotherapy EGFR tyrosine kinase inhibitors (TKIs).	('mutations', 'Var', (27, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('tyrosine kinase', 'Gene', '7294', (116, 131))	('EGFR', 'Gene', '1956', (111, 115))	('tyrosine kinase', 'Gene', (116, 131))	('EGFR', 'Gene', (111, 115))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
36682	31208370	However, some unclassical EGFR mutations are associated with poor responses with reversible EGFR TKIs.	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
36683	31208370	Among these are most EGFR exon 20 insertion (EGFRex20ins) mutations reported as far.	('EGFR', 'Gene', '1956', (21, 25))	('mutations', 'Var', (58, 67))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', (45, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('EGFR', 'Gene', '1956', (45, 49))
36685	31208370	It contains a C-helix (residues 762-766) and the loop following C-helix (residues 767-774), where the insertions could induce ligand-independent EGFR pathway activation and give rise to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ligand', 'molecular_function', 'GO:0005488', ('126', '132'))	('insertions', 'Var', (102, 112))	('residues 767-774', 'Var', (73, 89))	('EGFR', 'Gene', '1956', (145, 149))	('tumor', 'Disease', (186, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))	('EGFR', 'Gene', (145, 149))	('activation', 'PosReg', (158, 168))	('residues 762-766', 'Var', (23, 39))	('give rise to', 'Reg', (173, 185))	('induce', 'Reg', (119, 125))
36688	31208370	However, the genetic and clinical characteristics of NSCLCs harboring EGFRex20ins mutations in Asian populations remain unknown due to the lack of large comprehensive genomic studies.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('EGFR', 'Gene', '1956', (70, 74))	('mutations', 'Var', (82, 91))	('EGFR', 'Gene', (70, 74))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
36689	31208370	Preclinical and clinical studies have shown that most EGFRex20ins (except for few subtypes such as EGFR A763_Y764insFQEA) mutant tumors confer resistance to the 1st and 2nd generation EGFR TKIs because the insertions produce steric hindrance and activate EGFR without saliently decreasing affinity for ATP or enhancing affinity for EGFR TKIs.	('activate', 'PosReg', (246, 254))	('tumors', 'Disease', (129, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('184', '188'))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', '1956', (332, 336))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', (255, 259))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('EGFR', 'Gene', (184, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('332', '336'))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', (332, 336))	('EGFR', 'Gene', '1956', (255, 259))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('steric', 'MPA', (225, 231))	('EGFR', 'Gene', '1956', (184, 188))	('insertions', 'Var', (206, 216))	('resistance', 'MPA', (143, 153))	('ATP', 'Chemical', 'MESH:D000255', (302, 305))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (109, 120))	('mutant', 'Var', (122, 128))
36691	31208370	However, there are still no established molecular targeted drugs for NSCLC patients with EGFRx20ins mutations.	('mutations', 'Var', (100, 109))	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', (69, 74))	('patients', 'Species', '9606', (75, 83))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('EGFR', 'Gene', '1956', (89, 93))
36693	31208370	Osimertinib is an oral, potent, irreversible EGFR TKI selective for sensitizing EGFR and EGFR T790 M resistance mutations.	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', '1956', (80, 84))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('EGFR', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('T790 M', 'Mutation', 'rs121434569', (94, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('T790 M', 'Var', (94, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('sensitizing', 'MPA', (68, 79))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', '1956', (45, 49))
36694	31208370	Preclinical studies have reported that osimertinib was active in EGFRex20ins mutant cell lines and tumor xenografts with a wide therapeutic window.	('tumor', 'Disease', (99, 104))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('active', 'MPA', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutant', 'Var', (77, 83))	('osimertinib', 'Chemical', 'MESH:C000603933', (39, 50))
36710	31208370	Among the 2316 unselective NSCLC tumors, EGFR mutations were identified in 1095 cases (47.3%).	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('NSCLC tumors', 'Disease', 'MESH:D009369', (27, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('identified', 'Reg', (61, 71))	('EGFR', 'Gene', '1956', (41, 45))	('NSCLC tumors', 'Disease', (27, 39))
36711	31208370	EGFRex20ins mutations were detected in 53 cases, contributing 2.3% of all NSCLC cases and 4.8% of EGFR-mutant tumors.	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('NSCLC', 'Disease', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'Gene', '1956', (98, 102))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (0, 4))
36712	31208370	Compared with Foundation Medicine (FM) data representing the largest EGFRex20ins cohort, we found that although EGFR mutations were much more common in our Chinese NSCLC patients than that of Western population (47.3% vs 15.5% in FM), EGFRex20ins mutation represented a much smaller group in EGFR mutant NSCLC (4.8% vs 11.7% in FM, p < 0.001).	('EGFR', 'Gene', (112, 116))	('patients', 'Species', '9606', (170, 178))	('mutations', 'Var', (117, 126))	('NSCLC', 'Disease', (164, 169))	('EGFR', 'Gene', '1956', (292, 296))	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('EGFR', 'molecular_function', 'GO:0005006', ('292', '296'))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('EGFR', 'Gene', (292, 296))	('EGFR', 'Gene', (69, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (304, 309))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', (235, 239))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('NSCLC', 'Disease', (304, 309))	('NSCLC', 'Disease', 'MESH:D002289', (304, 309))
36714	31208370	The smaller proportion of EGFRex20ins in Chinese populations is due to the larger scale of EGFR mutations than western groups.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', (91, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', '1956', (91, 95))	('mutations', 'Var', (96, 105))
36716	31208370	Of the patients with EGFR mutations, EGFRex20ins ranked the fourth most common type, following EGFR exon 19 deletions (436/1095, 39.8%), L858R (410/1095, 37.4%) and T790 M mutations (58/1095, 5.3%) (Fig.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('L858R', 'Var', (137, 142))	('T790 M', 'Mutation', 'rs121434569', (165, 171))	('T790 M', 'Var', (165, 171))	('mutations', 'Var', (26, 35))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('deletions', 'Var', (108, 117))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('patients', 'Species', '9606', (7, 15))	('EGFR', 'Gene', (95, 99))
36717	31208370	The majority of EGFRex20ins mutations were identified in lung adenocarcinoma (92.5%, 49/53).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('lung adenocarcinoma', 'Disease', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('EGFR', 'Gene', '1956', (16, 20))	('identified', 'Reg', (43, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('mutations', 'Var', (28, 37))	('EGFR', 'Gene', (16, 20))
36720	31208370	In total, 20 different variants of exon EGFRex20ins were identified in 53 NSCLC patients.	('patients', 'Species', '9606', (80, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('EGFR', 'Gene', '1956', (40, 44))	('NSCLC', 'Disease', (74, 79))	('EGFR', 'Gene', (40, 44))	('identified', 'Reg', (57, 67))	('variants', 'Var', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
36721	31208370	The most frequent variant is A767_V769dup (32.1%, 17/53), followed by P772_H773dup (4/53, 7.5%), S768_D770dup (4/53, 7.5%), N771_H773dup (4/53, 7.5%), A763_Y764insFQEA (3/53, 5.7%).	('A767_V769dup', 'Var', (29, 41))	('A767_V769dup', 'Mutation', 'p.767,769dupV', (29, 41))	('H773dup', 'Mutation', 'p.773dupH', (75, 82))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (156, 167))	('H773dup', 'Mutation', 'p.773dupH', (129, 136))	('P772_H773dup', 'Var', (70, 82))	('N771_H773dup', 'Var', (124, 136))	('S768_D770dup', 'Var', (97, 109))	('A763_Y764insFQEA', 'Var', (151, 167))	('S768_D770dup', 'Mutation', 'p.768,770dupD', (97, 109))
36723	31208370	EGFRex20ins tended to be exclusive with NSCLC driver genes such as EGFR mutation ERBB2, ALK, BRAF and RET mutations.	('BRAF', 'Gene', (93, 97))	('ALK', 'Gene', (88, 91))	('EGFR', 'Gene', (0, 4))	('ERBB2', 'Gene', (81, 86))	('RET', 'Gene', (102, 105))	('ERBB2', 'Gene', '2064', (81, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('EGFR', 'Gene', (67, 71))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('ALK', 'Gene', '238', (88, 91))	('mutation', 'Var', (72, 80))	('NSCLC', 'Disease', (40, 45))	('RET', 'Gene', '5979', (102, 105))	('BRAF', 'Gene', '673', (93, 97))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
36725	31208370	Co-mutation pattern compared with EGFR ex19dels, L858R, T790 M and other EGFR uncommon mutations were summarized in Additional file 1: Figure S1 and Additional file 2: Figure S2.	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (34, 38))	('ex19dels', 'Var', (39, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('EGFR', 'Gene', (73, 77))	('L858R', 'Var', (49, 54))	('T790 M', 'Mutation', 'rs121434569', (56, 62))	('T790 M', 'Var', (56, 62))	('L858R', 'Mutation', 'rs121434568', (49, 54))	('EGFR', 'Gene', '1956', (34, 38))
36735	31208370	Patient 1 had EGFR A767_V769dup mutation and received first-line therapy with osimertinib.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('A767_V769dup', 'Var', (19, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('A767_V769dup', 'Mutation', 'p.767,769dupV', (19, 31))	('Patient', 'Species', '9606', (0, 7))	('osimertinib', 'Chemical', 'MESH:C000603933', (78, 89))
36753	31208370	Based on a large-scale study including 2316 NSCLC patient, our study demonstrated the EGFRex20ins distribution in EGFR mutant Chinese patients (4.8%), the most common EGFRex20ins mutation (A767_V769dup) and co-mutation (TP53), as well as clinical characteristics of EGFRex20ins in Chinese NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (289, 294))	('TP53', 'Gene', (220, 224))	('patients', 'Species', '9606', (134, 142))	('patient', 'Species', '9606', (134, 141))	('EGFR', 'Gene', '1956', (86, 90))	('patient', 'Species', '9606', (295, 302))	('EGFR', 'Gene', '1956', (266, 270))	('A767_V769dup', 'Mutation', 'p.767,769dupV', (189, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('mutant', 'Var', (119, 125))	('EGFR', 'Gene', (167, 171))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('TP53', 'Gene', '7157', (220, 224))	('NSCLC', 'Disease', 'MESH:D002289', (289, 294))	('NSCLC', 'Disease', (44, 49))	('A767_V769dup', 'Var', (189, 201))	('patients', 'Species', '9606', (295, 303))	('NSCLC', 'Disease', (289, 294))	('EGFR', 'Gene', '1956', (114, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', (266, 270))	('EGFR', 'Gene', '1956', (167, 171))	('patient', 'Species', '9606', (50, 57))
36757	31208370	Although the proportion of EGFR mutant patients was much larger in our Chinese cohort (47.3% vs 15.5%), which consists with previous studies, exon 20 insertions accounted for a smaller proportion compared to FM cohort in EGFR mutant NSCLC (4.8% vs. 11.7%, p < 0.001).	('NSCLC', 'Disease', (233, 238))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('insertions', 'Var', (150, 160))	('mutant', 'Var', (226, 232))	('NSCLC', 'Disease', 'MESH:D002289', (233, 238))	('exon 20 insertions', 'Var', (142, 160))	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', '1956', (221, 225))	('EGFR', 'molecular_function', 'GO:0005006', ('221', '225'))	('mutant', 'Var', (32, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (233, 238))	('EGFR', 'Gene', (221, 225))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))
36759	31208370	In the contrast, proportion of exon 20 insertion in EGFR- mutant patients in our study is similar to those reported in other Asian cohorts, ranging from 3.6-4%.	('mutant', 'Var', (58, 64))	('insertion', 'Var', (39, 48))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('patients', 'Species', '9606', (65, 73))	('exon 20', 'Gene', (31, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
36763	31208370	Most EGFRex20ins mutations (with the exception of a few subtypes such as A763_Y764insFQEA) are associated with poor responses with the 1st and 2nd generation EGFR TKIs.	('EGFR', 'Gene', (158, 162))	('A763_Y764insFQEA', 'Var', (73, 89))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'Gene', (5, 9))	('EGFR', 'Gene', '1956', (158, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (78, 89))
36766	31208370	Several preclinical studies have proved that osimertinib was active in specific lung cancer cell lines with EGFRex20ins mutations, while the clinical activity of the 3rd generation EGFR TKIs in EGFRex20ins tumors remains unknown.	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('EGFR', 'Gene', (181, 185))	('osimertinib', 'Chemical', 'MESH:C000603933', (45, 56))	('EGFR', 'Gene', '1956', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('EGFR', 'Gene', (108, 112))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('lung cancer', 'Disease', (80, 91))	('EGFR', 'Gene', '1956', (194, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('EGFR', 'Gene', (194, 198))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EGFR', 'Gene', '1956', (181, 185))
36767	31208370	Our study showed promising antitumor activity of osimertinib in NSCLC patients harboring certain EGFRex20ins mutations, with four patients attaining PR and two patients SD.	('patients', 'Species', '9606', (70, 78))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('patients', 'Species', '9606', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EGFR', 'Gene', '1956', (97, 101))	('SD', 'Disease', 'MESH:D029461', (169, 171))	('tumor', 'Disease', (31, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('osimertinib', 'Chemical', 'MESH:C000603933', (49, 60))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (109, 118))	('NSCLC', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
36770	31208370	Despite the documented activity of osimertinib in our six patients, in vitro study still demonstrated limited osimertinib effect in several EGFRex20ins mutant cell lines.	('EGFR', 'Gene', (140, 144))	('osimertinib', 'Chemical', 'MESH:C000603933', (110, 121))	('osimertinib', 'Chemical', 'MESH:C000603933', (35, 46))	('mutant', 'Var', (152, 158))	('patients', 'Species', '9606', (58, 66))	('EGFR', 'Gene', '1956', (140, 144))
36772	31208370	These studies indicate EGFRex20ins is a heterogeneous group of EGFR mutation and deserves more researches to fully determine osimertinib sensitivity in different EGFRex20ins tumors.	('EGFR', 'Gene', '1956', (63, 67))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('mutation', 'Var', (68, 76))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('osimertinib', 'Chemical', 'MESH:C000603933', (125, 136))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('EGFR', 'Gene', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
36773	31208370	A recent case report has showed that an advanced NSCLC patient with EGFRex20ins mutation, S768_D770dup, responded to osimertinib 160 mg daily.	('responded', 'MPA', (104, 113))	('NSCLC', 'Disease', (49, 54))	('EGFR', 'Gene', (68, 72))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('osimertinib', 'Chemical', 'MESH:C000603933', (117, 128))	('EGFR', 'Gene', '1956', (68, 72))	('patient', 'Species', '9606', (55, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('S768_D770dup', 'Mutation', 'p.768,770dupD', (90, 102))	('S768_D770dup', 'Var', (90, 102))
36774	31208370	The mutation detected was the same as that of patient 2 and patient 4, which might suggest favorable lower-dose osimertinib efficacy in tumors bearing EGFR S768_D770dup mutation.	('S768_D770dup', 'Mutation', 'p.768,770dupD', (156, 168))	('tumors', 'Disease', (136, 142))	('patient', 'Species', '9606', (60, 67))	('osimertinib', 'Chemical', 'MESH:C000603933', (112, 123))	('patient', 'Species', '9606', (46, 53))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('EGFR', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('S768_D770dup', 'Var', (156, 168))	('EGFR', 'Gene', '1956', (151, 155))
36775	31208370	Another case report also suggested that EGFR H773L/V774 M, an EGFR exon 20 mutation, could be suppressed by osimertinib, further supporting the osimertinib effect in specific EGFR exon 20 mutations.	('H773L', 'Var', (45, 50))	('EGFR', 'Gene', (175, 179))	('EGFR', 'Gene', '1956', (62, 66))	('osimertinib', 'Chemical', 'MESH:C000603933', (144, 155))	('H773L', 'SUBSTITUTION', 'None', (45, 50))	('EGFR', 'Gene', (62, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('osimertinib', 'Chemical', 'MESH:C000603933', (108, 119))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('EGFR', 'Gene', (40, 44))	('suppressed', 'NegReg', (94, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('175', '179'))	('EGFR', 'Gene', '1956', (175, 179))
36776	31208370	In addition, considering that EGFR T790 M was identified in patient 6 harboring EGFR A763_Y764insFQEA after acquired resistance to gefitinib, we found that EGFR T790 M served as a potential resistant mechanism in EGFR A763_Y764insFQEA positive NSCLC patients and occurrence of both mutations could be targeted by osimertinib.	('EGFR', 'Gene', (30, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('NSCLC', 'Disease', 'MESH:D002289', (244, 249))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('T790 M', 'Mutation', 'rs121434569', (161, 167))	('EGFR', 'Gene', '1956', (80, 84))	('osimertinib', 'Chemical', 'MESH:C000603933', (313, 324))	('A763_Y764insFQEA', 'Var', (85, 101))	('EGFR', 'Gene', '1956', (213, 217))	('NSCLC', 'Disease', (244, 249))	('EGFR', 'Gene', '1956', (156, 160))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (90, 101))	('A763_Y764insFQEA', 'Var', (218, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (244, 249))	('EGFR', 'Gene', '1956', (30, 34))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (223, 234))	('patients', 'Species', '9606', (250, 258))	('gefitinib', 'Chemical', 'MESH:D000077156', (131, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('patient', 'Species', '9606', (250, 257))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('patient', 'Species', '9606', (60, 67))	('EGFR', 'Gene', (213, 217))	('EGFR', 'Gene', (156, 160))	('T790 M', 'Mutation', 'rs121434569', (35, 41))
36777	31208370	This is the first case showing that T790 M mediated the acquired resistance to gefitinib for patient with EGFR A763_Y764insFQEA and osimertinib treatment was effective for patient with both EGFR A763_Y764insFQEA and EGFR T790 M. Still, there are several limitations in the study.	('T790 M', 'Var', (36, 42))	('gefitinib', 'Chemical', 'MESH:D000077156', (79, 88))	('EGFR', 'Gene', '1956', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('216', '220'))	('EGFR', 'Gene', (106, 110))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (116, 127))	('EGFR', 'Gene', (216, 220))	('acquired resistance to', 'MPA', (56, 78))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (200, 211))	('T790 M', 'Mutation', 'rs121434569', (221, 227))	('patient', 'Species', '9606', (172, 179))	('EGFR', 'Gene', (190, 194))	('patient', 'Species', '9606', (93, 100))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', '1956', (216, 220))	('T790 M', 'Mutation', 'rs121434569', (36, 42))	('A763_Y764insFQEA', 'Var', (111, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('osimertinib', 'Chemical', 'MESH:C000603933', (132, 143))
36782	31208370	AEs Adverse events CT Computed tomography EGFRex20ins Epidermal growth factor receptor exon 20 insertion L858R Leu858Arg MRI magnetic resonance imaging NGS Next generation sequencing NOS Non-small-cell lung cancer not otherwise specified NSCLC Non-small-cell lung cancer PD Progressive disease PFS Progression-free survival PR Partial response RECIST Response criteria in solid tumors SD Stable disease TKIs Tyrosine kinase inhibitors WF, YH, SH, ZZ, MW conceived of the study; LZ and WF designed the study; YH, SH, ZZ, MW analyzed data; JG, WW, HG, KW collected data; WF, YH, SH, ZZ wrote the manuscript.	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('Epidermal growth factor receptor', 'Gene', '1956', (54, 86))	('Non-small-cell lung cancer', 'Disease', (244, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('PD', 'Disease', 'MESH:D010300', (271, 273))	('NSCLC', 'Disease', (238, 243))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (191, 213))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (378, 384))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('54', '77'))	('Non-small-cell lung cancer', 'Disease', 'MESH:D002289', (244, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('EGFR', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Non-small-cell lung cancer', 'Disease', (187, 213))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('SD', 'Disease', 'MESH:D029461', (385, 387))	('Epidermal growth factor receptor', 'Gene', (54, 86))	('tumors', 'Disease', (378, 384))	('L858R', 'Mutation', 'rs121434568', (105, 110))	('Tyrosine kinase', 'Gene', '7294', (408, 423))	('Non-small-cell lung cancer', 'Disease', 'MESH:D002289', (187, 213))	('Leu858Arg', 'Var', (111, 120))	('Leu858Arg', 'SUBSTITUTION', 'None', (111, 120))	('EGFR', 'Gene', '1956', (42, 46))	('tumors', 'Disease', 'MESH:D009369', (378, 384))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (248, 270))	('Tyrosine kinase', 'Gene', (408, 423))	('AEs', 'Chemical', '-', (0, 3))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))
36795	31013618	Although each of these GAGs has a predominant disaccharide component as mentioned above, as a result of the non-template-driven biosynthetic pathway by which they are produced, these disaccharides can be modified at multiple positions by sulfation, acetylation, and/or epimerization, creating a tremendous amount of heterogeneity in any particular class of GAGs.	('disaccharide', 'Chemical', 'MESH:D004187', (183, 195))	('epimerization', 'Var', (269, 282))	('GAG', 'Chemical', 'MESH:D006025', (23, 26))	('disaccharide', 'Chemical', 'MESH:D004187', (46, 58))	('GAG', 'Chemical', 'MESH:D006025', (357, 360))	('disaccharide component', 'MPA', (46, 68))	('modified', 'Reg', (204, 212))	('sulfation', 'biological_process', 'GO:0051923', ('238', '247'))	('disaccharides', 'Chemical', 'MESH:D004187', (183, 196))
36799	31013618	They bind to different protein targets, primarily via electrostatic interactions between negatively-charged uronic acids and sulfate groups and positively-charged amino acids in the protein.	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('bind', 'Interaction', (5, 9))	('negatively-charged', 'Var', (89, 107))	('uronic acids', 'Protein', (108, 120))	('uronic acids', 'Chemical', 'MESH:D014574', (108, 120))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('electrostatic interactions', 'MPA', (54, 80))	('sulfate', 'Chemical', 'MESH:D013431', (125, 132))
36841	31013618	CS/DS are also shown to interact with the proteins involved in tumor growth and enhance their activity.	('tumor', 'Disease', (63, 68))	('proteins', 'Protein', (42, 50))	('CS/DS', 'Var', (0, 5))	('interact', 'Interaction', (24, 32))	('DS', 'Chemical', 'MESH:D003903', (3, 5))	('activity', 'MPA', (94, 102))	('enhance', 'PosReg', (80, 87))	('CS', 'Chemical', 'MESH:D002586', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
36849	31013618	Moreover, degradation of HA to smaller oligosaccharides by hyaluronidases is reported to induce cleaving of CD-44 in the tumor microenvironment, leading to tumor progression, as seen in breast, ovarian, glioma, and colon cancers.	('leading to', 'Reg', (145, 155))	('degradation', 'Var', (10, 21))	('oligosaccharides', 'Chemical', 'MESH:D009844', (39, 55))	('tumor', 'Disease', (156, 161))	('breast, ovarian, glioma', 'Disease', 'MESH:D005910', (186, 209))	('cleaving', 'MPA', (96, 104))	('CD-44', 'Gene', (108, 113))	('degradation', 'biological_process', 'GO:0009056', ('10', '21'))	('colon cancer', 'Phenotype', 'HP:0003003', (215, 227))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (121, 126))	('colon cancers', 'Phenotype', 'HP:0003003', (215, 228))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colon cancers', 'Disease', 'MESH:D015179', (215, 228))	('HA', 'Chemical', 'MESH:D006820', (25, 27))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('colon cancers', 'Disease', (215, 228))
36856	31013618	SST0001 is 100% N-acetylated and 25% glycol split high-molecular weight heparin, and hence, the microheterogeneity of the original heparin is retained in it.	('high-molecular weight heparin', 'MPA', (50, 79))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('SST0001', 'Var', (0, 7))	('heparin', 'Chemical', 'MESH:D006493', (72, 79))	('glycol', 'Chemical', 'MESH:D006018', (37, 43))	('heparin', 'Chemical', 'MESH:D006493', (131, 138))
36859	31013618	It is obtained from depolymerization of low molecular weight heparin followed by oxidation and borohydride reduction, resulting in a glycol split.	('borohydride', 'Chemical', 'MESH:D001894', (95, 106))	('low molecular weight', 'Chemical', '-', (40, 60))	('glycol', 'Chemical', 'MESH:D006018', (133, 139))	('heparin', 'Chemical', 'MESH:D006493', (61, 68))	('glycol split', 'MPA', (133, 145))	('depolymerization', 'Var', (20, 36))
36864	31013618	The inhibition of self-renewal was found to be because of activation of p38alpha/beta mitogen-activated protein kinase (MAPK), which led to inhibition of TCF4 signaling, a critical regulator of CSC self-renewal.	('p38alpha/beta', 'Var', (72, 85))	('CS', 'Chemical', 'MESH:D002586', (194, 196))	('inhibition', 'NegReg', (4, 14))	('self-renewal', 'CPA', (18, 30))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('inhibition', 'NegReg', (140, 150))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('activation', 'PosReg', (58, 68))	('MAPK', 'molecular_function', 'GO:0004707', ('120', '124'))	('TCF4 signaling', 'Pathway', (154, 168))
36867	31013618	Interestingly, the fragments generated from Hep I promoted tumor growth, whereas Hep III generated fragments were found to inhibit tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('promoted', 'PosReg', (50, 58))	('tumor', 'Disease', (59, 64))	('Hep I', 'CellLine', 'CVCL:C376', (44, 49))	('Hep I', 'CellLine', 'CVCL:C376', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Disease', (131, 136))	('inhibit', 'NegReg', (123, 130))	('rat', 'Species', '10116', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('fragments', 'Var', (19, 28))
36872	31013618	Novel molecules called neoglycans, produced by modifying CS chains with carbodiimide, reduced tumor growth in nude mice with breast cancer without apparent toxicity to the normal tissue.	('modifying', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('reduced', 'NegReg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CS', 'Chemical', 'MESH:D002586', (57, 59))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('carbodiimide', 'Chemical', 'MESH:D002234', (72, 84))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('glycans', 'Chemical', 'MESH:D011134', (26, 33))	('CS chains', 'Protein', (57, 66))	('breast cancer', 'Disease', (125, 138))	('toxicity', 'Disease', (156, 164))	('toxicity', 'Disease', 'MESH:D064420', (156, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('nude mice', 'Species', '10090', (110, 119))
36907	31013618	As previously mentioned, GAGs are complex heterogeneous molecules with exceptional structural diversity, which not only differ in their length, but are also modified at multiple positions through sulfation, acetylation, and epimerization.	('sulfation', 'Var', (196, 205))	('GAG', 'Chemical', 'MESH:D006025', (25, 28))	('acetylation', 'Var', (207, 218))	('sulfation', 'biological_process', 'GO:0051923', ('196', '205'))	('epimerization', 'Var', (224, 237))	('modified', 'Reg', (157, 165))
36926	31013618	PI-88 potently inhibits the activity of heparanase, an enzyme that plays a vital role in metastasis and angiogenesis.	('PI-88', 'Chemical', 'MESH:C120158', (0, 5))	('activity', 'MPA', (28, 36))	('angiogenesis', 'biological_process', 'GO:0001525', ('104', '116'))	('heparanase', 'Gene', (40, 50))	('PI-88', 'Var', (0, 5))	('inhibits', 'NegReg', (15, 23))	('heparanase', 'Gene', '10855', (40, 50))
36928	31013618	Although PI-88 also possesses anticoagulant activity, in addition to anticancer activity, it appeared to be well tolerated in preclinical models and was hence investigated further in clinical trials.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('rat', 'Species', '10116', (117, 120))	('PI-88', 'Var', (9, 14))	('anticoagulant activity', 'MPA', (30, 52))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('anticoagulant activity', 'biological_process', 'GO:0050819', ('30', '52'))	('PI-88', 'Chemical', 'MESH:C120158', (9, 14))	('anticoagulant activity', 'molecular_function', 'GO:0008435', ('30', '52'))
36947	31013618	G2.2 also inhibited the growth of tumor in CSC induced xenografts in vivo.	('G2.2', 'Var', (0, 4))	('tumor', 'Disease', (34, 39))	('CS', 'Chemical', 'MESH:D002586', (43, 45))	('inhibited', 'NegReg', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
36960	31013618	Di-S-IdoA showed a reduction in leukocyte recruitment into the lungs, indicating a potential use of the compound to reduce the inflammatory response.	('Di-S-IdoA', 'Var', (0, 9))	('leukocyte', 'CPA', (32, 41))	('inflammatory response', 'CPA', (127, 148))	('reduction', 'NegReg', (19, 28))	('Di-S-IdoA', 'Chemical', '-', (0, 9))	('inflammatory response', 'biological_process', 'GO:0006954', ('127', '148'))
36975	31013618	When endothelial lung cell death was induced in vitro using inhibitors for histone deacetylase and VEGF receptor, or through cigarette smoke, CDSO3 treatment significantly inhibited cell death when compared to control.	('cell death', 'biological_process', 'GO:0008219', ('182', '192'))	('VEGF', 'Gene', '7422', (99, 103))	('CDSO3', 'Chemical', '-', (142, 147))	('inhibitors', 'Var', (60, 70))	('cell death', 'CPA', (182, 192))	('cell death', 'biological_process', 'GO:0008219', ('22', '32'))	('inhibited', 'NegReg', (172, 181))	('VEGF', 'Gene', (99, 103))	('endothelial lung', 'Disease', (5, 21))
36995	31071657	Overexpression of ALDH2 inhibited malignant features of lung adenocarcinoma cells, such as proliferation, stemness and migration, whereas ALDH2 knockdown increased these features.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('malignant features of', 'CPA', (34, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))	('ALDH', 'molecular_function', 'GO:0004030', ('138', '142'))	('lung adenocarcinoma', 'Disease', (56, 75))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('inhibited', 'NegReg', (24, 33))	('stemness', 'Disease', (106, 114))	('stemness', 'Disease', 'MESH:D020295', (106, 114))	('knockdown', 'Var', (144, 153))	('ALDH2', 'Gene', (138, 143))	('ALDH2', 'Gene', (18, 23))	('increased', 'PosReg', (154, 163))	('ALDH', 'molecular_function', 'GO:0004030', ('18', '22'))
36999	31071657	Thus, activating ALDH2, such as via its agonist, may provide a novel strategy for treatment of lung cancer.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('activating', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ALDH2', 'Gene', (17, 22))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('ALDH', 'molecular_function', 'GO:0004030', ('17', '21'))
37011	31071657	Moreover, chromosomal instability promotes cancer metastasis via cytosolic DNA derived from genomic DNA rupture.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('chromosomal instability', 'Var', (10, 33))	('cancer', 'Disease', (43, 49))	('promotes', 'PosReg', (34, 42))	('chromosomal instability', 'Phenotype', 'HP:0040012', (10, 33))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
37023	31071657	HEK293T cells were transfected with lenti-shALDH2 (or nonspecific sequence) plasmid or lenti-ALDH2 (or GFP) plasmid used for virus production for ALDH2 knock down or overexpression.	('ALDH', 'molecular_function', 'GO:0004030', ('146', '150'))	('knock down', 'Var', (152, 162))	('ALDH', 'molecular_function', 'GO:0004030', ('93', '97'))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('ALDH2', 'Gene', (146, 151))	('overexpression', 'PosReg', (166, 180))
37069	31071657	Next, we analyzed the survival rate of lung adenocarcinoma patients with low or high ALDH2 expression using the Cancer Genome Atlas (TCGA) dataset.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('Cancer Genome Atlas', 'Disease', (112, 131))	('expression', 'MPA', (91, 101))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (112, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('ALDH2', 'Gene', (85, 90))	('patients', 'Species', '9606', (59, 67))	('lung adenocarcinoma', 'Disease', (39, 58))	('low', 'NegReg', (73, 76))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))	('high', 'Var', (80, 84))	('ALDH', 'molecular_function', 'GO:0004030', ('85', '89'))
37080	31071657	To characterize the biological functions of ALDH2 in lung adenocarcinoma, we established ALDH2-overexpression transfectants in lung adenocarcinoma cell lines A549 and H1299 (Figure 2, B and D), or silenced ALDH2 using short hairpin (sh) RNA in A549 cells (Figure 2G).	('ALDH', 'molecular_function', 'GO:0004030', ('89', '93'))	('silenced', 'NegReg', (197, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('lung adenocarcinoma cell lines A549', 'Disease', (127, 162))	('transfectants', 'Var', (110, 123))	('ALDH2-overexpression', 'Gene', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('ALDH', 'molecular_function', 'GO:0004030', ('44', '48'))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('A549', 'CellLine', 'CVCL:0023', (244, 248))	('ALDH2-overexpression', 'PosReg', (89, 109))	('ALDH2', 'Gene', (206, 211))	('RNA', 'cellular_component', 'GO:0005562', ('237', '240'))	('lung adenocarcinoma cell lines A549', 'Disease', 'MESH:D000077192', (127, 162))	('lung adenocarcinoma', 'Disease', (53, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('H1299', 'CellLine', 'CVCL:0060', (167, 172))	('ALDH', 'molecular_function', 'GO:0004030', ('206', '210'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
37081	31071657	The results showed that A549-ALDH2 and H1299-ALDH2 cells exhibited significantly reduced colony forming capacity as compared to A549-GFP and H1299-GFP cells in colony formation assay (Figure 2, C and E).	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (24, 34))	('H1299', 'CellLine', 'CVCL:0060', (141, 146))	('H1299-ALDH2', 'Var', (39, 50))	('colony forming capacity', 'CPA', (89, 112))	('ALDH', 'molecular_function', 'GO:0004030', ('29', '33'))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('H1299', 'CellLine', 'CVCL:0060', (39, 44))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (39, 50))	('ALDH', 'molecular_function', 'GO:0004030', ('45', '49'))	('A549-ALDH2', 'Var', (24, 34))	('formation', 'biological_process', 'GO:0009058', ('167', '176'))	('reduced', 'NegReg', (81, 88))
37082	31071657	In addition, H1299-ALDH2 cells exhibited significantly reduced number of 3D-spheres as compared to H1299-GFP, although the size of 3D-spheres in two cell lines appeared similar (Figure 2F).	('H1299', 'CellLine', 'CVCL:0060', (99, 104))	('reduced', 'NegReg', (55, 62))	('H1299-ALDH2', 'Var', (13, 24))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (13, 24))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))	('3D-spheres', 'CPA', (73, 83))	('ALDH', 'molecular_function', 'GO:0004030', ('19', '23'))
37085	31071657	The result showed that the tumor volumes of A549-shALDH2 were significantly larger than those of A549-shNS (Figure2H).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('larger', 'PosReg', (76, 82))	('A549-shALDH2', 'Var', (44, 56))	('tumor', 'Disease', (27, 32))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
37087	31071657	To determine the mechanisms involved, we next examined the side population of A549-GFP, A549-ALDH2 and H1299-GFP, H1299-ALDH2 cells, the side population is widely considered as a stem cell-like population.	('H1299', 'CellLine', 'CVCL:0060', (103, 108))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (114, 125))	('H1299', 'CellLine', 'CVCL:0060', (114, 119))	('A549-ALDH2', 'Var', (88, 98))	('H1299-GFP', 'Var', (103, 112))	('ALDH', 'molecular_function', 'GO:0004030', ('120', '124'))	('ALDH', 'molecular_function', 'GO:0004030', ('93', '97'))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (88, 98))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('A549-GFP', 'Var', (78, 86))	('H1299-ALDH2', 'Var', (114, 125))
37088	31071657	The results showed that the side population of A549-ALDH2 cells (4.79%) was decreased as compared to that of A549-GFP cells (8.76%) (Figure 3A).	('side population', 'CPA', (28, 43))	('ALDH', 'molecular_function', 'GO:0004030', ('52', '56'))	('decreased', 'NegReg', (76, 85))	('A549-ALDH2', 'Var', (47, 57))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (47, 57))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
37097	31071657	The results showed that the ROS level in A549-ALDH2 was significantly lower as compared to that in A549 (Figure 3D).	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('ROS level', 'MPA', (28, 37))	('ALDH', 'molecular_function', 'GO:0004030', ('46', '50'))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (41, 51))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('lower', 'NegReg', (70, 75))	('A549-ALDH2', 'Var', (41, 51))
37098	31071657	Thus, ALDH2 expression suppresses ROS in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('expression', 'Var', (12, 22))	('suppresses', 'NegReg', (23, 33))	('ALDH2', 'Gene', (6, 11))	('ALDH', 'molecular_function', 'GO:0004030', ('6', '10'))	('ROS', 'MPA', (34, 37))
37100	31071657	However, when exogenous ACE was added to H1299 and H1299-ALDH2 cells, the ROS level was significantly lower in H1299-ALDH2 cells as compared to that in H1299 cells (Figure 3F).	('lower', 'NegReg', (102, 107))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (111, 122))	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('H1299', 'CellLine', 'CVCL:0060', (152, 157))	('H1299', 'CellLine', 'CVCL:0060', (41, 46))	('H1299', 'CellLine', 'CVCL:0060', (111, 116))	('ACE', 'Chemical', 'MESH:D000079', (24, 27))	('ALDH', 'molecular_function', 'GO:0004030', ('57', '61'))	('ALDH', 'molecular_function', 'GO:0004030', ('117', '121'))	('H1299-ALDH2', 'Var', (111, 122))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('ROS level', 'MPA', (74, 83))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (51, 62))
37101	31071657	This suggests that H1299-ALDH2 cells have an enhanced capacity in detoxifying ACE-induced ROS, compared to H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (107, 112))	('H1299-ALDH2', 'Var', (19, 30))	('ALDH', 'molecular_function', 'GO:0004030', ('25', '29'))	('H1299', 'CellLine', 'CVCL:0060', (19, 24))	('enhanced', 'PosReg', (45, 53))	('detoxifying ACE-induced ROS', 'MPA', (66, 93))	('ROS', 'Chemical', 'MESH:D017382', (90, 93))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (19, 30))	('ACE', 'Chemical', 'MESH:D000079', (78, 81))
37103	31071657	Consistently, overexpression of ALDH2 inhibited CD44, the stem cell-like marker, in H1299-ALDH2 cells as compared to H1299-GFP cells in 3D culture, and depletion of ALDH2 increased CD44 expression in H1792-shALDH2 as compared to H1792-shNS cells (Figure 3G).	('H1792-shALDH2', 'Var', (200, 213))	('H1792-shNS', 'CellLine', 'CVCL:1495', (229, 239))	('overexpression', 'PosReg', (14, 28))	('increased', 'PosReg', (171, 180))	('H1299', 'CellLine', 'CVCL:0060', (117, 122))	('ALDH', 'molecular_function', 'GO:0004030', ('90', '94'))	('H1299', 'CellLine', 'CVCL:0060', (84, 89))	('CD44', 'Gene', '960', (48, 52))	('depletion', 'Var', (152, 161))	('CD44', 'Gene', (48, 52))	('ALDH2', 'Gene', (32, 37))	('ALDH', 'molecular_function', 'GO:0004030', ('32', '36'))	('ALDH', 'molecular_function', 'GO:0004030', ('165', '169'))	('CD44', 'Gene', '960', (181, 185))	('ALDH2', 'Gene', (165, 170))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (84, 95))	('CD44', 'Gene', (181, 185))	('inhibited', 'NegReg', (38, 47))	('expression', 'MPA', (186, 196))
37108	31071657	ALDH2 repression indeed resulted in an increased level of endogenous ACE in A549-shALDH2 cells as compared to that in control, A549-NS cells (Figure 4A).	('A549-shALDH2', 'Var', (76, 88))	('level of endogenous ACE', 'MPA', (49, 72))	('ACE', 'Chemical', 'MESH:D000079', (69, 72))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('ALDH2', 'Gene', (0, 5))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('increased', 'PosReg', (39, 48))	('A549-NS', 'CellLine', 'CVCL:0023', (127, 134))	('repression', 'Var', (6, 16))	('A549', 'CellLine', 'CVCL:0023', (127, 131))
37115	31071657	Without treatment, A549-GFP and A549-ALDH2 cells, H1299-GFP and H1299-ALDH2 cells exhibited similar levels of gammaH2AX (Figure 4, C and D).	('ALDH', 'molecular_function', 'GO:0004030', ('70', '74'))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('gammaH2AX', 'Gene', (110, 119))	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (64, 75))	('H1299', 'CellLine', 'CVCL:0060', (50, 55))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (32, 42))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('ALDH', 'molecular_function', 'GO:0004030', ('37', '41'))	('H1299-GFP', 'Var', (50, 59))	('H1299', 'CellLine', 'CVCL:0060', (64, 69))	('gammaH2AX', 'Gene', '15270', (110, 119))
37118	31071657	Taken together, ALDH2 overexpression confers the capacity to reduce ACE -mediated DNA damage.	('ALDH2', 'Gene', (16, 21))	('reduce', 'NegReg', (61, 67))	('ALDH', 'molecular_function', 'GO:0004030', ('16', '20'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('ACE -mediated DNA damage', 'MPA', (68, 92))	('ACE', 'Chemical', 'MESH:D000079', (68, 71))	('overexpression', 'Var', (22, 36))
37120	31071657	As expected, the endogenous ACE level was significantly higher in Aldh2-KO mouse lungs than that in wild-type ones (Figure 4E).	('endogenous ACE level', 'MPA', (17, 37))	('ACE', 'Chemical', 'MESH:D000079', (28, 31))	('Aldh2-KO', 'Var', (66, 74))	('Aldh', 'molecular_function', 'GO:0004030', ('66', '70'))	('mouse', 'Species', '10090', (75, 80))	('higher', 'PosReg', (56, 62))
37123	31071657	Of notion, administration of exogenous Ethanol drastically increased the endogenous ACE level in Aldh2-KO mouse lungs (Figure 4E), indicating that Aldh2 deficiency leads to accumulated ACE in vivo.	('ACE', 'Chemical', 'MESH:D000079', (185, 188))	('Aldh2', 'Gene', (147, 152))	('accumulated', 'PosReg', (173, 184))	('endogenous ACE level', 'MPA', (73, 93))	('ACE', 'MPA', (185, 188))	('Ethanol', 'Chemical', 'MESH:D000431', (39, 46))	('ACE', 'Chemical', 'MESH:D000079', (84, 87))	('Aldh', 'molecular_function', 'GO:0004030', ('97', '101'))	('deficiency', 'Var', (153, 163))	('increased', 'PosReg', (59, 68))	('Aldh', 'molecular_function', 'GO:0004030', ('147', '151'))	('mouse', 'Species', '10090', (106, 111))
37125	31071657	Consistent with in vitro assay, we examined gammaH2AX in lung tissues via Western blot and immunoblot analysis, the level of gammaH2AX was significantly increased in Aldh2-KO mouse lungs as compared to that in WT mouse lungs (Figure 4, F and G), suggesting an increased DNA damage response in Aldh2-KO mouse lungs.	('mouse', 'Species', '10090', (213, 218))	('Aldh', 'molecular_function', 'GO:0004030', ('293', '297'))	('increased', 'PosReg', (260, 269))	('DNA damage response', 'MPA', (270, 289))	('gammaH2AX', 'Gene', (125, 134))	('increased', 'PosReg', (153, 162))	('DNA damage response', 'biological_process', 'GO:0006974', ('270', '289'))	('mouse', 'Species', '10090', (302, 307))	('Aldh2-KO', 'Var', (166, 174))	('gammaH2AX', 'Gene', '15270', (44, 53))	('Aldh', 'molecular_function', 'GO:0004030', ('166', '170'))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('gammaH2AX', 'Gene', '15270', (125, 134))	('gammaH2AX', 'Gene', (44, 53))	('mouse', 'Species', '10090', (175, 180))
37128	31071657	Moreover, these results suggest that Aldh2 deficiency leads to increased ACE and DNA damage in lung tissues in vivo.	('increased', 'PosReg', (63, 72))	('ACE', 'Chemical', 'MESH:D000079', (73, 76))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('Aldh', 'molecular_function', 'GO:0004030', ('37', '41'))	('Aldh2', 'Gene', (37, 42))	('deficiency', 'Var', (43, 53))
37130	31071657	Taken together, ALDH2 overexpression confers the capacity to reduce ACE-mediated DNA damage.	('ALDH2', 'Gene', (16, 21))	('reduce', 'NegReg', (61, 67))	('ALDH', 'molecular_function', 'GO:0004030', ('16', '20'))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('ACE-mediated DNA damage', 'MPA', (68, 91))	('ACE', 'Chemical', 'MESH:D000079', (68, 71))	('overexpression', 'Var', (22, 36))
37131	31071657	Recent evidences demonstrate that chromosome instability or DNA damage generate cytosolic DNA, further promotes the metastatic features of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('chromosome instability', 'Phenotype', 'HP:0040012', (34, 56))	('DNA damage', 'Var', (60, 70))	('chromosome instability', 'Var', (34, 56))	('cytosolic DNA', 'MPA', (80, 93))	('promotes', 'PosReg', (103, 111))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('cancer', 'Disease', (139, 145))
37138	31071657	Thus, we also examined STING expression and found that STING was decreased in A549-ALDH2 cells as compared to A549-GFP cells (Supplemental data Figure 1B).	('STING', 'Gene', '340061', (23, 28))	('STING', 'Gene', (55, 60))	('decreased', 'NegReg', (65, 74))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('ALDH', 'molecular_function', 'GO:0004030', ('83', '87'))	('A549-ALDH2', 'Var', (78, 88))	('STING', 'Gene', (23, 28))	('examined', 'Reg', (14, 22))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('STING', 'Gene', '340061', (55, 60))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (78, 88))
37144	31071657	Consistently, the ratio of CD44+/CD24- population of H1299 was also significantly reduced following Alda-1 treatment (Figure 6B).	('CD24', 'Gene', '100133941', (33, 37))	('H1299', 'Var', (53, 58))	('CD24', 'Gene', (33, 37))	('Alda', 'Gene', (100, 104))	('CD44', 'Gene', '960', (27, 31))	('H1299', 'CellLine', 'CVCL:0060', (53, 58))	('CD44', 'Gene', (27, 31))	('Alda', 'Gene', '226', (100, 104))	('reduced', 'NegReg', (82, 89))
37149	31071657	Of notion, Alda-1-induced inhibition on 3D-sphere formation was more drastic in H1299-ALDH2 cells than in H1299-GFP cells (Figure 6D).	('H1299-ALDH2', 'CellLine', 'CVCL:0060', (80, 91))	('formation', 'biological_process', 'GO:0009058', ('50', '59'))	('H1299', 'CellLine', 'CVCL:0060', (80, 85))	('Alda', 'Gene', (11, 15))	('H1299', 'CellLine', 'CVCL:0060', (106, 111))	('3D-sphere formation', 'CPA', (40, 59))	('H1299-ALDH2', 'Var', (80, 91))	('Alda', 'Gene', '226', (11, 15))	('ALDH', 'molecular_function', 'GO:0004030', ('86', '90'))
37159	31071657	Thus, targeting ALDH2 may provide a novel strategy for lung cancer therapy.	('ALDH2', 'Gene', (16, 21))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('ALDH', 'molecular_function', 'GO:0004030', ('16', '20'))	('targeting', 'Var', (6, 15))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
37161	31071657	ACE is a highly reactive compound that could interact with DNA to form many kinds of adducts, leading to genetic mutations for carcinogenesis.	('genetic mutations', 'Var', (105, 122))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('carcinogenesis', 'Disease', (127, 141))	('leading to', 'Reg', (94, 104))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('ACE', 'Chemical', 'MESH:D000079', (0, 3))
37172	31071657	A recent study shows that chromosomal instability promotes metastasis by sustaining a tumor cell-autonomous response to cytosolic DNA.	('metastasis', 'CPA', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('tumor', 'Disease', (86, 91))	('chromosomal instability', 'Var', (26, 49))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('promotes', 'PosReg', (50, 58))	('chromosomal instability', 'Phenotype', 'HP:0040012', (26, 49))
37176	31071657	Consistent with increased DNA damages, Aldh2-KO mouse lungs exhibited drastically increased inflammation, injury as compared to those in wild-type ones.	('injury', 'Disease', (106, 112))	('mouse', 'Species', '10090', (48, 53))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('Aldh', 'molecular_function', 'GO:0004030', ('39', '43'))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('injury', 'Disease', 'MESH:D058186', (106, 112))	('inflammation', 'biological_process', 'GO:0006954', ('92', '104'))	('increased', 'PosReg', (16, 25))	('inflammation', 'Disease', (92, 104))	('increased', 'PosReg', (82, 91))	('Aldh2-KO', 'Var', (39, 47))
37177	31071657	In addition, the same study indicates that chromosomal instability and DNA damage lead to ruptured genomic DNA spilling into the cytosol, it further promotes metastasis in a STING-dependent manner.	('STING', 'Gene', (174, 179))	('ruptured', 'Var', (90, 98))	('chromosomal instability', 'Phenotype', 'HP:0040012', (43, 66))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('cytosol', 'cellular_component', 'GO:0005829', ('129', '136'))	('STING', 'Gene', '340061', (174, 179))	('metastasis', 'CPA', (158, 168))	('promotes', 'PosReg', (149, 157))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))
37178	31071657	In our study, we also observed the reduction of STING in A549-ALDH2 cells as compared to A549-GFP cells.	('STING', 'Gene', (48, 53))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('A549-ALDH2', 'CellLine', 'CVCL:0023', (57, 67))	('ALDH', 'molecular_function', 'GO:0004030', ('62', '66'))	('A549-ALDH2', 'Var', (57, 67))	('STING', 'Gene', '340061', (48, 53))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('reduction', 'NegReg', (35, 44))
37273	30515972	NSCLC cell lines including 95D, A549, Calu-1, H1299, H1650, NCI-H1703, NCI-H1975, NCI-H2009, NCI-H2030, NCI-H460, HCC827, PC9 and SK-MES-1 were purchased from ATCC and maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (Corning, Corning, NY, USA).	('H1299', 'CellLine', 'CVCL:0060', (46, 51))	('NCI-H1975', 'CellLine', 'CVCL:1511', (71, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('NCI-H1975', 'Var', (71, 80))	('HCC827', 'CellLine', 'CVCL:2063', (114, 120))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('SK-MES-1', 'CellLine', 'CVCL:0630', (130, 138))	('DMEM', 'Chemical', '-', (218, 222))	('NCI-H2030', 'CellLine', 'CVCL:1517', (93, 102))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (182, 216))	('NCI-H460', 'CellLine', 'CVCL:0459', (104, 112))	('NCI-H2009', 'CellLine', 'CVCL:1514', (82, 91))	('PC9', 'Gene', '255738', (122, 125))	('bovine', 'Species', '9913', (252, 258))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('H1650', 'CellLine', 'CVCL:1483', (53, 58))	('PC9', 'Gene', (122, 125))	('H1650', 'Var', (53, 58))	('NSCLC', 'Disease', (0, 5))	('NCI-H1703', 'CellLine', 'CVCL:1490', (60, 69))
37286	30515972	Western blotting analysis was performed according to a previously described standard method15 using the antibodies anti-Cbl-b (ab93205, 1:500; Abcam, Cambridge, MA, USA), anti-EGFR (ab52894, 1:1000; Abcam), anti-Flag (F2555, 1:2000; Sigma, St Louis, MO, USA), anti-ubiquitin (ab7780, 1:1000; Abcam), anti-p-AKT (ab81283, 1:500; Abcam), anti-AKT (ab8805, 1:1000; Abcam), anti-p-ERK (4370, 1:500; Cell Signaling, Danvers, MA, USA) and anti-ERK (4695, 1:1000; Cell Signaling).	('Signaling', 'biological_process', 'GO:0023052', ('400', '409'))	('p-ERK', 'Gene', '9451', (375, 380))	('p-ERK', 'Gene', (375, 380))	('AKT', 'Gene', (341, 344))	('ab8805', 'Var', (346, 352))	('ERK', 'Gene', (377, 380))	('Cell Signaling', 'CPA', (395, 409))	('ERK', 'molecular_function', 'GO:0004707', ('438', '441'))	('Cbl-b', 'Gene', (120, 125))	('AKT', 'Gene', (307, 310))	('EGFR', 'Gene', (176, 180))	('ERK', 'Gene', '2048', (377, 380))	('EGFR', 'molecular_function', 'GO:0005006', ('176', '180'))	('AKT', 'Gene', '207', (341, 344))	('ERK', 'Gene', (438, 441))	('ERK', 'molecular_function', 'GO:0004707', ('377', '380'))	('Signaling', 'biological_process', 'GO:0023052', ('462', '471'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('265', '274'))	('AKT', 'Gene', '207', (307, 310))	('ERK', 'Gene', '2048', (438, 441))	('EGFR', 'Gene', '1956', (176, 180))	('Cbl-b', 'Gene', '868', (120, 125))
37325	30515972	To further understand the biological effect of DUXAP9-206 deregulation in vitro, we established NSCLC cell lines (A549 and H1703) with stable overexpression or knockdown of DUXAP9-206 (Figure S2A,B).	('overexpression', 'PosReg', (142, 156))	('NSCLC', 'Disease', (96, 101))	('knockdown', 'Var', (160, 169))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('DUXAP9', 'Gene', (173, 179))	('DUXAP9', 'Gene', '503638', (173, 179))	('H1703', 'CellLine', 'CVCL:1490', (123, 128))	('DUXAP9', 'Gene', (47, 53))	('DUXAP9', 'Gene', '503638', (47, 53))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
37331	30515972	For this purpose, we first used A549 cell lines to establish cells with stable overexpression or knockdown of DUXAP9-206 labeled with firefly luciferase for injection of nude mice.	('knockdown', 'Var', (97, 106))	('nude mice', 'Species', '10090', (170, 179))	('DUXAP9', 'Gene', (110, 116))	('DUXAP9', 'Gene', '503638', (110, 116))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('overexpression', 'PosReg', (79, 93))
37337	30515972	Conversely, silencing of DUXAP9-206 significantly suppressed tumour growth rates (Figure 3D-F).	('tumour growth', 'Disease', (61, 74))	('suppressed', 'NegReg', (50, 60))	('tumour growth', 'Disease', 'MESH:D006130', (61, 74))	('DUXAP9', 'Gene', '503638', (25, 31))	('silencing', 'Var', (12, 21))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('DUXAP9', 'Gene', (25, 31))
37351	30515972	However, knockdown of DUXAP9-206 expression increased the association of Cbl-b with EGFR and ubiquitination of EGFR (Figure 5A).	('Cbl-b', 'Gene', '868', (73, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('association', 'Interaction', (58, 69))	('knockdown', 'Var', (9, 18))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'Gene', '1956', (111, 115))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (111, 115))	('DUXAP9', 'Gene', (22, 28))	('DUXAP9', 'Gene', '503638', (22, 28))	('ubiquitination', 'MPA', (93, 107))	('Cbl-b', 'Gene', (73, 78))	('increased', 'PosReg', (44, 53))	('EGFR', 'Gene', (84, 88))
37355	30515972	Moreover, knockdown of Cbl-b expression reversed the effects caused by DUXAP9-206 overexpression (Figure S7A).	('Cbl-b', 'Gene', '868', (23, 28))	('DUXAP9', 'Gene', '503638', (71, 77))	('DUXAP9', 'Gene', (71, 77))	('overexpression', 'PosReg', (82, 96))	('Cbl-b', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))
37381	30515972	Whether this mechanism also plays an important regulatory role in the EGFR mutant patients should be investigated further.	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('mutant', 'Var', (75, 81))
37388	30535445	To clarify the role of endogenous galectin-3, the effect of galectin-3 knockdown in NSCLC cells was investigated using scratch and invasion assays.	('galectin-3', 'Gene', '3958', (34, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('galectin-3', 'Gene', (60, 70))	('galectin', 'molecular_function', 'GO:0001577', ('34', '42'))	('knockdown', 'Var', (71, 80))	('galectin-3', 'Gene', (34, 44))	('galectin', 'molecular_function', 'GO:0001577', ('60', '68'))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('galectin-3', 'Gene', '3958', (60, 70))
37391	30535445	As revealed by scratch and invasion assays, the cell migratory and invasive activities were significantly increased under hypoxia, but were reduced by galectin-3 knockdown.	('galectin', 'molecular_function', 'GO:0001577', ('151', '159'))	('galectin-3', 'Gene', '3958', (151, 161))	('hypoxia', 'Disease', (122, 129))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('galectin-3', 'Gene', (151, 161))	('reduced', 'NegReg', (140, 147))	('increased', 'PosReg', (106, 115))	('knockdown', 'Var', (162, 171))
37392	30535445	Notably, addition of galectin-3 to the media did not improve the cell motility impaired by galectin-3 knockdown.	('galectin-3', 'Gene', '3958', (21, 31))	('galectin-3', 'Gene', (91, 101))	('cell motility', 'CPA', (65, 78))	('knockdown', 'Var', (102, 111))	('galectin', 'molecular_function', 'GO:0001577', ('91', '99'))	('cell motility', 'biological_process', 'GO:0048870', ('65', '78'))	('galectin-3', 'Gene', '3958', (91, 101))	('galectin-3', 'Gene', (21, 31))	('galectin', 'molecular_function', 'GO:0001577', ('21', '29'))
37394	30535445	RhoA level in the plasma membrane, but not in the cytoplasm, was increased under hypoxia and decreased by galectin-3 knockdown.	('increased', 'PosReg', (65, 74))	('RhoA', 'Gene', '387', (0, 4))	('galectin', 'molecular_function', 'GO:0001577', ('106', '114'))	('galectin-3', 'Gene', '3958', (106, 116))	('hypoxia', 'Disease', (81, 88))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('decreased', 'NegReg', (93, 102))	('galectin-3', 'Gene', (106, 116))	('plasma membrane', 'cellular_component', 'GO:0005886', ('18', '33'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('50', '59'))	('RhoA', 'Gene', (0, 4))	('knockdown', 'Var', (117, 126))
37395	30535445	RhoA activity was significantly enhanced under hypoxia and effectively inhibited by galectin-3 knockdown.	('galectin-3', 'Gene', (84, 94))	('RhoA', 'Gene', '387', (0, 4))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('inhibited', 'NegReg', (71, 80))	('hypoxia', 'Disease', (47, 54))	('knockdown', 'Var', (95, 104))	('galectin-3', 'Gene', '3958', (84, 94))	('enhanced', 'PosReg', (32, 40))	('galectin', 'molecular_function', 'GO:0001577', ('84', '92'))	('RhoA', 'Gene', (0, 4))
37396	30535445	In patients with pN0M0 invasive pulmonary adenocarcinoma, higher galectin-3 expression on tumor cells was significantly associated with tumor cell invasion into microvessels and tumor recurrence after surgery.	('galectin', 'molecular_function', 'GO:0001577', ('65', '73'))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (136, 141))	('galectin-3', 'Gene', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('associated with', 'Reg', (120, 135))	('galectin-3', 'Gene', '3958', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('invasive pulmonary adenocarcinoma', 'Disease', (23, 56))	('invasive pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (23, 56))	('patients', 'Species', '9606', (3, 11))	('higher', 'PosReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 56))	('pN0M0', 'Var', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('expression', 'MPA', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
37398	30535445	In pN0M0 invasive pulmonary adenocarcinoma, galectin-3 is a potential biomarker for predicting tumor recurrence after radical surgery.	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('galectin-3', 'Gene', (44, 54))	('galectin', 'molecular_function', 'GO:0001577', ('44', '52'))	('invasive pulmonary adenocarcinoma', 'Disease', (9, 42))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('invasive pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (9, 42))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (18, 42))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('galectin-3', 'Gene', '3958', (44, 54))	('pN0M0', 'Var', (3, 8))	('tumor', 'Disease', (95, 100))
37401	30535445	For localized pN0M0 NSCLC, surgical resection offers a good prognosis, with 5-year survival rates of 70-90%.	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('pN0M0', 'Var', (14, 19))	('NSCLC', 'Disease', (20, 25))
37402	30535445	However, these data also imply that 10-30% of patients with pN0M0 NSCLC experience tumor recurrence within 5 years despite radical surgery.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('patients', 'Species', '9606', (46, 54))	('NSCLC', 'Disease', (66, 71))	('tumor', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('pN0M0', 'Var', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
37412	30535445	On the basis of these data, we hypothesized that galectin-3 would be upregulated in NSCLC cells in the hypoxic tumor microenvironment, which would promote aggressive cell motility, leading to tumor recurrence after surgery in patients with pN0M0 NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NSCLC', 'Disease', (246, 251))	('upregulated', 'PosReg', (69, 80))	('aggressive cell motility', 'CPA', (155, 179))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('hypoxic tumor', 'Disease', 'MESH:D009369', (103, 116))	('NSCLC', 'Disease', (84, 89))	('galectin', 'molecular_function', 'GO:0001577', ('49', '57'))	('leading to', 'Reg', (181, 191))	('patients', 'Species', '9606', (226, 234))	('galectin-3', 'Gene', (49, 59))	('hypoxic tumor', 'Disease', (103, 116))	('pN0M0', 'Var', (240, 245))	('tumor', 'Disease', (192, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('galectin-3', 'Gene', '3958', (49, 59))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cell motility', 'biological_process', 'GO:0048870', ('166', '179'))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('promote', 'PosReg', (147, 154))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
37415	30535445	In addition, we demonstrated that galectin-3 is a potential biomarker for predicting tumor recurrence in pN0M0 invasive pulmonary adenocarcinoma after radical surgery.	('galectin-3', 'Gene', '3958', (34, 44))	('tumor', 'Disease', (85, 90))	('invasive pulmonary adenocarcinoma', 'Disease', (111, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('invasive pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (111, 144))	('galectin', 'molecular_function', 'GO:0001577', ('34', '42'))	('galectin-3', 'Gene', (34, 44))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 144))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('pN0M0', 'Var', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
37440	30535445	Tumor tissue samples were obtained from 57 patients (Table I) with pN0M0 invasive pulmonary adenocarcinoma who underwent radical surgery at Shiga University of Medical Science Hospital between January 2008 and December 2012.	('invasive pulmonary adenocarcinoma', 'Disease', (73, 106))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('invasive pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (73, 106))	('patients', 'Species', '9606', (43, 51))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 106))	('pN0M0', 'Var', (67, 72))
37456	30535445	In these transfectants, the proliferative activity of the cells was not affected by galectin-3 knockdown (Fig.	('knockdown', 'Var', (95, 104))	('galectin-3', 'Gene', '3958', (84, 94))	('galectin-3', 'Gene', (84, 94))	('galectin', 'molecular_function', 'GO:0001577', ('84', '92'))
37460	30535445	In addition, galectin-3 knockdown significantly inhibited the migration of both cell lines under hypoxia (Fig.	('hypoxia', 'Disease', (97, 104))	('hypoxia', 'Disease', 'MESH:D000860', (97, 104))	('migration of', 'CPA', (62, 74))	('galectin', 'molecular_function', 'GO:0001577', ('13', '21'))	('galectin-3', 'Gene', (13, 23))	('inhibited', 'NegReg', (48, 57))	('knockdown', 'Var', (24, 33))	('galectin-3', 'Gene', '3958', (13, 23))
37463	30535445	In addition, galectin-3 knockdown significantly inhibited the invasive activity of both cell lines under hypoxia (Fig.	('invasive activity of both cell lines', 'CPA', (62, 98))	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('galectin', 'molecular_function', 'GO:0001577', ('13', '21'))	('galectin-3', 'Gene', (13, 23))	('inhibited', 'NegReg', (48, 57))	('knockdown', 'Var', (24, 33))	('galectin-3', 'Gene', '3958', (13, 23))
37465	30535445	The results showed that exogenous supplementation of recombinant galectin-3 protein could not reverse the inhibition of cell migration induced by galectin-3 knockdown (Fig.	('inhibition of cell migration', 'biological_process', 'GO:0030336', ('106', '134'))	('galectin-3', 'Gene', (146, 156))	('galectin-3', 'Gene', '3958', (65, 75))	('galectin', 'molecular_function', 'GO:0001577', ('65', '73'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('galectin-3', 'Gene', '3958', (146, 156))	('knockdown', 'Var', (157, 166))	('galectin-3', 'Gene', (65, 75))	('galectin', 'molecular_function', 'GO:0001577', ('146', '154'))	('cell migration', 'CPA', (120, 134))
37478	30535445	Furthermore, these increases were significantly decreased by galectin-3 knockdown (Fig.	('galectin-3', 'Gene', (61, 71))	('decreased', 'NegReg', (48, 57))	('galectin', 'molecular_function', 'GO:0001577', ('61', '69'))	('increases', 'PosReg', (19, 28))	('galectin-3', 'Gene', '3958', (61, 71))	('knockdown', 'Var', (72, 81))
37479	30535445	In the NSCLC cells with galectin-3 knockdown, the protein levels of cytoplasmic RhoA and vinculin did not increase even under hypoxia.	('vinculin', 'Gene', '7414', (89, 97))	('knockdown', 'Var', (35, 44))	('galectin', 'molecular_function', 'GO:0001577', ('24', '32'))	('galectin-3', 'Gene', '3958', (24, 34))	('NSCLC', 'Disease', (7, 12))	('RhoA', 'Gene', (80, 84))	('vinculin', 'Gene', (89, 97))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('RhoA', 'Gene', '387', (80, 84))	('hypoxia', 'Disease', (126, 133))	('hypoxia', 'Disease', 'MESH:D000860', (126, 133))	('galectin-3', 'Gene', (24, 34))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('NSCLC', 'Phenotype', 'HP:0030358', (7, 12))
37480	30535445	We also evaluated the activation of RhoA by measuring the level of RhoA-GTP and found that the level of RhoA-GTP was significantly increased under the hypoxic condition in both NSCLC cell lines; however, galectin-3 knockdown inhibited the increase in activated RhoA under hypoxia (Fig.	('galectin', 'molecular_function', 'GO:0001577', ('204', '212'))	('RhoA', 'Gene', '387', (104, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('hypoxic condition', 'Disease', (151, 168))	('hypoxic condition', 'Disease', 'MESH:D009135', (151, 168))	('hypoxia', 'Disease', (272, 279))	('inhibited', 'NegReg', (225, 234))	('RhoA', 'Gene', (261, 265))	('RhoA', 'Gene', (36, 40))	('hypoxia', 'Disease', 'MESH:D000860', (272, 279))	('RhoA', 'Gene', '387', (261, 265))	('RhoA', 'Gene', (67, 71))	('RhoA', 'Gene', '387', (36, 40))	('GTP', 'Chemical', 'MESH:D006160', (72, 75))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('GTP', 'Chemical', 'MESH:D006160', (109, 112))	('RhoA', 'Gene', (104, 108))	('galectin-3', 'Gene', (204, 214))	('galectin-3', 'Gene', '3958', (204, 214))	('knockdown', 'Var', (215, 224))	('NSCLC', 'Disease', (177, 182))	('RhoA', 'Gene', '387', (67, 71))
37483	30535445	To evaluate the association between galectin-3 expression on tumor cells and clinicopathological findings, we performed immunohistochemical staining for 57 patients with pN0M0 invasive pulmonary adenocarcinoma who underwent radical surgery (Table I).	('patients', 'Species', '9606', (156, 164))	('invasive pulmonary adenocarcinoma', 'Disease', (176, 209))	('galectin', 'molecular_function', 'GO:0001577', ('36', '44'))	('galectin-3', 'Gene', (36, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('pN0M0', 'Var', (170, 175))	('invasive pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (176, 209))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (185, 209))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('galectin-3', 'Gene', '3958', (36, 46))	('tumor', 'Disease', (61, 66))
37491	30535445	In addition, we showed that galectin-3 is a potential biomarker for predicting tumor recurrence in pN0M0 invasive pulmonary adenocarcinoma after radical surgery.	('tumor', 'Disease', (79, 84))	('galectin-3', 'Gene', '3958', (28, 38))	('invasive pulmonary adenocarcinoma', 'Disease', (105, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('galectin', 'molecular_function', 'GO:0001577', ('28', '36'))	('galectin-3', 'Gene', (28, 38))	('invasive pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (105, 138))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('pN0M0', 'Var', (99, 104))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 138))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
37496	30535445	In the present study, we showed that both the protein and mRNA levels of galectin-3 were upregulated and that galectin-3 knockdown inhibited the migratory and invasive activities of NSCLC cells.	('knockdown', 'Var', (121, 130))	('galectin', 'molecular_function', 'GO:0001577', ('110', '118'))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('NSCLC', 'Disease', (182, 187))	('protein', 'MPA', (46, 53))	('upregulated', 'PosReg', (89, 100))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('galectin-3', 'Gene', '3958', (73, 83))	('galectin-3', 'Gene', '3958', (110, 120))	('galectin', 'molecular_function', 'GO:0001577', ('73', '81'))	('inhibited', 'NegReg', (131, 140))	('galectin-3', 'Gene', (73, 83))	('galectin-3', 'Gene', (110, 120))	('mRNA levels', 'MPA', (58, 69))
37502	30535445	Furthermore, the addition of recombinant galectin-3 protein into the culture media did not reverse the impairment of migratory activity caused by galectin-3 knockdown in NSCLC cells.	('galectin-3', 'Gene', (146, 156))	('galectin-3', 'Gene', '3958', (41, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('galectin', 'molecular_function', 'GO:0001577', ('41', '49'))	('galectin-3', 'Gene', '3958', (146, 156))	('NSCLC', 'Disease', (170, 175))	('galectin-3', 'Gene', (41, 51))	('knockdown', 'Var', (157, 166))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('migratory activity', 'CPA', (117, 135))	('galectin', 'molecular_function', 'GO:0001577', ('146', '154'))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
37507	30535445	Based on these reports, although high levels of exogenous galectin-3 could enhance tumor cell motility, the levels used in previous studies is much higher than those predicted in the tumor microenvironment.	('exogenous', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('galectin-3', 'Gene', '3958', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('galectin', 'molecular_function', 'GO:0001577', ('58', '66'))	('galectin-3', 'Gene', (58, 68))	('tumor', 'Disease', (183, 188))	('enhance', 'PosReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cell motility', 'biological_process', 'GO:0048870', ('89', '102'))
37518	30535445	In the present study, we found that the level of RhoA in the plasma membrane was increased under hypoxia and was decreased by galectin-3 knockdown, whereas RhoA expression in the cytoplasm was unchanged.	('level', 'MPA', (40, 45))	('RhoA', 'Gene', (49, 53))	('hypoxia', 'Disease', (97, 104))	('hypoxia', 'Disease', 'MESH:D000860', (97, 104))	('RhoA', 'Gene', '387', (49, 53))	('RhoA', 'Gene', (156, 160))	('galectin-3', 'Gene', '3958', (126, 136))	('galectin-3', 'Gene', (126, 136))	('RhoA', 'Gene', '387', (156, 160))	('knockdown', 'Var', (137, 146))	('plasma membrane', 'cellular_component', 'GO:0005886', ('61', '76'))	('increased', 'PosReg', (81, 90))	('decreased', 'NegReg', (113, 122))	('cytoplasm', 'cellular_component', 'GO:0005737', ('179', '188'))	('galectin', 'molecular_function', 'GO:0001577', ('126', '134'))
37519	30535445	We also found that RhoA activity was significantly enhanced under hypoxic conditions and was effectively inhibited by galectin-3 knockdown in NSCLC cells.	('galectin-3', 'Gene', (118, 128))	('inhibited', 'NegReg', (105, 114))	('NSCLC', 'Disease', (142, 147))	('hypoxic conditions', 'Disease', (66, 84))	('knockdown', 'Var', (129, 138))	('galectin', 'molecular_function', 'GO:0001577', ('118', '126'))	('RhoA', 'Gene', (19, 23))	('enhanced', 'PosReg', (51, 59))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('hypoxic conditions', 'Disease', 'MESH:D009135', (66, 84))	('RhoA', 'Gene', '387', (19, 23))	('galectin-3', 'Gene', '3958', (118, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
37520	30535445	In addition, more vinculin was localized to the plasma membrane under hypoxia, and galectin-3 knockdown inhibited this localization.	('knockdown', 'Var', (94, 103))	('galectin-3', 'Gene', '3958', (83, 93))	('vinculin', 'Gene', '7414', (18, 26))	('galectin', 'molecular_function', 'GO:0001577', ('83', '91'))	('hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('vinculin', 'Gene', (18, 26))	('localization', 'biological_process', 'GO:0051179', ('119', '131'))	('hypoxia', 'Disease', (70, 77))	('inhibited', 'NegReg', (104, 113))	('plasma membrane', 'cellular_component', 'GO:0005886', ('48', '63'))	('galectin-3', 'Gene', (83, 93))
37522	30535445	Galectin-3 was more highly expressed in LK-2 cells than in A549 cells, which was associated with the effect of galectin-3 knockdown on RhoA activation.	('galectin', 'molecular_function', 'GO:0001577', ('111', '119'))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('LK-2', 'CellLine', 'CVCL:1377', (40, 44))	('Galectin-3', 'Gene', (0, 10))	('galectin-3', 'Gene', '3958', (111, 121))	('RhoA', 'Gene', (135, 139))	('RhoA', 'Gene', '387', (135, 139))	('knockdown', 'Var', (122, 131))	('Galectin-3', 'Gene', '3958', (0, 10))	('galectin-3', 'Gene', (111, 121))	('Galectin', 'molecular_function', 'GO:0001577', ('0', '8'))
37523	30535445	However, in terms of tumor cell migration and invasion, A549 cells were more strongly inhibited by galectin-3 knockdown than LK-2 cells.	('knockdown', 'Var', (110, 119))	('tumor', 'Disease', (21, 26))	('cell migration', 'biological_process', 'GO:0016477', ('27', '41'))	('galectin-3', 'Gene', (99, 109))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('galectin', 'molecular_function', 'GO:0001577', ('99', '107'))	('inhibited', 'NegReg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('galectin-3', 'Gene', '3958', (99, 109))	('LK-2', 'CellLine', 'CVCL:1377', (125, 129))	('invasion', 'CPA', (46, 54))
37524	30535445	Previous reports have verified that galectin-3 enhances invasion of KRAS mutant tumor cells, such as pancreatic adenocarcinoma cells, via binding to K-Ras protein.	('galectin-3', 'Gene', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('KRAS', 'Gene', (68, 72))	('galectin-3', 'Gene', '3958', (36, 46))	('K-Ras', 'Gene', '3845', (149, 154))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 126))	('galectin', 'molecular_function', 'GO:0001577', ('36', '44'))	('binding', 'Interaction', (138, 145))	('mutant', 'Var', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('tumor', 'Disease', (80, 85))	('enhances', 'PosReg', (47, 55))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (101, 126))	('pancreatic adenocarcinoma', 'Disease', (101, 126))	('invasion', 'CPA', (56, 64))	('K-Ras', 'Gene', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('KRAS', 'Gene', '3845', (68, 72))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))
37525	30535445	A549 cells carry a KRAS mutation (G12S) and LK-2 cells harbor wild-type KRAS.	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('KRAS', 'Gene', (72, 76))	('G12S', 'Var', (34, 38))	('LK-2', 'CellLine', 'CVCL:1377', (44, 48))	('KRAS', 'Gene', '3845', (72, 76))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('G12S', 'Mutation', 'rs121913530', (34, 38))
37536	30535445	In pN0M0 invasive pulmonary adenocarcinomas, galectin-3 is a potential biomarker for predicting tumor recurrence after radical surgery and may be an attractive therapeutic target.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('galectin-3', 'Gene', '3958', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('tumor', 'Disease', (96, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('galectin', 'molecular_function', 'GO:0001577', ('45', '53'))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (18, 42))	('invasive pulmonary adenocarcinomas', 'Disease', (9, 43))	('invasive pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (9, 43))	('galectin-3', 'Gene', (45, 55))	('pN0M0', 'Var', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
37600	30577835	The study that concluded this gene set observed the aberration in NSCLC with oncogenic form of KRAS and inactivated PTEN, in which condition resulted in shorter survival.	('KRAS', 'Gene', '3845', (95, 99))	('NSCLC', 'Disease', (66, 71))	('aberration', 'Var', (52, 62))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('shorter', 'NegReg', (153, 160))	('KRAS', 'Gene', (95, 99))	('PTEN', 'Gene', (116, 120))	('survival', 'MPA', (161, 169))
37617	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))
37627	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))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('arrest', 'Disease', (102, 108))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('91', '108'))	('mitigated', 'NegReg', (42, 51))	('NSCLC', 'Disease', (52, 57))	('apoptosis', 'CPA', (113, 122))	('inducing', 'PosReg', (73, 81))	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('knockdown', 'Var', (32, 41))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('G1-phase', 'biological_process', 'GO:0051318', ('82', '90'))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('arrest', 'Disease', 'MESH:D006323', (102, 108))	('PCAT6', 'Gene', (26, 31))
37638	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))	('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))	('PCAT6', 'Gene', (134, 139))	('epigenetically', 'Var', (84, 98))	('LATS2', 'Gene', (111, 116))	('LATS2', 'Gene', '26524', (111, 116))
37697	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))	('transfection', 'Var', (22, 34))	('RIP', 'Gene', (205, 208))	('PMSF', 'Chemical', 'MESH:D010664', (90, 94))	('RIP', 'Gene', '84268', (205, 208))	('lysis', 'biological_process', 'GO:0019835', ('66', '71'))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))
37716	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))
37720	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))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('SK-MES-1', 'CellLine', 'CVCL:0630', (91, 99))	('PCAT6', 'Gene', '100506696', (31, 36))	('proliferation rate', 'CPA', (60, 78))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('inhibits', 'NegReg', (47, 55))
37723	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))	('cell growth', 'biological_process', 'GO:0016049', ('48', '59'))	('overexpression', 'Var', (13, 27))
37727	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))	('S phase', 'biological_process', 'GO:0051320', ('61', '68'))	('PCAT6', 'Gene', '100506696', (4, 9))	('G1 phase', 'biological_process', 'GO:0051318', ('117', '125'))	('knockdown', 'Var', (10, 19))	('PCAT6', 'Gene', (4, 9))
37730	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))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
37732	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))
37739	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))
37748	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))
37758	30314898	Importantly, The MTT and colony formation as says abilities of cell growth and proliferation were partially recovered by LATS2 knockdown (Fig.	('cell growth', 'biological_process', 'GO:0016049', ('63', '74'))	('recovered', 'PosReg', (108, 117))	('formation', 'biological_process', 'GO:0009058', ('32', '41'))	('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))
37760	30314898	Continuing advances in transcriptomics indicate that the study of epigenetic regulation of lncRNAs in cancer is emerging as a potential research field.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('epigenetic', 'Var', (66, 76))	('regulation', 'biological_process', 'GO:0065007', ('77', '87'))
37762	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.	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('tumor', 'Disease', (137, 142))	('lncRNAs', 'Var', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('DNA repair', 'biological_process', 'GO:0006281', ('237', '247'))	('DNA repair', 'CPA', (237, 247))	('apoptosis', 'CPA', (226, 235))	('cell adhesion', 'biological_process', 'GO:0007155', ('252', '265'))	('cell cycle', 'biological_process', 'GO:0007049', ('197', '207'))	('DNA', 'cellular_component', 'GO:0005574', ('237', '240'))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('cell cycle', 'CPA', (197, 207))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('cell adhesion', 'CPA', (252, 265))	('differentiation', 'CPA', (209, 224))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('impacting', 'Reg', (183, 192))
37763	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))	('NCALD', 'Gene', (120, 125))	('LSD1', 'Gene', (101, 105))	('interacts', 'Interaction', (61, 70))	('represses', 'NegReg', (110, 119))	('NCALD', 'Gene', '83988', (120, 125))	('LSD1', 'Gene', '23028', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('lincRNA 00673', 'Var', (47, 60))	('NSCLC', 'Disease', (140, 145))
37768	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))	('LATS2', 'Gene', '26524', (97, 102))	('PCAT6', 'Gene', '100506696', (136, 141))	('upregulated', 'PosReg', (118, 129))	('LATS2', 'Gene', (97, 102))	('knockdown', 'Var', (142, 151))
37771	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))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('tumor', 'Disease', (160, 165))	('epigenetic imbalance', 'Var', (110, 130))
37773	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))	('molecular function', 'molecular_function', 'GO:0003674', ('114', '132'))	('PRC2', 'Gene', (136, 140))	('transcriptional repression', 'MPA', (225, 251))
37777	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))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (52, 77))	('TTF-1', 'Gene', '7270', (196, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('aggressive tumor behavior', 'Disease', (52, 77))	('patients', 'Species', '9606', (121, 129))	('lung adenocarcinomas', 'Disease', (155, 175))
37779	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', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('sensitivity', 'MPA', (14, 25))	('NSCLC', 'Disease', (33, 38))	('mutant', 'Var', (53, 59))	('boost', 'PosReg', (4, 9))	('etoposide', 'Chemical', 'MESH:D005047', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('BRG1', 'Gene', (63, 67))	('mutant', 'Var', (68, 74))
37792	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))
37797	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))
37802	30384810	It has been well-documented that mutations of CFTR gene are the cause of cystic fibrosis, the most common fatal hereditary lung disease in Caucasian population; the function of cystic fibrosis transmembrane conductance regulator in the development of lung cancer however has not yet been established.	('transmembrane', 'cellular_component', 'GO:0044214', ('193', '206'))	('transmembrane', 'cellular_component', 'GO:0016021', ('193', '206'))	('cause', 'Reg', (64, 69))	('mutations', 'Var', (33, 42))	('lung cancer', 'Disease', (251, 262))	('cystic fibrosis', 'Disease', 'MESH:D003550', (73, 88))	('cystic fibrosis', 'Disease', 'MESH:D003550', (177, 192))	('hereditary lung disease', 'Disease', 'MESH:D030342', (112, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('lung disease', 'Phenotype', 'HP:0002088', (123, 135))	('cystic fibrosis transmembrane conductance regulator', 'molecular_function', 'GO:0005260', ('177', '228'))	('cystic fibrosis transmembrane conductance regulator', 'Gene', '1080', (177, 228))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('lung cancer', 'Disease', 'MESH:D008175', (251, 262))	('hereditary lung disease', 'Disease', (112, 135))	('cystic fibrosis', 'Disease', (73, 88))	('CFTR', 'Gene', (46, 50))	('cystic fibrosis', 'Disease', (177, 192))
37819	30384810	It has been defined that mutations of CFTR gene are the cause of cystic fibrosis disease, a heterogeneous recessive genetic disorder.	('mutations', 'Var', (25, 34))	('recessive genetic disorder', 'Disease', (106, 132))	('cystic fibrosis disease', 'Disease', 'MESH:D003550', (65, 88))	('CFTR', 'Gene', (38, 42))	('cystic fibrosis disease', 'Disease', (65, 88))	('cause', 'Reg', (56, 61))	('recessive genetic disorder', 'Disease', 'MESH:D030342', (106, 132))
37825	30384810	A knockdown of CFTR enhanced the sensitivity of prostate cancer cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('enhanced', 'PosReg', (20, 28))	('knockdown', 'Var', (2, 11))	('sensitivity', 'MPA', (33, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('prostate cancer', 'Disease', (48, 63))	('CFTR', 'Gene', (15, 19))
37826	30384810	Such an oncogenic role of CFTR was also observed in ovarian cancer, in which the CFTR expression was associated with the aggression of tumor in vivo and knockdown of CFTR inhibited the progressive potency of cancer cells in vitro.	('cancer', 'Disease', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('inhibited', 'NegReg', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('aggression', 'biological_process', 'GO:0002118', ('121', '131'))	('aggression', 'Phenotype', 'HP:0000718', (121, 131))	('ovarian cancer', 'Disease', (52, 66))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('aggression of tumor', 'Disease', 'MESH:D001523', (121, 140))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('aggression of tumor', 'Disease', (121, 140))	('knockdown', 'Var', (153, 162))	('associated', 'Reg', (101, 111))	('CFTR', 'Gene', (81, 85))	('cancer', 'Disease', (60, 66))	('ovarian cancer', 'Disease', 'MESH:D010051', (52, 66))	('CFTR', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
37827	30384810	In the case of lung cancer, an early case-control study on the correlation between the genetic variants of the CFTR gene and the risk of lung cancer demonstrated that the deltaF508 mutation and genotypes with minor alleles of rs10487372 and rs213950 single-nucleotide polymorphism of CFTR gene were inversely associated with lung cancer risk.	('associated', 'Reg', (309, 319))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('CFTR', 'Gene', (111, 115))	('rs10487372', 'Mutation', 'rs10487372', (226, 236))	('lung cancer', 'Disease', (15, 26))	('deltaF508', 'Var', (171, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('lung cancer', 'Disease', 'MESH:D008175', (325, 336))	('lung cancer', 'Phenotype', 'HP:0100526', (325, 336))	('rs10487372', 'Var', (226, 236))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('deltaF508', 'Mutation', 'rs10487372', (171, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('lung cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('inversely', 'NegReg', (299, 308))	('rs213950', 'Mutation', 'rs213950', (241, 249))	('rs213950 single-nucleotide polymorphism', 'Var', (241, 280))	('lung cancer', 'Disease', (325, 336))	('CFTR', 'Gene', (284, 288))
37830	30384810	The 5-aza-2'-deoxycytidine-induced demethylation could increase CFTR gene expression.	('demethylation', 'Var', (35, 48))	('expression', 'MPA', (74, 84))	('increase', 'PosReg', (55, 63))	('CFTR gene', 'Gene', (64, 73))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('demethylation', 'biological_process', 'GO:0070988', ('35', '48'))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (4, 26))
37832	30384810	Interestingly, the hypermethylation of CFTR gene was associated with a significantly poorer survival in young patients with NSCLC, but not in elderly patients.	('poorer', 'NegReg', (85, 91))	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('patients', 'Species', '9606', (150, 158))	('survival', 'MPA', (92, 100))	('hypermethylation', 'Var', (19, 35))	('patients', 'Species', '9606', (110, 118))	('CFTR gene', 'Gene', (39, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
37891	30384810	Of importance, the ectopic expression of CFTR significantly inhibited the capacity of migration and invasion of A549 cells, regardless of the presence of nicotine (P < .01; Figures 3 and 4).	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('ectopic expression', 'Var', (19, 37))	('CFTR', 'Gene', (41, 45))	('inhibited', 'NegReg', (60, 69))	('nicotine', 'Chemical', 'MESH:D009538', (154, 162))
37892	30384810	In contrast, knockdown of CFTR by shRNA showed a dramatically enhanced potency of migration and invasion in both nicotine-treated and untreated A549 cells (P < .01; Figures 3 and 4).	('CFTR', 'Gene', (26, 30))	('A549', 'CellLine', 'CVCL:0023', (144, 148))	('shRNA', 'Gene', (34, 39))	('nicotine', 'Chemical', 'MESH:D009538', (113, 121))	('enhanced', 'PosReg', (62, 70))	('migration', 'CPA', (82, 91))	('knockdown', 'Var', (13, 22))
37893	30384810	These results suggest that CFTR may play an inhibitory role in progressive characteristics in lung adenocarcinoma A549 cells, and ectopic expression of CFTR is able to suppress the migration and invasion of A549 cells.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('ectopic expression', 'Var', (130, 148))	('A549', 'CellLine', 'CVCL:0023', (207, 211))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('CFTR', 'Gene', (152, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('suppress', 'NegReg', (168, 176))	('lung adenocarcinoma A549', 'Disease', (94, 118))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (94, 118))
37899	30384810	In contrast, the shRNA-mediated knockdown of CFTR resulted in a significantly increased clonogenicity in A549 cells (P < .01; Figure 5).	('clonogenicity in A549 cells', 'CPA', (88, 115))	('knockdown', 'Var', (32, 41))	('CFTR', 'Gene', (45, 49))	('increased', 'PosReg', (78, 87))	('A549', 'CellLine', 'CVCL:0023', (105, 109))
37910	30384810	In contrast, a knockdown of CFTR expression by shRNA led an opposite effect, that is, reduction or loss of CFTR promoted progressive abilities of A549 cells, regardless of the exposure of nicotine.	('reduction', 'NegReg', (86, 95))	('knockdown', 'Var', (15, 24))	('promoted', 'PosReg', (112, 120))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('nicotine', 'Chemical', 'MESH:D009538', (188, 196))	('loss', 'NegReg', (99, 103))	('progressive abilities', 'CPA', (121, 142))	('CFTR', 'Gene', (107, 111))
37924	30384810	Vice versa, a chronic exposure of nicotine could mimic the phenotype of the deficiency of alpha7-nAChR in mice or its inactivation in human airway epithelial cells in vitro.	('human', 'Species', '9606', (134, 139))	('mice', 'Species', '10090', (106, 110))	('alpha7-nAChR', 'Gene', (90, 102))	('nAChR', 'molecular_function', 'GO:0022848', ('97', '102'))	('inactivation', 'NegReg', (118, 130))	('nicotine', 'Chemical', 'MESH:D009538', (34, 42))	('deficiency', 'Var', (76, 86))	('alpha7-nAChR', 'Gene', '11441', (90, 102))
37930	30384810	A knockdown of CFTR in ovarian cancer cells and Ph+ ALL cells suppressed their metastatic capability, suggesting that CFTR played an oncogenic role in these 2 types of malignancies.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('knockdown', 'Var', (2, 11))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('ovarian cancer', 'Disease', (23, 37))	('suppressed', 'NegReg', (62, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('malignancies', 'Disease', (168, 180))	('metastatic capability', 'CPA', (79, 100))	('CFTR', 'Gene', (15, 19))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))
37933	30384810	However, a recent study demonstrated that the knockdown CFTR led an enhancement of sensitivity of prostate cancer cells to cisplatin via an inhibition of autophagy.	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('knockdown', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('sensitivity', 'MPA', (83, 94))	('prostate cancer', 'Disease', (98, 113))	('autophagy', 'biological_process', 'GO:0016236', ('154', '163'))	('CFTR', 'Gene', (56, 60))	('enhancement', 'PosReg', (68, 79))	('inhibition', 'NegReg', (140, 150))	('autophagy', 'biological_process', 'GO:0006914', ('154', '163'))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('autophagy', 'CPA', (154, 163))
37935	30384810	In the present study, an ectopic expression of CFTR was found to significantly inhibit the migration, invasion, and clonogenicity in lung cancer A549 cells, and knockdown of CFTR displayed an opposite effect, that is, enhancing the progressive properties in this lung cancer cell type, regardless of the presence of nicotine.	('lung cancer', 'Disease', (263, 274))	('CFTR', 'Gene', (47, 51))	('CFTR', 'Gene', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('progressive properties', 'CPA', (232, 254))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('inhibit', 'NegReg', (79, 86))	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('knockdown', 'Var', (161, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('migration', 'CPA', (91, 100))	('ectopic expression', 'Var', (25, 43))	('enhancing', 'PosReg', (218, 227))	('clonogenicity', 'CPA', (116, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('invasion', 'CPA', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('nicotine', 'Chemical', 'MESH:D009538', (316, 324))
37944	30384810	In the present study, although the overexpression of CFTR failed to alter the expression of EMT markers and ALDH; however, the abundance of stem cell pluripotency-related transcription factors, cell proliferation markers, and lung CSC marker CD133 was reduced in Ad/CFTR-infected A549 cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('194', '212'))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('CD133', 'Chemical', '-', (242, 247))	('ALDH', 'molecular_function', 'GO:0004030', ('108', '112'))	('CD133', 'Gene', (242, 247))	('reduced', 'NegReg', (252, 259))	('Ad/CFTR-infected', 'Var', (263, 279))	('A549', 'CellLine', 'CVCL:0023', (280, 284))	('cell proliferation', 'CPA', (194, 212))	('transcription', 'biological_process', 'GO:0006351', ('171', '184'))	('ALDH', 'Gene', (108, 112))	('abundance', 'MPA', (127, 136))
37949	30384810	Conversely, a knockdown of CFTR expression by shRNA resulted in an enhanced progressive potency of A549 cells.	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('CFTR expression', 'Gene', (27, 42))	('knockdown', 'Var', (14, 23))	('progressive potency of A549 cells', 'CPA', (76, 109))	('enhanced', 'PosReg', (67, 75))
38048	30285867	While our numbers are small, the suggestion is that indeed, transplant enhances the risk of lung cancer.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('enhances', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('transplant', 'Var', (60, 70))
38059	30285867	The role of genetics in IPF could play a pivotal role in the development of lung cancer, but the mechanistic pathway has not been fully elucidated.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('genetics', 'Var', (12, 20))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('IPF', 'Gene', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
38069	30285867	More recent studies, however, have argued there that the mortality of lung cancer in IPF patients is higher than for lung cancer alone and that the presence of IPF is associated with a prognosis worse than lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('higher', 'PosReg', (101, 107))	('IPF', 'Gene', (85, 88))	('presence', 'Var', (148, 156))	('lung cancer', 'Disease', (206, 217))	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
38100	29664235	miR-1-3p and miR-206 sensitizes HGF-induced gefitinib-resistant human lung cancer cells through inhibition of c-Met signalling and EMT  miR-1-3p and miR-206 sensitizes HGF-induced gefitinib-resistant human lung cancer cells through inhibition of c-Met signalling and EMT Hepatocyte growth factor (HGF) overexpression is an important mechanism in acquired epidermal growth factor receptor (EGFR) kinase inhibitor gefitinib resistance in lung cancers with EGFR activating mutations.	('lung cancer', 'Disease', (206, 217))	('c-Met', 'Gene', (110, 115))	('lung cancer', 'Disease', (70, 81))	('EGFR', 'Gene', '1956', (389, 393))	('EGFR', 'molecular_function', 'GO:0005006', ('389', '393'))	('HGF', 'Gene', '3082', (168, 171))	('human', 'Species', '9606', (200, 205))	('miR-206', 'Gene', (149, 156))	('miR-206', 'Gene', '406989', (149, 156))	('HGF', 'Gene', '3082', (32, 35))	('miR-206', 'Gene', (13, 20))	('HGF', 'Gene', (168, 171))	('EGFR', 'Gene', (454, 458))	('gefitinib', 'Chemical', 'MESH:D000077156', (412, 421))	('gefitinib', 'Chemical', 'MESH:D000077156', (180, 189))	('Hepatocyte growth factor', 'Gene', '3082', (271, 295))	('lung cancers', 'Disease', 'MESH:D008175', (436, 448))	('miR-206', 'Gene', '406989', (13, 20))	('epidermal growth factor receptor', 'Gene', (355, 387))	('c-Met', 'Gene', '4233', (246, 251))	('HGF', 'Gene', (32, 35))	('lung cancer', 'Disease', 'MESH:D008175', (436, 447))	('lung cancers', 'Disease', (436, 448))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('human', 'Species', '9606', (64, 69))	('epidermal growth factor receptor', 'Gene', '1956', (355, 387))	('Hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('271', '295'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('395', '411'))	('lung cancer', 'Phenotype', 'HP:0100526', (436, 447))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('c-Met', 'Gene', '4233', (110, 115))	('lung cancers', 'Phenotype', 'HP:0100526', (436, 448))	('EGFR', 'molecular_function', 'GO:0005006', ('454', '458'))	('EGFR', 'Gene', (389, 393))	('signalling', 'biological_process', 'GO:0023052', ('116', '126'))	('EMT', 'biological_process', 'GO:0001837', ('131', '134'))	('EGFR', 'Gene', '1956', (454, 458))	('gefitinib', 'Chemical', 'MESH:D000077156', (44, 53))	('HGF', 'Gene', '3082', (297, 300))	('cancers', 'Phenotype', 'HP:0002664', (441, 448))	('EMT', 'biological_process', 'GO:0001837', ('267', '270'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('355', '378'))	('signalling', 'biological_process', 'GO:0023052', ('252', '262'))	('c-Met', 'Gene', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (441, 447))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HGF', 'Gene', (297, 300))	('mutations', 'Var', (470, 479))	('Hepatocyte growth factor', 'Gene', (271, 295))
38102	29664235	However, whether miR-1-3p and miR-206 can overcome HGF-induced gefitinib resistance in EGFR mutant lung cancer is not clear.	('lung cancer', 'Disease', (99, 110))	('EGFR', 'Gene', '1956', (87, 91))	('gefitinib', 'Chemical', 'MESH:D000077156', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('overcome', 'PosReg', (42, 50))	('EGFR', 'Gene', (87, 91))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('mutant', 'Var', (92, 98))	('HGF-induced gefitinib resistance', 'MPA', (51, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
38103	29664235	In this study, we showed that miR-1-3p and miR-206 restored the sensitivities of lung cancer cells PC-9 and HCC-827 to gefitinib in present of HGF.	('sensitivities', 'MPA', (64, 77))	('lung cancer', 'Disease', (81, 92))	('miR-1-3p', 'Var', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('miR-206', 'Var', (43, 50))	('HCC-827', 'CellLine', 'CVCL:2063', (108, 115))	('restored', 'PosReg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('gefitinib', 'Chemical', 'MESH:D000077156', (119, 128))
38104	29664235	For the mechanisms, we demonstrated that both miR-1-3p and miR-206 directly target HGF receptor c-Met in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('c-Met', 'Gene', (96, 101))	('c-Met', 'Gene', '4233', (96, 101))	('miR-206', 'Gene', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('miR-1-3p', 'Var', (46, 54))	('target', 'Reg', (76, 82))	('lung cancer', 'Disease', (105, 116))
38105	29664235	Knockdown of c-Met mimicked the effects of miR-1-3p and miR-206 transfections Meanwhile, c-Met overexpression attenuated the effects of miR-1-3p and miR-206 in HGF-induced gefitinib resistance of lung cancers.	('c-Met', 'Gene', '4233', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('gefitinib', 'Chemical', 'MESH:D000077156', (172, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('attenuated', 'NegReg', (110, 120))	('overexpression', 'PosReg', (95, 109))	('lung cancers', 'Disease', 'MESH:D008175', (196, 208))	('lung cancers', 'Phenotype', 'HP:0100526', (196, 208))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('lung cancers', 'Disease', (196, 208))	('c-Met', 'Gene', '4233', (13, 18))	('miR-206', 'Var', (149, 156))	('c-Met', 'Gene', (13, 18))	('c-Met', 'Gene', (89, 94))
38106	29664235	Furthermore, we showed that miR-1-3p and miR-206 inhibited c-Met downstream Akt and Erk pathway and blocked HGF-induced epithelial-mesenchymal transition (EMT).	('c-Met', 'Gene', '4233', (59, 64))	('EMT', 'biological_process', 'GO:0001837', ('155', '158'))	('miR-1-3p', 'Var', (28, 36))	('HGF-induced', 'Gene', (108, 119))	('Akt', 'Gene', (76, 79))	('miR-206', 'Var', (41, 48))	('Erk', 'Gene', (84, 87))	('Erk', 'molecular_function', 'GO:0004707', ('84', '87'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('120', '153'))	('Akt', 'Gene', '207', (76, 79))	('Erk', 'Gene', '5594', (84, 87))	('inhibited', 'NegReg', (49, 58))	('blocked', 'NegReg', (100, 107))	('c-Met', 'Gene', (59, 64))
38107	29664235	Finally, we demonstrated that miR-1-3p and miR-206 can increase gefitinib sensitivity in xenograft mouse models in vivo.	('miR-1-3p', 'Var', (30, 38))	('gefitinib', 'Chemical', 'MESH:D000077156', (64, 73))	('mouse', 'Species', '10090', (99, 104))	('increase', 'PosReg', (55, 63))	('miR-206', 'Var', (43, 50))	('gefitinib sensitivity', 'MPA', (64, 85))
38108	29664235	Our study for the first time indicated the new function of miR-1-3p and miR-206 in overcoming HGF-induced gefitinib resistance in EGFR mutant lung cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('mutant', 'Var', (135, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('overcoming HGF-induced gefitinib resistance', 'MPA', (83, 126))	('EGFR', 'Gene', '1956', (130, 134))	('gefitinib', 'Chemical', 'MESH:D000077156', (106, 115))	('EGFR', 'Gene', (130, 134))
38110	29664235	Targeted therapy with tyrosine-kinase inhibitors (TKI) including gefitinib has dramatically improved the rates of response and survival in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).	('response', 'MPA', (114, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('148', '171'))	('NSCLC', 'Disease', (224, 229))	('-mutated', 'Var', (187, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('EGFR', 'Gene', '1956', (182, 186))	('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))	('epidermal growth factor receptor', 'Gene', (148, 180))	('epidermal growth factor receptor', 'Gene', '1956', (148, 180))	('cell lung cancer', 'Disease', 'MESH:D008175', (206, 222))	('improved', 'PosReg', (92, 100))	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('EGFR', 'Gene', (182, 186))	('cell lung cancer', 'Disease', (206, 222))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))
38118	29664235	Furthermore, we and other researchers have found that low expression of miR-206 is related to lung cancer invasion and metastasis.18, 19 However, the role of miR-1-3p and miR-206 in HGF-induced gefitinib resistance of lung cancer is not clear.	('lung cancer', 'Disease', (218, 229))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('miR-206', 'Var', (171, 178))	('lung cancer', 'Disease', (94, 105))	('gefitinib', 'Chemical', 'MESH:D000077156', (194, 203))	('lung cancer', 'Disease', 'MESH:D008175', (218, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
38119	29664235	This study was performed to investigate whether miR-1-3p and miR-206 increased the sensitivity of HGF-induced gefitinib resistance in EGFR mutant lung cancer cells.	('increased', 'PosReg', (69, 78))	('EGFR', 'Gene', (134, 138))	('miR-206', 'Var', (61, 68))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('gefitinib', 'Chemical', 'MESH:D000077156', (110, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('sensitivity', 'MPA', (83, 94))	('mutant', 'Var', (139, 145))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('EGFR', 'Gene', '1956', (134, 138))
38120	29664235	We assessed this issue using human lung cancer cells, PC9 and HCC-827, both harbouring deletions in exon19 of EGFR.	('HCC-827', 'CellLine', 'CVCL:2063', (62, 69))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('deletions in exon19', 'Var', (87, 106))	('PC9', 'Gene', '255738', (54, 57))	('human', 'Species', '9606', (29, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PC9', 'Gene', (54, 57))
38121	29664235	The results showed that HGF-induced gefitinib resistance and miR-1-3p and miR-206 could circumvent the HGF-induced gefitinib resistance by targeting c-Met-Akt-Erk pathway and suppressing epithelial-mesenchymal transition (EMT).	('Erk', 'Gene', (159, 162))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('187', '220'))	('miR-206', 'Var', (74, 81))	('gefitinib', 'Chemical', 'MESH:D000077156', (115, 124))	('gefitinib', 'Chemical', 'MESH:D000077156', (36, 45))	('Erk', 'molecular_function', 'GO:0004707', ('159', '162'))	('circumvent', 'NegReg', (88, 98))	('c-Met', 'Gene', (149, 154))	('suppressing', 'NegReg', (175, 186))	('Erk', 'Gene', '5594', (159, 162))	('gefitinib resistance', 'MPA', (115, 135))	('c-Met', 'Gene', '4233', (149, 154))	('EMT', 'biological_process', 'GO:0001837', ('222', '225'))	('Akt', 'Gene', '207', (155, 158))	('miR-1-3p', 'Var', (61, 69))	('targeting', 'Reg', (139, 148))	('Akt', 'Gene', (155, 158))
38139	29664235	Lysates were subjected to Western blotting assay as described previously21 and detected with antibodies against p-Met, c-Met, p-EGFR, EGFR, phospho-AKT, total AKT, phospho-ERK, total ERK, GAPDH, E-cadherin, Vimentin and Snail (Cell signalling technology).	('GAPDH', 'Gene', (188, 193))	('signalling', 'biological_process', 'GO:0023052', ('232', '242'))	('Vimentin', 'Gene', (207, 215))	('E-cadherin', 'Gene', (195, 205))	('E-cadherin', 'Gene', '999', (195, 205))	('AKT', 'Gene', '207', (159, 162))	('Vimentin', 'cellular_component', 'GO:0045099', ('207', '215'))	('EGFR', 'Gene', '1956', (134, 138))	('ERK', 'Gene', '5594', (183, 186))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('EGFR', 'Gene', (128, 132))	('p-Met', 'Var', (112, 117))	('AKT', 'Gene', (148, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('197', '205'))	('c-Met', 'Gene', '4233', (119, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('ERK', 'Gene', (183, 186))	('ERK', 'molecular_function', 'GO:0004707', ('172', '175'))	('ERK', 'molecular_function', 'GO:0004707', ('183', '186'))	('Vimentin', 'cellular_component', 'GO:0045098', ('207', '215'))	('ERK', 'Gene', '5594', (172, 175))	('GAPDH', 'Gene', '2597', (188, 193))	('AKT', 'Gene', '207', (148, 151))	('EGFR', 'Gene', (134, 138))	('AKT', 'Gene', (159, 162))	('EGFR', 'Gene', '1956', (128, 132))	('Vimentin', 'Gene', '7431', (207, 215))	('c-Met', 'Gene', (119, 124))	('ERK', 'Gene', (172, 175))
38152	29664235	PC-9 and HCC827 cell lines (both harbouring EGFR exon 19 deletion) are highly sensitive to gefitinib.	('sensitive', 'MPA', (78, 87))	('deletion', 'Var', (57, 65))	('EGFR', 'Gene', '1956', (44, 48))	('HCC827', 'CellLine', 'CVCL:2063', (9, 15))	('EGFR', 'Gene', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('gefitinib', 'Chemical', 'MESH:D000077156', (91, 100))
38155	29664235	In addition, we found that gefitinib increased the expression of miR-1-3p and miR-206, whereas HGF attenuated this effect in both cells (Figure S2A,B).	('miR-206', 'Var', (78, 85))	('gefitinib', 'Chemical', 'MESH:D000077156', (27, 36))	('miR-1-3p', 'Gene', (65, 73))	('expression', 'MPA', (51, 61))	('increased', 'PosReg', (37, 46))
38161	29664235	The results showed that either miR-1-3p or miR-206 mimics could obviously reversed HGF-induced gefitinib resistance compared with mimics negative control (NC) (Figure 2C).	('miR-1-3p', 'Var', (31, 39))	('miR-206', 'Gene', (43, 50))	('gefitinib', 'Chemical', 'MESH:D000077156', (95, 104))	('reversed', 'NegReg', (74, 82))	('HGF-induced', 'Disease', (83, 94))
38162	29664235	These results suggested that miR-1-3p/miR-206 are potential suppressors of HGF-induced gefitinib resistance in PC-9 and HCC827 cells.	('miR-1-3p/miR-206', 'Var', (29, 45))	('gefitinib', 'Chemical', 'MESH:D000077156', (87, 96))	('HCC827', 'CellLine', 'CVCL:2063', (120, 126))	('suppressors', 'NegReg', (60, 71))
38167	29664235	The results showed that both miR-1-3p and miR-206 mimics led to a significant decrease in the luciferase activity in c-Met wild-type (wt) constructs group, In contract, there is no decrease in mutant type (mut) group (Figure 3B).	('c-Met', 'Gene', (117, 122))	('decrease', 'NegReg', (78, 86))	('c-Met', 'Gene', '4233', (117, 122))	('miR-206 mimics', 'Var', (42, 56))	('luciferase activity', 'molecular_function', 'GO:0047077', ('94', '113'))	('miR-1-3p', 'Var', (29, 37))	('activity', 'MPA', (105, 113))	('luciferase activity', 'molecular_function', 'GO:0045289', ('94', '113'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('94', '113'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('94', '113'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('94', '113'))	('luciferase', 'Enzyme', (94, 104))
38168	29664235	Western blot analyses showed that the miR-1-3p/miR-206 mimic treatments induced down-regulation of protein expression of c-Met in two lung cancer cells (Figure 3C).	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('c-Met', 'Gene', (121, 126))	('c-Met', 'Gene', '4233', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('miR-1-3p/miR-206', 'Var', (38, 54))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('protein expression', 'MPA', (99, 117))	('down-regulation', 'NegReg', (80, 95))	('regulation of protein expression', 'biological_process', 'GO:0010468', ('85', '117'))
38169	29664235	These data showed that c-Met is a direct target of miR-1-3p/miR-206 in HCC827 and PC-9 cells.	('HCC827', 'CellLine', 'CVCL:2063', (71, 77))	('c-Met', 'Gene', (23, 28))	('miR-1-3p/miR-206', 'Var', (51, 67))	('c-Met', 'Gene', '4233', (23, 28))
38170	29664235	To confirm the roles of c-Met in overcoming HGF-induced gefitinib resistance by miR-1-3p and miR-206, we analysed whether c-Met knockdown by shRNA can mimic the effect of miR-1-3p and miR-206 transfection.	('c-Met', 'Gene', '4233', (122, 127))	('c-Met', 'Gene', (24, 29))	('c-Met', 'Gene', '4233', (24, 29))	('gefitinib', 'Chemical', 'MESH:D000077156', (56, 65))	('knockdown', 'Var', (128, 137))	('gefitinib resistance', 'MPA', (56, 76))	('overcoming', 'PosReg', (33, 43))	('c-Met', 'Gene', (122, 127))
38173	29664235	Next, we sought to examine whether c-Met overexpression can attenuate the effects of miR-1-3p/miR-206 on HGF-induced gefitinib resistance.	('gefitinib', 'Chemical', 'MESH:D000077156', (117, 126))	('c-Met', 'Gene', (35, 40))	('c-Met', 'Gene', '4233', (35, 40))	('gefitinib resistance', 'MPA', (117, 137))	('miR-1-3p/miR-206', 'Var', (85, 101))	('attenuate', 'NegReg', (60, 69))
38177	29664235	Some previous reports have showed that HGF induced gefitinib resistance through PI3K/Akt and Erk signalling pathway.29, 30, 31 To determine whether PI3K/Akt pathway is also an important mechanism in overcoming HGF-induced gefitinib resistance by miR-1-3p/miR-206, we examined the activities of c-Met, EGFR, Akt and Erk by Western blotting.	('Akt', 'Gene', '207', (153, 156))	('Erk', 'molecular_function', 'GO:0004707', ('93', '96'))	('Akt', 'Gene', (85, 88))	('EGFR', 'Gene', '1956', (301, 305))	('gefitinib', 'Chemical', 'MESH:D000077156', (222, 231))	('Akt', 'Gene', (307, 310))	('Akt', 'Gene', '207', (85, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('301', '305'))	('Akt', 'Gene', '207', (307, 310))	('c-Met', 'Gene', '4233', (294, 299))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('Erk', 'molecular_function', 'GO:0004707', ('315', '318'))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('Erk', 'Gene', (315, 318))	('EGFR', 'Gene', (301, 305))	('miR-1-3p/miR-206', 'Var', (246, 262))	('Erk', 'Gene', '5594', (315, 318))	('Erk', 'Gene', (93, 96))	('gefitinib', 'Chemical', 'MESH:D000077156', (51, 60))	('Akt', 'Gene', (153, 156))	('Erk', 'Gene', '5594', (93, 96))	('c-Met', 'Gene', (294, 299))	('signalling pathway', 'biological_process', 'GO:0007165', ('97', '115'))
38178	29664235	The results showed that miR-1-3p or miR-206 alone decreased the expression of c-Met in different degree (Figure 5A,B).	('miR-206', 'Var', (36, 43))	('expression', 'MPA', (64, 74))	('miR-1-3p', 'Var', (24, 32))	('c-Met', 'Gene', (78, 83))	('decreased', 'NegReg', (50, 59))	('c-Met', 'Gene', '4233', (78, 83))
38180	29664235	However, the combination of miR-1-3p or miR-206 mimics and gefitinib, significantly inhibited HGF-induced p-c-Met expression.	('gefitinib', 'Chemical', 'MESH:D000077156', (59, 68))	('miR-1-3p', 'Var', (28, 36))	('c-Met', 'Gene', (108, 113))	('c-Met', 'Gene', '4233', (108, 113))	('combination', 'Interaction', (13, 24))	('miR-206', 'Gene', (40, 47))	('inhibited', 'NegReg', (84, 93))
38181	29664235	Moreover, the combination of miR-1-3p or miR-206 mimics and gefitinib also obviously inhibited phosphorylation of Akt and Erk1/2 in both cell lines.	('Erk1/2', 'Gene', (122, 128))	('Akt', 'Gene', (114, 117))	('inhibited', 'NegReg', (85, 94))	('miR-206', 'Gene', (41, 48))	('miR-1-3p', 'Var', (29, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('Erk1/2', 'Gene', '5595;5594', (122, 128))	('Erk1', 'molecular_function', 'GO:0004707', ('122', '126'))	('Akt', 'Gene', '207', (114, 117))	('combination', 'Interaction', (14, 25))	('phosphorylation', 'MPA', (95, 110))	('gefitinib', 'Chemical', 'MESH:D000077156', (60, 69))
38182	29664235	Interestingly, we also found that miR-1-3p or miR-206 mimic transfection could suppress the EGFR expression in PC-9 and HCC827 cells, which may increase the effect of two miRNAs on overcoming gefitinib resistance.	('transfection', 'Var', (60, 72))	('miR-1-3p', 'Var', (34, 42))	('HCC827', 'CellLine', 'CVCL:2063', (120, 126))	('gefitinib', 'Chemical', 'MESH:D000077156', (192, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('suppress', 'NegReg', (79, 87))	('expression', 'MPA', (97, 107))	('miR-206', 'Var', (46, 53))
38183	29664235	Therefore, our results suggested that miR-1-3p/miR-206 is able to down-regulate c-Met and EGFR expression and inhibit downstream Akt and Erk pathways in HGF-induced gefitinib-resistant NSCLC cells.	('Erk', 'Gene', '5594', (137, 140))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('Akt', 'Gene', '207', (129, 132))	('c-Met', 'Gene', (80, 85))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('gefitinib', 'Chemical', 'MESH:D000077156', (165, 174))	('down-regulate', 'NegReg', (66, 79))	('c-Met', 'Gene', '4233', (80, 85))	('EGFR', 'Gene', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('miR-1-3p/miR-206', 'Var', (38, 54))	('Akt', 'Gene', (129, 132))	('inhibit', 'NegReg', (110, 117))	('Erk', 'molecular_function', 'GO:0004707', ('137', '140'))	('Erk', 'Gene', (137, 140))	('expression', 'MPA', (95, 105))	('NSCLC', 'Disease', (185, 190))
38186	29664235	MiR-1-3p and miR-206 treatment induced a transition from spindle-like to epithelial-like morphology (Figure 6C), as evidenced by the up-regulation of E-cadherin and down-regulation of Vimentin and Snail in both HGF treated PC-9 and HCC827 cells (Figure 6D).	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('Vimentin', 'cellular_component', 'GO:0045099', ('184', '192'))	('regulation', 'biological_process', 'GO:0065007', ('170', '180'))	('miR-206', 'Var', (13, 20))	('Vimentin', 'cellular_component', 'GO:0045098', ('184', '192'))	('spindle', 'cellular_component', 'GO:0005819', ('57', '64'))	('regulation', 'biological_process', 'GO:0065007', ('136', '146'))	('Vimentin', 'Gene', (184, 192))	('E-cadherin', 'Gene', (150, 160))	('E-cadherin', 'Gene', '999', (150, 160))	('MiR-1-3p', 'Var', (0, 8))	('up-regulation', 'PosReg', (133, 146))	('Vimentin', 'Gene', '7431', (184, 192))	('down-regulation', 'NegReg', (165, 180))	('HCC827', 'CellLine', 'CVCL:2063', (232, 238))	('Snail', 'CPA', (197, 202))
38187	29664235	Immunofluorescence stain of EMT markers of E-cadherin and Vimentin in PC-9 cells and HCC-827 cells confirmed that HGF-induced EMT can be reversed by miR-1-3p and miR-206 transfection (Figure 6E,F).	('Vimentin', 'Gene', (58, 66))	('E-cadherin', 'Gene', (43, 53))	('Vimentin', 'cellular_component', 'GO:0045099', ('58', '66'))	('Vimentin', 'Gene', '7431', (58, 66))	('E-cadherin', 'Gene', '999', (43, 53))	('EMT', 'biological_process', 'GO:0001837', ('28', '31'))	('miR-1-3p', 'Var', (149, 157))	('cadherin', 'molecular_function', 'GO:0008014', ('45', '53'))	('EMT', 'biological_process', 'GO:0001837', ('126', '129'))	('miR-206', 'Var', (162, 169))	('HCC-827', 'CellLine', 'CVCL:2063', (85, 92))	('Vimentin', 'cellular_component', 'GO:0045098', ('58', '66'))	('EMT', 'CPA', (126, 129))
38188	29664235	These findings suggested that miR-1-3p and miR-206 reverses EMT in HGF stimulated lung cancer cells might be another important mechanism correlated with overcoming resistance to gefitinib.	('miR-1-3p', 'Var', (30, 38))	('gefitinib', 'Chemical', 'MESH:D000077156', (178, 187))	('miR-206', 'Var', (43, 50))	('reverses', 'NegReg', (51, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('EMT', 'CPA', (60, 63))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))
38189	29664235	To further determine whether miR-1-3p and miR-206 can overcome HGF-induced gefitinib resistance in vivo, a gefitinib-resistant xenograft tumour model (PC-9/HGF) was used in the nude mice.	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('gefitinib', 'Chemical', 'MESH:D000077156', (107, 116))	('nude mice', 'Species', '10090', (177, 186))	('miR-206', 'Var', (42, 49))	('tumour', 'Disease', (137, 143))	('miR-1-3p', 'Var', (29, 37))	('gefitinib', 'Chemical', 'MESH:D000077156', (75, 84))	('HGF-induced', 'Disease', (63, 74))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
38193	29664235	Importantly, the combination of miR-1-3p (or miR-206) and gefitinib reduced the size of PC-9/HGF tumours (Figure 7A,B).	('HGF tumours', 'Disease', 'MESH:C562884', (93, 104))	('gefitinib', 'Chemical', 'MESH:D000077156', (58, 67))	('size', 'MPA', (80, 84))	('miR-206', 'Var', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('reduced', 'NegReg', (68, 75))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('HGF tumours', 'Disease', (93, 104))
38197	29664235	In this study, we reported that miR-1-3p and miR-206 can overcome HGF-induced gefitinib resistance in EGFR mutant lung cancer cells in vitro and in vivo, and the mechanisms were related to inhibit Akt/Erk pathways and meanwhile suppress HGF-induced EMT (Figure 8).	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('Erk', 'Gene', (201, 204))	('Akt', 'Gene', (197, 200))	('gefitinib', 'Chemical', 'MESH:D000077156', (78, 87))	('Erk', 'Gene', '5594', (201, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('EGFR', 'Gene', '1956', (102, 106))	('Akt', 'Gene', '207', (197, 200))	('miR-206', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('inhibit', 'NegReg', (189, 196))	('HGF-induced EMT', 'CPA', (237, 252))	('EMT', 'biological_process', 'GO:0001837', ('249', '252'))	('Erk', 'molecular_function', 'GO:0004707', ('201', '204'))	('lung cancer', 'Disease', (114, 125))	('EGFR', 'Gene', (102, 106))	('HGF-induced gefitinib resistance', 'MPA', (66, 98))	('mutant', 'Var', (107, 113))	('suppress', 'NegReg', (228, 236))	('overcome', 'PosReg', (57, 65))
38198	29664235	The study showed the novel anti-tumour function of miR-1-3p and miR-206 in lung cancer.	('lung cancer', 'Disease', (75, 86))	('miR-206', 'Var', (64, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('miR-1-3p', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
38203	29664235	HGF overexpression-induced TKIs resistance is associated with c-Met phosphorylation and reactivation of phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway in EGFR mutant NSCLC.22, 30 Targeting HGF-c-Met pathway by HGF antibody or c-Met inhibitors restore the HGF-induced resistance in lung cancer cells.37, 38 In addition, some miRNAs were also reported overcoming gefitinib resistance by targeting c-Met in different types of lung cancer cells,such as in lung cancer stem cells (miR-128),39 in primary or acquired gefitinib-resistant lung cancer cells (mir-19a, miR-200a and miR-130a),40, 41, 42 and in HGF-induced lung cancer cells (miR-34a).43 Consistent with these studies, we found that enforced expression of miR-1-3p/miR-206 attenuated gefitinib resistance induced by HGF in EGFR mutant lung cancer cells, and the mechanisms were also involved in targeting c-Met and its downstream pathways.	('phosphatidylinositol 3-kinase', 'Gene', (104, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (465, 476))	('gefitinib', 'Chemical', 'MESH:D000077156', (374, 383))	('c-Met', 'Gene', (206, 211))	('lung cancer', 'Disease', (294, 305))	('involved', 'Reg', (851, 859))	('c-Met', 'Gene', (62, 67))	('c-Met', 'Gene', '4233', (408, 413))	('lung cancer', 'Disease', 'MESH:D008175', (544, 555))	('antibody', 'cellular_component', 'GO:0019815', ('227', '235'))	('lung cancer', 'Disease', (436, 447))	('c-Met', 'Gene', '4233', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (630, 636))	('Akt', 'Gene', '207', (141, 144))	('gefitinib', 'Chemical', 'MESH:D000077156', (524, 533))	('gefitinib resistance induced', 'MPA', (752, 780))	('lung cancer', 'Disease', 'MESH:D008175', (803, 814))	('lung cancer', 'Phenotype', 'HP:0100526', (544, 555))	('miR-200a', 'Gene', '406983', (572, 580))	('mutant', 'Var', (796, 802))	('cancer', 'Phenotype', 'HP:0002664', (549, 555))	('c-Met', 'Gene', '4233', (873, 878))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('gefitinib', 'Chemical', 'MESH:D000077156', (752, 761))	('lung cancer', 'Disease', (625, 636))	('EGFR', 'Gene', '1956', (791, 795))	('cancer', 'Phenotype', 'HP:0002664', (470, 476))	('antibody', 'cellular_component', 'GO:0019814', ('227', '235'))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('lung cancer', 'Disease', 'MESH:D008175', (294, 305))	('lung cancer', 'Disease', 'MESH:D008175', (436, 447))	('NSCLC', 'Disease', (179, 184))	('EGFR', 'Gene', (167, 171))	('lung cancer', 'Disease', (465, 476))	('c-Met', 'Gene', (408, 413))	('lung cancer', 'Phenotype', 'HP:0100526', (294, 305))	('c-Met', 'Gene', '4233', (206, 211))	('c-Met', 'Gene', '4233', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (436, 447))	('c-Met', 'Gene', (239, 244))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('HGF', 'Gene', (784, 787))	('EGFR', 'molecular_function', 'GO:0005006', ('791', '795'))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (104, 133))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('miR-34a', 'Gene', (644, 651))	('mir-19a', 'Gene', '406979', (563, 570))	('antibody', 'molecular_function', 'GO:0003823', ('227', '235'))	('lung cancer', 'Disease', 'MESH:D008175', (625, 636))	('lung cancer', 'Disease', (544, 555))	('miR-130a', 'Gene', '406919', (585, 593))	('signalling pathway', 'biological_process', 'GO:0007165', ('145', '163'))	('c-Met', 'Gene', (873, 878))	('miR-200a', 'Gene', (572, 580))	('antibody', 'cellular_component', 'GO:0042571', ('227', '235'))	('lung cancer', 'Disease', (803, 814))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('lung cancer', 'Phenotype', 'HP:0100526', (625, 636))	('mir-19a', 'Gene', (563, 570))	('miR-34a', 'Gene', '407040', (644, 651))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('miR-130a', 'Gene', (585, 593))	('EGFR', 'Gene', (791, 795))	('lung cancer', 'Disease', 'MESH:D008175', (465, 476))	('cancer', 'Phenotype', 'HP:0002664', (441, 447))	('EGFR', 'Gene', '1956', (167, 171))	('attenuated', 'NegReg', (741, 751))	('Akt', 'Gene', (141, 144))
38204	29664235	To confirm the relationship of miR-1-3p/miR-206 targeting c-Met and HGF-induced gefitinib resistance, we performed loss or gain of function assays.	('c-Met', 'Gene', (58, 63))	('c-Met', 'Gene', '4233', (58, 63))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))	('miR-1-3p/miR-206', 'Var', (31, 47))	('gain', 'PosReg', (123, 127))
38205	29664235	The results showed that c-Met knockdown reduced the HGF-induced gefitinib resistance.	('gefitinib', 'Chemical', 'MESH:D000077156', (64, 73))	('c-Met', 'Gene', (24, 29))	('c-Met', 'Gene', '4233', (24, 29))	('reduced', 'NegReg', (40, 47))	('knockdown', 'Var', (30, 39))	('HGF-induced gefitinib resistance', 'MPA', (52, 84))
38208	29664235	Previous studies showed that miR-206 target c-Met directly in lung cancer cells.44 In our study, we further demonstrated that both miR-1-3p and miR-206 have common target c-Met in EGFR mutant PC-9 and HCC-827 cells.	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('mutant', 'Var', (185, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('miR-206', 'Gene', (144, 151))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('lung cancer', 'Disease', (62, 73))	('HCC-827', 'CellLine', 'CVCL:2063', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('c-Met', 'Gene', (44, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('c-Met', 'Gene', '4233', (44, 49))	('c-Met', 'Gene', (171, 176))	('c-Met', 'Gene', '4233', (171, 176))
38210	29664235	Therefore, we suppose that combination of c-Met inhibitors and c-Met targeting miRNA, such as miR-1-3p/miR-206, might be a better anti-resistant strategy in overcoming HGF-induced gefitinib resistance.	('c-Met', 'Gene', (63, 68))	('miR-1-3p/miR-206', 'Var', (94, 110))	('overcoming', 'PosReg', (157, 167))	('c-Met', 'Gene', '4233', (63, 68))	('c-Met', 'Gene', '4233', (42, 47))	('gefitinib', 'Chemical', 'MESH:D000077156', (180, 189))	('c-Met', 'Gene', (42, 47))
38214	29664235	Whereas transfection of miR-1-3p and miR-206 caused HGF-expressed PC-9 and HCC-827 cells to undergo mesenchymal-epithelial transition, the reverse of EMT.	('undergo', 'Reg', (92, 99))	('miR-206', 'Var', (37, 44))	('miR-1-3p', 'Var', (24, 32))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('100', '133'))	('HCC-827', 'CellLine', 'CVCL:2063', (75, 82))	('EMT', 'biological_process', 'GO:0001837', ('150', '153'))	('HGF-expressed', 'Gene', (52, 65))
38215	29664235	Together these findings indicate that suppressing EMT is another critical factor that miR-1-3p and miR-206 overcoming HGF-induced gefitinib resistance.	('HGF-induced gefitinib resistance', 'MPA', (118, 150))	('miR-206', 'Gene', (99, 106))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('miR-1-3p', 'Var', (86, 94))	('overcoming', 'NegReg', (107, 117))	('EMT', 'CPA', (50, 53))	('gefitinib', 'Chemical', 'MESH:D000077156', (130, 139))
38216	29664235	Previous study reported that miR-1 regulated EMT by directly target Slug gene in prostate cancer.47 However, whether EMT-related genes are target directly by miR-1-3p and miR-206 need further experimental verification.	('EMT', 'biological_process', 'GO:0001837', ('117', '120'))	('Slug', 'Gene', (68, 72))	('prostate cancer', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('EMT', 'biological_process', 'GO:0001837', ('45', '48'))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('Slug', 'Gene', '6591', (68, 72))	('miR-1-3p', 'Var', (158, 166))
38217	29664235	In summary, we demonstrated in vitro and in vivo that miR-1-3p and miR-206 can restore HGF-induced gefitinib resistance in EGFR activating lung cancer cells.	('lung cancer', 'Disease', (139, 150))	('EGFR', 'Gene', (123, 127))	('HGF-induced gefitinib resistance', 'MPA', (87, 119))	('EGFR', 'Gene', '1956', (123, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('restore', 'PosReg', (79, 86))	('miR-1-3p', 'Var', (54, 62))	('miR-206', 'Var', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('gefitinib', 'Chemical', 'MESH:D000077156', (99, 108))
38228	29398577	Of tested baseline biomarkers, undetectable interleukin (IL)-1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04-7.93; P < .001) was the only significant survival covariate.	('IL)-1', 'molecular_function', 'GO:0005149', ('57', '62'))	('undetectable', 'Var', (31, 43))	('interleukin (IL)-1b', 'Gene', '3553', (44, 63))	('interleukin (IL)-1b', 'Gene', (44, 63))
38232	29398577	Baseline angioprotein-1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F-fluorothymidine (FLT) positron emission tomography (PET).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FLT', 'Chemical', '-', (210, 213))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('127', '149'))	('tumor', 'Disease', (86, 91))	('hepatocyte growth factor', 'Gene', (28, 52))	('correlations', 'Interaction', (171, 183))	('18F-fluorothymidine', 'Chemical', '-', (189, 208))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('28', '52'))	('vascular cell adhesion molecule 1', 'Gene', '7412', (118, 151))	('vascular cell adhesion molecule 1', 'Gene', (118, 151))	('hepatocyte growth factor', 'Gene', '3082', (28, 52))	('cell adhesion', 'biological_process', 'GO:0007155', ('127', '140'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('changes', 'Var', (107, 114))
38264	29398577	Cell death (apoptosis and total cell death) was measured using cytokeratin 18 cleaved (M30) and intact (M65) ELISAs (respectively) from Peviva (now VLV Bio, Nacka, Sweden) and run as previously described.	('cytokeratin 18', 'Gene', '3875', (63, 77))	('Cell death', 'biological_process', 'GO:0008219', ('0', '10'))	('M30', 'Var', (87, 90))	('cell death', 'biological_process', 'GO:0008219', ('32', '42'))	('apoptosis', 'biological_process', 'GO:0097194', ('12', '21'))	('apoptosis', 'biological_process', 'GO:0006915', ('12', '21'))	('cytokeratin 18', 'Gene', (63, 77))
38266	29398577	M30, M65, and osteopontin were measured in plasma; all other proteins were measured in serum.	('M65', 'Var', (5, 8))	('M30', 'Var', (0, 3))	('osteopontin', 'Gene', '6696', (14, 25))	('osteopontin', 'Gene', (14, 25))
38296	29398577	As shown, undetectable IL-1b and TNFalpha were the strongest covariates associated with poor survival, with only IL-1b remaining significant after Bonferroni correction.	('IL-1b', 'Gene', '3553', (23, 28))	('TNFalpha', 'Gene', '7124', (33, 41))	('IL-1', 'molecular_function', 'GO:0005149', ('23', '27'))	('IL-1', 'molecular_function', 'GO:0005149', ('113', '117'))	('IL-1b', 'Gene', '3553', (113, 118))	('undetectable', 'Var', (10, 22))	('IL-1b', 'Gene', (23, 28))	('TNFalpha', 'Gene', (33, 41))	('IL-1b', 'Gene', (113, 118))
38327	29398577	In our study, undetectable IL-1b is associated with poor prognosis which agrees with these preclinical observations, but not with a clinical study that reported that high IL-1b was independently associated with worse OS (HR, 2.24; 95% CI, 1.01-4.98; P = .047) in stage IIIB-IV NSCLC patients treated with chemotherapy.	('OS', 'Chemical', '-', (217, 219))	('IL-1', 'molecular_function', 'GO:0005149', ('171', '175'))	('IL-1b', 'Gene', (27, 32))	('SCLC', 'Phenotype', 'HP:0030357', (278, 282))	('undetectable', 'Var', (14, 26))	('IL-1b', 'Gene', '3553', (171, 176))	('patients', 'Species', '9606', (283, 291))	('NSCLC', 'Phenotype', 'HP:0030358', (277, 282))	('IL-1', 'molecular_function', 'GO:0005149', ('27', '31'))	('IL-1b', 'Gene', '3553', (27, 32))	('NSCLC', 'Disease', (277, 282))	('high', 'Var', (166, 170))	('IL-1b', 'Gene', (171, 176))	('NSCLC', 'Disease', 'MESH:D002289', (277, 282))
38343	29398577	In our study, detectable day-21 FGFb was correlated with improved survival in SCLC as well as NSCLC in univariate analysis, albeit of borderline significance (P = .045).	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('survival', 'MPA', (66, 74))	('NSCLC', 'Disease', (94, 99))	('SCLC', 'Gene', '7864', (78, 82))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('improved', 'PosReg', (57, 65))	('SCLC', 'Gene', (78, 82))	('SCLC', 'Gene', '7864', (95, 99))	('SCLC', 'Phenotype', 'HP:0030357', (78, 82))	('detectable', 'Var', (14, 24))	('FGFb', 'Gene', '2247', (32, 36))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))	('SCLC', 'Gene', (95, 99))	('FGFb', 'Gene', (32, 36))
38376	29398577	Changes in VCAM-1 correlated with proliferation imaging, highlighting for the first time a potential role of blood biomarkers as less-invasive imaging surrogates.	('VCAM-1', 'Gene', (11, 17))	('proliferation imaging', 'MPA', (34, 55))	('Changes', 'Var', (0, 7))	('VCAM-1', 'Gene', '7412', (11, 17))
38379	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))	('S-phase', 'biological_process', 'GO:0051320', ('70', '77'))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('crucial cancer', 'Disease', (128, 142))
38383	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))	('MAPK', 'molecular_function', 'GO:0004707', ('137', '141'))	('YBX1', 'Gene', '4904', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('S-phase', 'biological_process', 'GO:0051320', ('55', '62'))	('AKT', 'Gene', '207', (133, 136))	('hnRNPK', 'Gene', '3190', (172, 178))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('AKT', 'Gene', (133, 136))	('YBX1', 'Gene', (179, 183))	('cancer', 'Disease', (63, 69))
38385	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))
38403	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.	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('separation', 'MPA', (134, 144))	('EtU', 'Chemical', '-', (104, 107))	('EtU-labeled', 'Var', (104, 115))	('S-phase', 'biological_process', 'GO:0051320', ('177', '184'))
38425	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).	('Methylation', 'biological_process', 'GO:0032259', ('146', '157'))	('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))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('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))
38427	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))
38428	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))
38446	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))
38464	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).	('RNA', 'cellular_component', 'GO:0005562', ('189', '192'))	('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))	('LIHC', 'Disease', 'None', (130, 134))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('MCF7', 'CellLine', 'CVCL:0031', (154, 158))
38466	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))
38467	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))	('S-phase', 'biological_process', 'GO:0051320', ('41', '48'))	('SCAT7', 'Gene', (13, 18))	('S-phase progression', 'CPA', (41, 60))	('altered', 'Reg', (29, 36))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (112, 137))
38469	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))
38470	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))
38476	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))
38480	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.	('IL8', 'molecular_function', 'GO:0005153', ('205', '208'))	('activity', 'MPA', (121, 129))	('IL8', 'Gene', (205, 208))	('SCAT7', 'Var', (21, 26))	('p16', 'Gene', '1029', (191, 194))	('p15', 'Gene', (196, 199))	('beta-galactosidase', 'Gene', '2720', (102, 120))	('beta-galactosidase', 'Gene', (102, 120))	('repression', 'NegReg', (150, 160))	('p15', 'Gene', '1030', (196, 199))	('transcriptional', 'MPA', (134, 149))	('IL8', 'Gene', '3576', (205, 208))	('beta-galactosidase activity', 'molecular_function', 'GO:0004565', ('102', '129'))	('tamoxifen', 'Chemical', 'MESH:D013629', (51, 60))	('senescence', 'biological_process', 'GO:0010149', ('69', '79'))	('senescence', 'biological_process', 'GO:0010149', ('172', '182'))	('p16', 'Gene', (191, 194))	('less', 'NegReg', (97, 101))
38481	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))	('senescence', 'biological_process', 'GO:0010149', ('84', '94'))	('SCAT7', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
38483	29491376	Downregulation of SCAT7 induced the senescence phenotype in both HeLa and A549 cells while Caki-2 cells remained unaffected (Fig.	('senescence', 'biological_process', 'GO:0010149', ('36', '46'))	('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))
38488	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))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('knockdown', 'Var', (82, 91))	('CCND1', 'Gene', (0, 5))	('SCAT7', 'Gene', (76, 81))	('CCND1', 'Gene', '595', (0, 5))
38494	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.	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('HeLa', 'CellLine', 'CVCL:0030', (91, 95))	('mRNA levels', 'MPA', (43, 54))	('knockdown', 'Var', (20, 29))	('FGFR2', 'Gene', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR2', 'Gene', (113, 118))	('FGFR2', 'Gene', '2263', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('affected', 'Reg', (30, 38))	('FGFR3', 'Gene', (65, 70))	('Caki-2', 'CellLine', 'CVCL:0235', (144, 150))	('FGFR2', 'Gene', '2263', (113, 118))	('FGFR3', 'Gene', '2261', (65, 70))	('FGF7', 'Gene', (72, 76))	('SCAT7', 'Gene', (14, 19))	('FGF21', 'Gene', '26291', (82, 87))	('FGF7', 'Gene', '2252', (72, 76))	('FGF21', 'Gene', (82, 87))
38501	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))	('depletion', 'Var', (135, 144))	('SCAT7', 'Gene', (129, 134))	('HeLa', 'CellLine', 'CVCL:0030', (152, 156))	('FGFR2', 'Gene', '2263', (34, 39))	('depletion', 'Var', (40, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('cell proliferation', 'CPA', (65, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('cell cycle', 'CPA', (53, 63))	('cell cycle', 'biological_process', 'GO:0007049', ('53', '63'))	('Caki-2', 'CellLine', 'CVCL:0235', (161, 167))	('vitality', 'CPA', (89, 97))
38510	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))
38513	29491376	The activities of the MAPK and AKT pathways downstream to FGFRs were also reduced upon hnRNPK or YBX1 knockdown (Fig.	('MAPK', 'molecular_function', 'GO:0004707', ('22', '26'))	('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))
38517	29491376	Our analysis revealed a significant enrichment of SCAT7 at the FGFR2 (-250 to -750 bp relative to TSS (Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR2', 'Gene', (63, 68))	('-250 to -750 bp', 'Var', (70, 85))	('FGFR2', 'Gene', '2263', (63, 68))	('SCAT7', 'MPA', (50, 55))
38518	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))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))
38527	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', (123, 128))	('FGFR2', 'Gene', '2263', (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))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('FGFR3', 'Gene', (94, 99))
38534	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))
38535	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))
38538	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))
38558	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))	('S-phase', 'biological_process', 'GO:0051320', ('49', '56'))	('tumor', 'Disease', (162, 167))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('modulating', 'Reg', (111, 121))	('epigenetic alterations', 'Var', (85, 107))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('transcriptional activities', 'MPA', (128, 154))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
38560	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))
38567	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).	('p15', 'Gene', (248, 251))	('tumor suppressor', 'biological_process', 'GO:0051726', ('210', '226'))	('beta-galactosidase', 'Gene', '2720', (134, 152))	('tumor', 'Disease', (210, 215))	('beta-galactosidase', 'Gene', (134, 152))	('p15', 'Gene', '1030', (248, 251))	('knockdown', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('cell cycle arrest', 'CPA', (164, 181))	('p16', 'Gene', (239, 242))	('p16', 'Gene', '1029', (239, 242))	('cellular senescence', 'CPA', (104, 123))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('164', '181'))	('p21', 'Gene', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('p21', 'Gene', '644914', (234, 237))	('cellular senescence', 'biological_process', 'GO:0090398', ('104', '123'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (164, 181))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('210', '226'))	('secretion', 'biological_process', 'GO:0046903', ('153', '162'))
38572	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))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('multiple cancer', 'Disease', (156, 171))
38574	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))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('multiple cancer', 'Disease', 'MESH:D009369', (77, 92))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('SCAT7', 'Gene', (58, 63))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('FGF/FGFR', 'Gene', (19, 27))	('cancer', 'Disease', (188, 194))	('knockdown', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
38580	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))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('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))
38581	29491376	Also, a missense mutation in FGFR2 was found to drive a durable response to nucleolin-targeted therapy in metastatic KIRC.	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('FGFR2', 'Gene', '2263', (29, 34))	('FGFR2', 'Gene', (29, 34))	('missense mutation', 'Var', (8, 25))	('response to nucleolin-targeted therapy', 'MPA', (64, 102))
38582	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))	('FGFR members', 'Gene', (30, 42))	('mutations', 'Var', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('LUAD tumorogenesis', 'Disease', 'MESH:D002471', (236, 254))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('activating', 'PosReg', (50, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('patients', 'Species', '9606', (86, 94))
38583	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))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('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))
38584	29491376	The engineered mouse model showed more than 50% tumor regression when treated with a pan-FGFR inhibitor.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('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))
38585	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))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR1', 'Gene', '2260', (44, 49))	('KRAS-mutant', 'Var', (116, 127))	('adaptive resistance', 'MPA', (76, 95))	('MEK', 'Gene', (99, 102))
38586	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))	('FGFR', 'molecular_function', 'GO:0005007', ('175', '179'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('targeting', 'Var', (66, 75))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SCAT7', 'Gene', (76, 81))
38606	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).	('S-phase', 'biological_process', 'GO:0051320', ('68', '75'))	('T3h-T5h', 'Var', (116, 123))	('T3h-T5h', 'Chemical', '-', (116, 123))	('S-phase', 'biological_process', 'GO:0051320', ('102', '109'))	('T1.5h-T3.5 h', 'Var', (78, 90))	('S-phase', 'biological_process', 'GO:0051320', ('132', '139'))	('T0h-T2h', 'Chemical', '-', (46, 53))
38642	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))
38645	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))
38692	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))
38776	28974854	Improper characterization of time delay would result in positional errors in delivering the dose during gating, and this leads to missing of target or overdose of critical organs.	('overdose', 'Disease', 'MESH:D062787', (151, 159))	('missing', 'MPA', (130, 137))	('result in', 'Reg', (46, 55))	('delivering the dose', 'MPA', (77, 96))	('leads to', 'Reg', (121, 129))	('overdose', 'Disease', (151, 159))	('errors', 'Reg', (67, 73))	('Improper', 'Var', (0, 8))
38818	28974854	The target motion along with DMLC leaf motion was included through MLC leaf velocity modification whereas the target motion perpendicular to MLC leaf motion was accommodated by shifting the MLC leaves appropriately.	('MLC', 'Gene', '43323', (67, 70))	('MLC', 'Gene', '43323', (190, 193))	('DMLC', 'Gene', '43323', (29, 33))	('DMLC', 'Gene', (29, 33))	('MLC', 'Gene', '43323', (30, 33))	('MLC', 'Gene', (67, 70))	('MLC', 'Gene', (190, 193))	('MLC', 'Gene', (30, 33))	('modification', 'Var', (85, 97))	('MLC', 'Gene', '43323', (141, 144))	('MLC', 'Gene', (141, 144))
38883	28615236	Three discrete components make up the cytoskeleton: microfilaments (6 nm, actin), microtubules (25 nm) and intermediate filaments (10 nm, keratin, vimentin, lamin, desmin, etc.).	('lamin', 'Gene', (157, 162))	('desmin', 'Gene', (164, 170))	('lamin', 'Gene', '4000', (157, 162))	('intermediate filaments', 'CPA', (107, 129))	('microtubules', 'Protein', (82, 94))	('vimentin', 'cellular_component', 'GO:0045099', ('147', '155'))	('vimentin', 'cellular_component', 'GO:0045098', ('147', '155'))	('desmin', 'Gene', '1674', (164, 170))	('10', 'Var', (131, 133))	('25', 'Var', (96, 98))	('desmin', 'cellular_component', 'GO:0045098', ('164', '170'))	('keratin', 'Protein', (138, 145))	('desmin', 'cellular_component', 'GO:0045100', ('164', '170'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('38', '50'))	('vimentin', 'Gene', '7431', (147, 155))	('vimentin', 'Gene', (147, 155))
38901	28615236	A multitude of diverse alterations in tubulin/MTs have been identified and exhaustively characterized as the cause for different varieties of cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cause', 'Reg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('alterations', 'Var', (23, 34))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('tubulin/MTs', 'Protein', (38, 49))
38904	28615236	In fact, various PTMs in tubulin are correlated with tumor growth and enhanced metastasis including prostate and pancreatic cancers.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (113, 131))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancers', 'Disease', 'MESH:D010190', (113, 131))	('pancreatic cancers', 'Disease', (113, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('enhanced', 'PosReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prostate', 'Disease', (100, 108))	('tumor', 'Disease', (53, 58))	('tubulin', 'Protein', (25, 32))	('metastasis', 'CPA', (79, 89))	('PTMs', 'Var', (17, 21))
38907	28615236	Interestingly, these alterations not only contribute to tumorigenesis but also function as another major mechanism underlying non-responsiveness of cancer cells to MTAs, besides the intrinsic or acquired drug resistance involving over-expression of drug-efflux pumps.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('efflux', 'biological_process', 'GO:0140352', ('254', '260'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('contribute', 'Reg', (42, 52))	('drug resistance', 'Phenotype', 'HP:0020174', (204, 219))	('drug resistance', 'biological_process', 'GO:0042493', ('204', '219'))	('drug resistance', 'biological_process', 'GO:0009315', ('204', '219'))	('drug-efflux pumps', 'MPA', (249, 266))	('alterations', 'Var', (21, 32))	('efflux', 'biological_process', 'GO:0140115', ('254', '260'))
38912	28615236	In serous ovarian carcinomas, which is a sub-category constituting about 2/3rd of EOCs, low BRCA1 expression occurs in more than 50% of cases.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (10, 27))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (10, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (3, 28))	('low', 'Var', (88, 91))	('BRCA1', 'Gene', '672', (92, 97))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (3, 28))	('BRCA1', 'Gene', (92, 97))	('serous ovarian carcinomas', 'Disease', (3, 28))	('expression', 'MPA', (98, 108))
38914	28615236	BRCA1 also influences sensitivity of breast cancer cells to MTAs, for instance, a BRCA1 mutant cell line is more sensitive to vinorelbine, a vinca alkaloid, compared to the cell lines with wild-type allele.	('breast cancer', 'Disease', (37, 50))	('BRCA1', 'Gene', (82, 87))	('BRCA1', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('influences', 'Reg', (11, 21))	('sensitive', 'MPA', (113, 122))	('mutant', 'Var', (88, 94))	('vinorelbine', 'MPA', (126, 137))	('BRCA1', 'Gene', '672', (82, 87))	('more', 'PosReg', (108, 112))	('BRCA1', 'Gene', '672', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('vinorelbine', 'Chemical', 'MESH:D000077235', (126, 137))
38929	28615236	Therefore, a defective ABK regulatory system results in erroneous kMT attachments leading to chromosomal mis-segregation and chromosomal instability (CIN), a hallmark of cancer.	('CIN', 'Disease', (150, 153))	('erroneous', 'Var', (56, 65))	('CIN', 'Disease', 'MESH:D007674', (150, 153))	('ABK', 'Gene', (23, 26))	('chromosomal instability', 'Disease', (125, 148))	('chromosomal instability', 'Phenotype', 'HP:0040012', (125, 148))	('leading to', 'Reg', (82, 92))	('chromosomal mis-segregation', 'CPA', (93, 120))	('kMT', 'Protein', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CIN', 'Phenotype', 'HP:0040012', (150, 153))	('hallmark of cancer', 'Disease', (158, 176))	('hallmark of cancer', 'Disease', 'MESH:D009369', (158, 176))
38930	28615236	In fact cancer cells with CIN possess an inherently reduced capacity to correct erroneous kMT attachments and especially merotely.	('erroneous', 'Var', (80, 89))	('cancer', 'Disease', (8, 14))	('reduced', 'NegReg', (52, 59))	('CIN', 'Disease', 'MESH:D007674', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('CIN', 'Phenotype', 'HP:0040012', (26, 29))	('kMT', 'Protein', (90, 93))	('correct', 'Reg', (72, 79))	('CIN', 'Disease', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
38933	28615236	Consequently, Hec1 depletion in tumor cell lines and in xenografts induced mitotic abnormalities and cell death.	('depletion', 'Var', (19, 28))	('induced', 'Reg', (67, 74))	('Hec1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('Hec1', 'Gene', '10403', (14, 18))	('mitotic abnormalities and cell death', 'Disease', 'MESH:D003643', (75, 111))	('tumor', 'Disease', (32, 37))
38936	28615236	Implications of over-expression and silencing of Ndc80 in the tumorigenesis of pancreatic cancer has recently been illustrated.	('Ndc80', 'Gene', (49, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('pancreatic cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (62, 67))	('over-expression', 'PosReg', (16, 31))	('silencing', 'Var', (36, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
38938	28615236	Disruption of Ndc80 and Nuf2 complex formation using a small molecule inhibitor, INH1, has been shown to reduce proliferation in breast cancer cells and reduce tumor growth in a xenograft mouse model.	('breast cancer', 'Disease', (129, 142))	('reduce', 'NegReg', (153, 159))	('mouse', 'Species', '10090', (188, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('reduce', 'NegReg', (105, 111))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('complex', 'Interaction', (29, 36))	('INH1', 'Gene', (81, 85))	('Nuf2', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('formation', 'biological_process', 'GO:0009058', ('37', '46'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Ndc80', 'Gene', (14, 19))	('tumor', 'Disease', (160, 165))	('proliferation', 'CPA', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Disruption', 'Var', (0, 10))
38939	28615236	The siRNA mediated knockdown of Ndc80 and Nuf2 has been shown to induce abnormal mitotic exit and apoptosis in colorectal cancer and gastric cancer cell lines.	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('apoptosis', 'CPA', (98, 107))	('mitotic exit', 'CPA', (81, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('knockdown', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Ndc80', 'Gene', (32, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('Nuf2', 'Gene', (42, 46))	('induce', 'Reg', (65, 71))	('mitotic exit', 'biological_process', 'GO:0010458', ('81', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('gastric cancer', 'Disease', (133, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))
38940	28615236	Targeted knockdown of Knl1 (a constituent of KMN network), a member of the cancer/testis gene family that is predominantly expressed in the testis and widely expressed in primary tumors of different origins, induced apoptotic cell death in human cancer cell lines in vitro independent of the p53 status and markedly impeded the growth of implanted tumors in vivo.	('human', 'Species', '9606', (240, 245))	('testis', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('Knl1', 'Gene', '57082', (22, 26))	('p53', 'Gene', '7157', (292, 295))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('induced', 'Reg', (208, 215))	('cancer', 'Disease', (246, 252))	('testis', 'Disease', 'MESH:D013736', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('impeded', 'NegReg', (316, 323))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('apoptotic cell death', 'CPA', (216, 236))	('tumors', 'Disease', (348, 354))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('p53', 'Gene', (292, 295))	('knockdown', 'Var', (9, 18))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('testis', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('tumors', 'Disease', (179, 185))	('cancer', 'Disease', (75, 81))	('testis', 'Disease', 'MESH:D013736', (82, 88))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('216', '236'))	('Knl1', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
38944	28615236	Perturbation of function of both the Ndc80 complex and Cdt1 interfere with the spindle assembly checkpoint which is defective in cancer cells, hence promote them to divide uncontrollably.	('Ndc80 complex', 'cellular_component', 'GO:0031262', ('37', '50'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('spindle assembly checkpoint', 'CPA', (79, 106))	('Cdt1', 'Gene', '81620', (55, 59))	('promote', 'PosReg', (149, 156))	('interfere', 'NegReg', (60, 69))	('Ndc80', 'Gene', (37, 42))	('divide', 'CPA', (165, 171))	('cancer', 'Disease', (129, 135))	('Cdt1', 'Gene', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Perturbation', 'Var', (0, 12))	('spindle assembly checkpoint', 'biological_process', 'GO:0071173', ('79', '106'))	('spindle', 'cellular_component', 'GO:0005819', ('79', '86'))	('function', 'MPA', (16, 24))
38945	28615236	Over-expression of Cdt1 has been associated with many human cancers.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cdt1', 'Gene', '81620', (19, 23))	('associated', 'Reg', (33, 43))	('Over-expression', 'Var', (0, 15))	('Cdt1', 'Gene', (19, 23))	('human', 'Species', '9606', (54, 59))
38950	28615236	Thus, according to the kMT stabilostat model proposed by Bakhoum et al., hypostable kMT attachments fail to adequately satisfy the SAC leading to mitotic delay/arrest, while hyperstable attachments cannot undergo appropriate error correction and persist to carry the attachment errors into anaphase leading to chromosomal missegregation and CIN.	('leading to', 'Reg', (299, 309))	('errors', 'Var', (278, 284))	('SAC', 'biological_process', 'GO:0071173', ('131', '134'))	('CIN', 'Phenotype', 'HP:0040012', (341, 344))	('attachment errors', 'Var', (267, 284))	('SAC', 'cellular_component', 'GO:0035003', ('131', '134'))	('anaphase', 'biological_process', 'GO:0051322', ('290', '298'))	('chromosomal missegregation', 'CPA', (310, 336))	('CIN', 'Disease', (341, 344))	('CIN', 'Disease', 'MESH:D007674', (341, 344))
38958	28615236	Moreover, Bub1 binding to KT is achieved by Mps1 kinase-mediated phosphorylation of MELT repeats on Knl1, a protein within the KMN network.	('Knl1', 'Gene', (100, 104))	('Bub1', 'Gene', '699', (10, 14))	('binding', 'molecular_function', 'GO:0005488', ('15', '22'))	('Knl1', 'Gene', '57082', (100, 104))	('Mps1', 'Gene', (44, 48))	('MELT repeats', 'Var', (84, 96))	('Bub1', 'Gene', (10, 14))	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('binding', 'Interaction', (15, 22))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('Mps1', 'Gene', '219972', (44, 48))
38960	28615236	A study using a low-molecular weight inhibitor of Mps1 showed that the inhibitor could decrease the proliferation and viability of both tumor and non-cancer cells but induces apoptosis via Poly (ADP-ribose) polymerase (PARP) cleavage specifically in the malignant cells.	('induces', 'Reg', (167, 174))	('cleavage', 'MPA', (225, 233))	('inhibitor', 'Var', (71, 80))	('Poly (ADP-ribose) polymerase', 'Gene', (189, 217))	('PARP', 'Gene', '142', (219, 223))	('Mps1', 'Gene', (50, 54))	('PARP', 'Gene', (219, 223))	('viability', 'CPA', (118, 127))	('tumor', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('non-cancer', 'Disease', 'MESH:D009369', (146, 156))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('non-cancer', 'Disease', (146, 156))	('apoptosis', 'CPA', (175, 184))	('Poly (ADP-ribose) polymerase', 'Gene', '142', (189, 217))	('decrease', 'NegReg', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Mps1', 'Gene', '219972', (50, 54))
38961	28615236	Therefore, even though the specificity and effectiveness of using small molecule inhibitors against the kinases like Mps1 and Bub1 in terms of targeting only tumor cells and sparing healthy cells warrants further investigation, Mps1 inhibitors have been promising in preclinical trials with some entering into the phase I clinical trials.	('tumor', 'Disease', (158, 163))	('Mps1', 'Gene', (228, 232))	('Bub1', 'Gene', '699', (126, 130))	('Bub1', 'Gene', (126, 130))	('clinical', 'Species', '191496', (270, 278))	('inhibitors', 'Var', (233, 243))	('Mps1', 'Gene', '219972', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('clinical', 'Species', '191496', (322, 330))	('Mps1', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Mps1', 'Gene', '219972', (228, 232))
38963	28615236	Several human tumor cells have been shown to harbor mutations in mitotic SAC genes encoding Bub1, BubR1, Mad1, Mad2 and in all the three members of Zw10-Rod-Zwilch complex.	('Mad1', 'Gene', (105, 109))	('BubR1', 'Gene', '701', (98, 103))	('Mad1', 'Gene', '8379', (105, 109))	('Mad', 'biological_process', 'GO:0072671', ('111', '114'))	('Mad', 'biological_process', 'GO:0072671', ('105', '108'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Zw10', 'Gene', (148, 152))	('BubR1', 'Gene', (98, 103))	('SAC', 'cellular_component', 'GO:0035003', ('73', '76'))	('human', 'Species', '9606', (8, 13))	('Zw10', 'Gene', '9183', (148, 152))	('Mad2', 'Gene', (111, 115))	('Bub1', 'Gene', (92, 96))	('mutations', 'Var', (52, 61))	('tumor', 'Disease', (14, 19))	('SAC', 'biological_process', 'GO:0071173', ('73', '76'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('Mad2', 'Gene', '4085', (111, 115))	('Bub1', 'Gene', '699', (92, 96))
38964	28615236	In prostate and pancreatic cancers, amino acids for Mad1 (R59C, R556C, R359Q and frameshift generating a stop codon at amino acid 318) and Bub1 (Y259C, H265N) are disrupted, respectively.	('R59C', 'Mutation', 'rs121908982', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pancreatic cancers', 'Disease', (16, 34))	('H265N', 'Var', (152, 157))	('R359Q', 'Mutation', 'p.R359Q', (71, 76))	('Bub1', 'Gene', '699', (139, 143))	('Y259C', 'Mutation', 'p.Y259C', (145, 150))	('pancreatic cancers', 'Disease', 'MESH:D010190', (16, 34))	('frameshift', 'Var', (81, 91))	('R556C', 'Var', (64, 69))	('R59C', 'Var', (58, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('Mad', 'biological_process', 'GO:0072671', ('52', '55'))	('Bub1', 'Gene', (139, 143))	('R359Q', 'Var', (71, 76))	('R556C', 'Mutation', 'rs371561369', (64, 69))	('H265N', 'Mutation', 'p.H265N', (152, 157))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('Mad1', 'Gene', (52, 56))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (16, 34))	('prostate', 'Disease', (3, 11))	('Mad1', 'Gene', '8379', (52, 56))
38968	28615236	Tau, an extensively investigated MAP is shown to be variably expressed in breast cancer cells and consistent with its MT-stabilizing function, loss of Tau expression was shown to sensitize breast cancer cells to the effect of paclitaxel.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Tau', 'Gene', (151, 154))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer', 'Disease', (189, 202))	('MAP', 'molecular_function', 'GO:0004239', ('33', '36'))	('sensitize', 'Reg', (179, 188))	('loss', 'Var', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (226, 236))
38970	28615236	Besides this, expression of MAP2 has been associated with increased sensitivity to MTAs in docetaxel-sensitive pancreatic ductal adenocarcinoma.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (111, 143))	('expression', 'Var', (14, 24))	('increased', 'PosReg', (58, 67))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (111, 143))	('MAP', 'molecular_function', 'GO:0004239', ('28', '31'))	('MAP2', 'Gene', (28, 32))	('associated', 'Reg', (42, 52))	('MAP2', 'Gene', '4133', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('sensitivity to MTAs', 'MPA', (68, 87))	('docetaxel', 'Chemical', 'MESH:D000077143', (91, 100))	('pancreatic ductal adenocarcinoma', 'Disease', (111, 143))
38971	28615236	Phosphorylated MAP4, a ubiquitously expressed MAP, has been correlated with a decrease in Taxol sensitivity in ovarian cancer cells lines.	('Phosphorylated', 'Var', (0, 14))	('ovarian cancer', 'Disease', (111, 125))	('decrease', 'NegReg', (78, 86))	('Taxol sensitivity', 'MPA', (90, 107))	('MAP', 'molecular_function', 'GO:0004239', ('15', '18'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('MAP', 'molecular_function', 'GO:0004239', ('46', '49'))	('Taxol', 'Chemical', 'MESH:D017239', (90, 95))	('MAP4', 'Gene', (15, 19))	('MAP4', 'Gene', '4134', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
38974	28615236	Targeting Stathmin using antisense in K562 leukemia cell line resulted in abrogation of malignant phenotype.	('leukemia', 'Disease', (43, 51))	('Stathmin', 'Gene', (10, 18))	('malignant phenotype', 'CPA', (88, 107))	('K562', 'CellLine', 'CVCL:0004', (38, 42))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('abrogation', 'NegReg', (74, 84))	('antisense', 'Var', (25, 34))	('leukemia', 'Disease', 'MESH:D007938', (43, 51))	('Stathmin', 'Gene', '3925', (10, 18))
38975	28615236	Similarly, adenovirus mediated delivery of anti-stathmin ribozymes in prostate cancer cells resulted in massive dose-dependent inhibition of proliferation, accumulation of cells in G2-M and apoptosis.	('stathmin', 'Gene', (48, 56))	('stathmin', 'Gene', '3925', (48, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('190', '199'))	('proliferation', 'CPA', (141, 154))	('cells in G2-M', 'CPA', (172, 185))	('inhibition', 'NegReg', (127, 137))	('accumulation', 'PosReg', (156, 168))	('ribozymes', 'Var', (57, 66))	('prostate cancer', 'Disease', (70, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('190', '199'))	('apoptosis', 'CPA', (190, 199))
38991	28615236	Therefore, any abnormality in choreography of these highly coordinated events is catastrophic leading to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('abnormality', 'Var', (15, 26))	('leading to', 'Reg', (94, 104))
38997	28615236	Although, mutations or de-regulation of Cdk1 has not been reported in cancer, inhibition of Cdk1 has been shown to induce cell cycle arrest and apoptosis in breast cancer and gastric carcinoma.	('gastric carcinoma', 'Disease', 'MESH:D013274', (175, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('gastric carcinoma', 'Disease', (175, 192))	('Cdk1', 'Gene', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (175, 192))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('Cdk1', 'Gene', '983', (92, 96))	('breast cancer', 'Disease', (157, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('Cdk', 'molecular_function', 'GO:0004693', ('40', '43'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('122', '139'))	('cancer', 'Disease', (70, 76))	('de-regulation', 'NegReg', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Cdk1', 'Gene', (40, 44))	('cancer', 'Disease', (164, 170))	('regulation', 'biological_process', 'GO:0065007', ('26', '36'))	('Cdk1', 'Gene', '983', (40, 44))	('cell cycle arrest', 'CPA', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Cdk', 'molecular_function', 'GO:0004693', ('92', '95'))	('inhibition', 'Var', (78, 88))	('apoptosis', 'CPA', (144, 153))	('induce', 'PosReg', (115, 121))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
39012	28615236	Concomitantly, knockdown of Plk1 using antisense oligonucleotides or RNAi showed reduced cellular proliferation and a corresponding increase in cell death in many cancer cell lines including prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Plk1', 'Gene', '5347', (28, 32))	('reduced', 'NegReg', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('Plk1', 'Gene', (28, 32))	('increase', 'PosReg', (132, 140))	('cell death', 'CPA', (144, 154))	('antisense oligonucleotides', 'Var', (39, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (191, 206))	('oligonucleotides', 'Chemical', 'MESH:D009841', (49, 65))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('prostate cancer', 'Phenotype', 'HP:0012125', (191, 206))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('RNAi', 'biological_process', 'GO:0016246', ('69', '73'))	('prostate cancer', 'Disease', (191, 206))	('cancer', 'Disease', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cellular proliferation', 'CPA', (89, 111))	('cancer', 'Disease', (200, 206))
39022	28615236	The outward force created by Kif11 and Kif15 is counteracted by KifC1 (a Kinesin-14 motor), a minus-end directed motor, to help maintain the spindle length.	('KifC1', 'Gene', '3833', (64, 69))	('Kif15', 'Gene', (39, 44))	('Kinesin', 'molecular_function', 'GO:0003777', ('73', '80'))	('spindle length', 'CPA', (141, 155))	('Kif15', 'Gene', '56992', (39, 44))	('spindle', 'cellular_component', 'GO:0005819', ('141', '148'))	('KifC1', 'Gene', (64, 69))	('Kif11', 'Var', (29, 34))
39026	28615236	Very early studies in Drosophila and Xenopus had demonstrated that the inactivation of respective Kif11 homologues, KLP61F and Eg5 led to mitotic arrest with accumulation of monoastral spindle.	('Eg5', 'Gene', (127, 130))	('Drosophila', 'Species', '7227', (22, 32))	('KLP61F', 'Gene', '38135', (116, 122))	('accumulation', 'PosReg', (158, 170))	('monoastral spindle', 'CPA', (174, 192))	('KLP61F', 'Gene', (116, 122))	('Kif11', 'Gene', (98, 103))	('mitotic arrest', 'Disease', (138, 152))	('Xenopus', 'Species', '8355', (37, 44))	('mitotic arrest', 'Disease', 'MESH:D006323', (138, 152))	('spindle', 'cellular_component', 'GO:0005819', ('185', '192'))	('inactivation', 'Var', (71, 83))
39032	28615236	Following the suite is CENP-E which is also found to be expressed in elevated levels in several tumors and thus its inhibitors like GSK923295A have been developed that induced mitotic delay, apoptosis and tumor regression.	('apoptosis', 'CPA', (191, 200))	('induced', 'PosReg', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumors', 'Disease', (96, 102))	('GSK923295A', 'Chemical', 'MESH:C571460', (132, 142))	('CENP-E', 'Gene', '1062', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mitotic delay', 'CPA', (176, 189))	('GSK', 'molecular_function', 'GO:0050321', ('132', '135'))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('191', '200'))	('apoptosis', 'biological_process', 'GO:0006915', ('191', '200'))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (205, 210))	('GSK923295A', 'Var', (132, 142))	('CENP-E', 'Gene', (23, 29))
39038	28615236	Many reviews expansively document the various studies that highlight the amplification of various Kinesin genes in cancer.	('cancer', 'Disease', (115, 121))	('Kinesin genes', 'Gene', (98, 111))	('Kinesin', 'molecular_function', 'GO:0003777', ('98', '105'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('amplification', 'Var', (73, 86))
39041	28615236	Depletion of MCAK has been found to increase the sensitivity of paclitaxel-resistant cells to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('increase', 'PosReg', (36, 44))	('sensitivity', 'MPA', (49, 60))	('MCAK', 'Gene', (13, 17))	('MCAK', 'Gene', '11004', (13, 17))	('Depletion', 'Var', (0, 9))	('paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))
39044	28615236	Dr. Mulder's laboratory previously had shown that km23-1, a light chain of dynein (also called DYNLRB1/LC7-1/robl-1/DNLC2A/DYRB1) is defective in 50% of ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('defective', 'NegReg', (133, 142))	('dynein', 'molecular_function', 'GO:0003777', ('75', '81'))	('DNLC2A', 'Gene', (116, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('km23-1', 'Var', (50, 56))	('DYNLRB1', 'Gene', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('DNLC2A', 'Gene', '83658', (116, 122))	('ovarian cancers', 'Phenotype', 'HP:0100615', (153, 168))	('ovarian cancers', 'Disease', (153, 168))	('DYNLRB1', 'Gene', '83658', (95, 102))
39047	28615236	Usually mitotic inhibitors rely on the induction of apoptosis by prolonged mitotic arrest attained via activation of the SAC resulting from aberrant spindle dynamics.	('mitotic arrest', 'Disease', 'MESH:D006323', (75, 89))	('SAC', 'cellular_component', 'GO:0035003', ('121', '124'))	('aberrant', 'Var', (140, 148))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('39', '61'))	('spindle', 'cellular_component', 'GO:0005819', ('149', '156'))	('SAC', 'biological_process', 'GO:0071173', ('121', '124'))	('mitotic arrest', 'Disease', (75, 89))
39052	28615236	Moreover, deregulated expression and mutations in APC/C subunits or its co-activators (Cdc20 and Cdh1) have been linked with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Cdc20', 'Gene', (87, 92))	('APC', 'Gene', '324', (50, 53))	('APC', 'cellular_component', 'GO:0005680', ('50', '53'))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('Cdh1', 'Gene', (97, 101))	('mutations', 'Var', (37, 46))	('Cdh1', 'Gene', '999', (97, 101))	('deregulated', 'Var', (10, 21))	('APC', 'Gene', (50, 53))	('linked', 'Reg', (113, 119))	('expression', 'MPA', (22, 32))
39053	28615236	Accordingly, depletion of Cdc20 was able to elicit metaphase arrest in cell lines and killing of tumor cells in a mouse model.	('metaphase arrest in', 'CPA', (51, 70))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('elicit', 'Reg', (44, 50))	('depletion', 'Var', (13, 22))	('tumor', 'Disease', (97, 102))	('mouse', 'Species', '10090', (114, 119))	('killing', 'CPA', (86, 93))	('Cdc20', 'Gene', (26, 31))	('metaphase', 'biological_process', 'GO:0051323', ('51', '60'))
39067	28615236	One of the HDACs, HDAC3, was shown to be localized on the mitotic spindle and its knockdown resulted in impaired kMT attachments, collapsed spindle surrounded by a dome-like configuration of chromosomes and subsequent activation of SAC in HDAC3-depleted cells.	('SAC', 'biological_process', 'GO:0071173', ('232', '235'))	('impaired', 'NegReg', (104, 112))	('HDAC3', 'Gene', '8841', (18, 23))	('HDAC3', 'Gene', (18, 23))	('activation', 'PosReg', (218, 228))	('SAC', 'MPA', (232, 235))	('kMT attachments', 'CPA', (113, 128))	('knockdown', 'Var', (82, 91))	('SAC', 'cellular_component', 'GO:0035003', ('232', '235'))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('58', '73'))	('HDAC3', 'Gene', '8841', (239, 244))	('spindle', 'cellular_component', 'GO:0005819', ('140', '147'))	('HDAC3', 'Gene', (239, 244))
39069	28615236	Since Aurora B kinase is more active in deacetylated state, inhibition of HDAC3, a substrate for this kinase, resulted in reduced kinase activity and significant defects in Aurora B-dependent mitotic processes, including kMT attachment and chromosome congression.	('Aurora B', 'Gene', '9212', (173, 181))	('inhibition', 'Var', (60, 70))	('defects', 'NegReg', (162, 169))	('chromosome congression', 'biological_process', 'GO:0051310', ('240', '262'))	('kMT attachment', 'CPA', (221, 235))	('Aurora B', 'Gene', (6, 14))	('chromosome congression', 'CPA', (240, 262))	('Aurora B', 'Gene', '9212', (6, 14))	('HDAC3', 'Gene', '8841', (74, 79))	('kinase activity', 'MPA', (130, 145))	('HDAC3', 'Gene', (74, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('240', '250'))	('reduced', 'NegReg', (122, 129))	('Aurora B', 'Gene', (173, 181))	('kinase activity', 'molecular_function', 'GO:0016301', ('130', '145'))
39090	28615236	Moreover, cancer cells that make aberrant amounts of Cdt1 are expected to experience problems in both replication and mitosis and thus artificially ramping up Cdt1 in such cells is envisioned to push them through an apoptotic pathway.	('mitosis', 'Disease', (118, 125))	('mitosis', 'biological_process', 'GO:0000278', ('118', '125'))	('mitosis', 'Disease', 'None', (118, 125))	('replication', 'CPA', (102, 113))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Cdt1', 'Gene', '81620', (159, 163))	('Cdt1', 'Gene', '81620', (53, 57))	('aberrant', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('Cdt1', 'Gene', (159, 163))	('apoptotic pathway', 'Pathway', (216, 233))	('ramping up', 'PosReg', (148, 158))	('Cdt1', 'Gene', (53, 57))	('push', 'PosReg', (195, 199))
39143	28423676	In addition, we applied two TGF-beta1/Smad2/3 signaling pathway inhibitors, LY364947 and SB431542, to separately pretreated A549 and H1299 cells.	('LY364947', 'Var', (76, 84))	('TGF-beta1', 'Gene', '7040', (28, 37))	('Smad2/3', 'Gene', '4087;4088', (38, 45))	('TGF-beta1', 'Gene', (28, 37))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('LY364947', 'Chemical', 'MESH:C520284', (76, 84))	('SB431542', 'Var', (89, 97))	('H1299', 'CellLine', 'CVCL:0060', (133, 138))	('signaling pathway', 'biological_process', 'GO:0007165', ('46', '63'))	('SB431542', 'Chemical', 'MESH:C459179', (89, 97))	('Smad2/3', 'Gene', (38, 45))
39144	28423676	When A549 and H1299 cells were incubated with TCM and treated with LY364947 and SB431542, FUT4/LeY expression was partially suppressed (Figure 2C).	('SB431542', 'Chemical', 'MESH:C459179', (80, 88))	('SB431542', 'Var', (80, 88))	('FUT4', 'Gene', (90, 94))	('LY364947', 'Var', (67, 75))	('FUT4', 'Gene', '2526', (90, 94))	('LY364947', 'Chemical', 'MESH:C520284', (67, 75))	('A549', 'CellLine', 'CVCL:0023', (5, 9))	('suppressed', 'NegReg', (124, 134))	('H1299', 'CellLine', 'CVCL:0060', (14, 19))
39168	28423676	To confirm the specific effect of FUT4/LeY on the Ezrin phosphorylation in EMT process, we constructed the WT and T567D-mutant Ezrin vector and transfected them into A549-shFUT4 cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('FUT4', 'Gene', '2526', (34, 38))	('T567D', 'Mutation', 'p.T567D', (114, 119))	('FUT4', 'Gene', (173, 177))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('EMT', 'biological_process', 'GO:0001837', ('75', '78'))	('T567D-mutant', 'Var', (114, 126))	('FUT4', 'Gene', '2526', (173, 177))	('FUT4', 'Gene', (34, 38))
39169	28423676	Western blots analysis showed that the down-regulation of Ezrin phosphorylation and mesenchymal markers after knockdown of FUT4 can be counteracted by the overexpression of WT Ezrin but not T567D-mutant Ezrin (Figure 4G and 4H).	('knockdown', 'Var', (110, 119))	('FUT4', 'Gene', '2526', (123, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('down-regulation', 'NegReg', (39, 54))	('T567D', 'Mutation', 'p.T567D', (190, 195))	('FUT4', 'Gene', (123, 127))	('mesenchymal markers', 'CPA', (84, 103))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))	('Ezrin', 'Protein', (58, 63))	('T567D-mutant', 'Var', (190, 202))
39213	28423676	Our previous studies confirmed that phosphorylated Ezrin could mediate EMT in pancreatic cancer cells through the FAK pathway and promote invasion and metastasis.	('phosphorylated', 'Var', (36, 50))	('promote', 'PosReg', (130, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('EMT', 'biological_process', 'GO:0001837', ('71', '74'))	('FAK', 'Gene', '5747', (114, 117))	('mediate', 'Reg', (63, 70))	('pancreatic cancer', 'Disease', (78, 95))	('FAK', 'molecular_function', 'GO:0004717', ('114', '117'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('Ezrin', 'Protein', (51, 56))	('FAK', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
39214	28423676	In this study, during the EMT induced by TCM, Ezrin phosphorylation (T567) increased significantly (Figure 4A), which is similar to the expression of FUT4/LeY (Figure 2B).	('FUT4', 'Gene', '2526', (150, 154))	('EMT', 'biological_process', 'GO:0001837', ('26', '29'))	('TCM', 'Var', (41, 44))	('FUT4', 'Gene', (150, 154))	('increased', 'PosReg', (75, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))
39228	28423676	A549 cells were cultured in F12K medium supplemented with 10% fetal bovine serum (FBS; Invitrogen, Tokyo, Japan).	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('bovine', 'Species', '9913', (68, 74))	('FBS', 'Disease', 'MESH:D005198', (82, 85))	('F12K', 'SUBSTITUTION', 'None', (28, 32))	('F12K', 'Var', (28, 32))	('FBS', 'Disease', (82, 85))
39249	28423676	Membranes were blocked in a buffer (TBS: 50 mM Tris-HCl, 150 mM NaCl, pH 7.4) containing 5% bovine serum albumin and 0.1% Tween-20, followed by incubation with the primary antibodys Phospho-Smad2 (Ser465/467)/Smad3 (Ser423/425)( D27F4, 1:1,000, CST), FUT4 (ab181461, 1:1,000, Abcam), LeY (BG-8,1:200, Abcam), N-Cadherin (ab18203, 1:1,000, Abcam), Fibronectin (ab2413, 1:2,000, Abcam), Vimentin (ab8978, 1:2,000, Abcam), ZEB1 (D80D3, 1:2,000, CST), Snail (ab53519, 1:2,000, Abcam), Ezrin (#3145, 1:2000, CST), UEA (LifeSpan BioSciences), p-Ezrin (Thr567) (#3726, 1:1000, CST) or beta-actin (20536-1-AP, 1:2,000, Proteintech) diluted in the same buffer.	('CST', 'Gene', (442, 445))	('Ser', 'cellular_component', 'GO:0005790', ('216', '219'))	('ZEB1', 'Gene', (420, 424))	('Smad2', 'Gene', '4087', (190, 195))	('Snail', 'Gene', (448, 453))	('CST', 'Gene', (503, 506))	('FUT4', 'Gene', '2526', (251, 255))	('CST', 'Gene', '106478911', (245, 248))	('N-Cadherin', 'Gene', (309, 319))	('N-Cadherin', 'Gene', '1000', (309, 319))	('CST', 'Gene', '106478911', (570, 573))	('FUT4', 'Gene', (251, 255))	('Ser', 'cellular_component', 'GO:0005790', ('197', '200'))	('Vimentin', 'cellular_component', 'GO:0045099', ('385', '393'))	('Smad2', 'Gene', (190, 195))	('Vimentin', 'Gene', '7431', (385, 393))	('20536-1-AP', 'Var', (590, 600))	('ZEB1', 'Gene', '6935', (420, 424))	('Fibronectin', 'Gene', '2335', (347, 358))	('CST', 'Gene', '106478911', (442, 445))	('N', 'Chemical', 'MESH:D009584', (309, 310))	('Tris', 'Chemical', '-', (47, 51))	('CST', 'Gene', (245, 248))	('bovine', 'Species', '9913', (92, 98))	('Snail', 'Gene', '6615', (448, 453))	('AP, 1', 'cellular_component', 'GO:0005907', ('598', '603'))	('Vimentin', 'Gene', (385, 393))	('CST', 'Gene', (570, 573))	('Smad3', 'Gene', '4088', (209, 214))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('Fibronectin', 'Gene', (347, 358))	('Smad3', 'Gene', (209, 214))	('CST', 'Gene', '106478911', (503, 506))	('Vimentin', 'cellular_component', 'GO:0045098', ('385', '393'))	('Cadherin', 'molecular_function', 'GO:0008014', ('311', '319'))
39265	28256611	P. aeruginosa formed antibiotic resistant biofilms on 3-D cells without affecting cell viability.	('P. aeruginosa', 'Var', (0, 13))	('P. aeruginosa', 'Species', '287', (0, 13))	('antibiotic resistant', 'MPA', (21, 41))
39275	28256611	Furthermore, during chronic lung infections, such as in individuals with cystic fibrosis, P. aeruginosa forms biofilms - a phenotype that contributes to high (adaptive) antibiotic resistance and mediates long-term host colonization.	('high', 'PosReg', (153, 157))	('lung infections', 'Disease', 'MESH:D008171', (28, 43))	('P. aeruginosa', 'Species', '287', (90, 103))	('cystic fibrosis', 'Disease', 'MESH:D003550', (73, 88))	('P. aeruginosa', 'Var', (90, 103))	('lung infections', 'Phenotype', 'HP:0006532', (28, 43))	('cystic fibrosis', 'Disease', (73, 88))	('lung infections', 'Disease', (28, 43))	('chronic lung infections', 'Phenotype', 'HP:0002783', (20, 43))
39281	28256611	In addition to the above-mentioned in vivo-like characteristics of normal cells, the 3-D epithelial model that was derived from A549 cells showed lower expression of cancer markers when compared to conventional A549 monolayers, thus reflecting a more normal differentiated tissue phenotype.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('lower', 'NegReg', (146, 151))	('A549', 'Var', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('A549', 'CellLine', 'CVCL:0023', (211, 215))	('expression', 'MPA', (152, 162))
39283	28256611	(2005) demonstrated an infection profile with P. aeruginosa that was more relevant to the in vivo scenario, with regards to bacterial adhesion and invasion, and host-secreted cytokines.	('P. aeruginosa', 'Var', (46, 59))	('P. aeruginosa', 'Species', '287', (46, 59))	('bacterial adhesion', 'CPA', (124, 142))	('invasion', 'CPA', (147, 155))
39291	28256611	In the present study, we found that P. aeruginosa formed biofilms on 3-D A549 lung epithelial cells that could not be eradicated with high concentrations of antibiotics, hereby mimicking aspects of the in vivo bacterial phenotype.	('P. aeruginosa', 'Var', (36, 49))	('P. aeruginosa', 'Species', '287', (36, 49))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('biofilms', 'CPA', (57, 65))
39324	28256611	Bacterial association with 3-D cells or plastic was slightly affected by 50 mug/mL DJK-5 (Fig.	('50 mug/mL', 'Var', (73, 82))	('mug', 'molecular_function', 'GO:0043739', ('76', '79'))	('Bacterial', 'CPA', (0, 9))	('DJK-5', 'Chemical', '-', (83, 88))	('DJK-5', 'Gene', (83, 88))
39355	28256611	In addition, P. aeruginosa biofilms pre-formed on cystic fibrosis bronchial epithelial (CFBE) cells were previously found to exert enhanced tolerance to antimicrobial agents as compared to biofilms grown on plastic.	('cystic fibrosis', 'Disease', (50, 65))	('fibrosis bronchial epithelial', 'Disease', 'MESH:D005355', (57, 86))	('P. aeruginosa', 'Var', (13, 26))	('pre', 'molecular_function', 'GO:0003904', ('36', '39'))	('tolerance', 'CPA', (140, 149))	('P. aeruginosa', 'Species', '287', (13, 26))	('enhanced', 'PosReg', (131, 139))	('cystic fibrosis', 'Disease', 'MESH:D003550', (50, 65))	('fibrosis bronchial epithelial', 'Disease', (57, 86))
39357	28256611	Recently, biofilm formation by P. aeruginosa was found to be inhibited by an antimicrobial peptide (WLBU2) both when biofilms were formed on plastic or on CFBE cells.	('biofilm formation', 'CPA', (10, 27))	('P. aeruginosa', 'Species', '287', (31, 44))	('inhibited', 'NegReg', (61, 70))	('P. aeruginosa', 'Var', (31, 44))	('biofilm formation', 'biological_process', 'GO:0042710', ('10', '27'))
39415	27432227	Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases.	('mutations', 'Var', (101, 110))	('crizotinib', 'Chemical', 'MESH:D000077547', (162, 172))	('crizotinib', 'Chemical', 'MESH:D000077547', (76, 86))	('ALK', 'Gene', (97, 100))
39417	27432227	We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents.	('G1202R', 'Mutation', 'rs1057519783', (144, 150))	('increases', 'PosReg', (153, 162))	('ALK', 'Gene', (74, 77))	('G1202R -', 'Var', (144, 152))
39418	27432227	To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.	('ceritinib', 'Chemical', 'MESH:C586847', (174, 183))	('ALK', 'Gene', (256, 259))	('patient', 'Species', '9606', (195, 202))	('lorlatinib', 'Chemical', 'MESH:C000590786', (148, 158))	('lorlatinib', 'Chemical', 'MESH:C000590786', (321, 331))	('sensitivity to lorlatinib', 'MPA', (306, 331))	('mutations', 'Var', (271, 280))
39419	27432227	Anaplastic lymphoma kinase (ALK) rearrangements define a distinct molecular subtype of non-small cell lung cancer (NSCLC; ref).	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (87, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('NSCLC', 'Disease', (115, 120))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('rearrangements', 'Var', (33, 47))	('ALK', 'Gene', (28, 31))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (91, 113))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (87, 113))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('SCLC', 'Phenotype', 'HP:0030357', (116, 120))	('non-small cell lung cancer', 'Disease', (87, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
39422	27432227	In randomized phase III trials, crizotinib produced significant improvements in objective response rates (ORRs) and progression-free survival (PFS) compared to cytotoxic chemotherapy, establishing crizotinib as a standard treatment for advanced ALK-positive NSCLC.	('NSCLC', 'Disease', (258, 263))	('crizotinib', 'Chemical', 'MESH:D000077547', (32, 42))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('crizotinib', 'Chemical', 'MESH:D000077547', (197, 207))	('objective', 'MPA', (80, 89))	('improvements', 'PosReg', (64, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('crizotinib', 'Var', (32, 42))	('SCLC', 'Phenotype', 'HP:0030357', (259, 263))	('progression-free survival', 'CPA', (116, 141))
39425	27432227	Broadly speaking, such mechanisms have been classified as involving either on-target genetic alterations (e.g., ALK resistance mutations, ALK gene amplification) or off-target mechanisms of resistance (e.g., up-regulation of bypass signaling pathways, such as EGFR, KIT, IGF-1R, SRC, MEK/ERK and others; ref).	('EGFR', 'Gene', (260, 264))	('up-regulation', 'PosReg', (208, 221))	('IGF-1R', 'Gene', '3480', (271, 277))	('MEK', 'Gene', (284, 287))	('KIT', 'molecular_function', 'GO:0005020', ('266', '269'))	('SRC', 'Gene', (279, 282))	('IGF-1R', 'Gene', (271, 277))	('ERK', 'Gene', (288, 291))	('ALK', 'Gene', (138, 141))	('EGFR', 'Gene', '1956', (260, 264))	('mutations', 'Var', (127, 136))	('ALK resistance', 'Gene', (112, 126))	('ERK', 'Gene', '2048', (288, 291))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('ERK', 'molecular_function', 'GO:0004707', ('288', '291'))	('regulation', 'biological_process', 'GO:0065007', ('211', '221'))	('EGFR', 'molecular_function', 'GO:0005006', ('260', '264'))	('SRC', 'Gene', '6714', (279, 282))	('bypass signaling pathways', 'Pathway', (225, 250))	('MEK', 'Gene', '5609', (284, 287))
39430	27432227	In preclinical models, second-generation ALK inhibitors overcome several crizotinib-resistant ALK mutations.	('mutations', 'Var', (98, 107))	('crizotinib', 'Chemical', 'MESH:D000077547', (73, 83))	('ALK', 'Gene', (94, 97))
39435	27432227	Using a combination of genetic sequencing, histological analyses and functional drug screens, we find that the frequency and spectrum of ALK resistance mutations evolve as patients relapse on different ALK inhibitors.	('ALK resistance', 'Gene', (137, 151))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (152, 161))
39436	27432227	Moreover, in a series of ceritinib-resistant, patient-derived cell lines, we demonstrate that the presence of ALK resistance mutations is associated with sensitivity to the novel, third-generation ALK inhibitor lorlatinib.	('mutations', 'Var', (125, 134))	('patient', 'Species', '9606', (46, 53))	('ceritinib', 'Chemical', 'MESH:C586847', (25, 34))	('associated', 'Reg', (138, 148))	('lorlatinib', 'Chemical', 'MESH:C000590786', (211, 221))	('ALK resistance', 'Gene', (110, 124))	('sensitivity to', 'MPA', (154, 168))
39437	27432227	In contrast, cell lines without ALK resistance mutations are resistant to lorlatinib.	('lorlatinib', 'Chemical', 'MESH:C000590786', (74, 84))	('resistant', 'MPA', (61, 70))	('mutations', 'Var', (47, 56))
39442	27432227	We first investigated the frequency of ALK resistance mutations in 51 ALK-positive patients progressing on crizotinib.	('crizotinib', 'Chemical', 'MESH:D000077547', (107, 117))	('ALK resistance', 'Gene', (39, 53))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (83, 91))
39448	27432227	ALK resistance mutations were identified in 11 (20%) specimens (Figure 1A) among 10 (20%) patients.	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (90, 98))	('ALK resistance', 'Gene', (0, 14))
39449	27432227	Consistent with prior reports, the most common ALK resistance mutations were L1196M and G1269A, but these were present in only 7% and 4% of all of the crizotinib-resistant specimens, respectively.	('ALK resistance', 'Gene', (47, 61))	('L1196M', 'Mutation', 'rs1057519784', (77, 83))	('L1196M', 'Var', (77, 83))	('G1269A', 'Var', (88, 94))	('G1269A', 'Mutation', 'rs148987382', (88, 94))	('crizotinib', 'Chemical', 'MESH:D000077547', (151, 161))
39450	27432227	The remaining ALK resistance mutations included: C1156Y (2%), G1202R (2%), I1171T (2%), S1206Y (2%), and E1210K (2%).	('E1210K', 'Mutation', 'p.E1210K', (105, 111))	('S1206Y', 'Var', (88, 94))	('C1156Y', 'Var', (49, 55))	('S1206Y', 'Mutation', 'rs1057519782', (88, 94))	('E1210K', 'Var', (105, 111))	('I1171T', 'Mutation', 'rs1057519698', (75, 81))	('C1156Y', 'Mutation', 'rs1057519859', (49, 55))	('I1171T', 'Var', (75, 81))	('ALK', 'Gene', (14, 17))	('G1202R', 'Var', (62, 68))	('G1202R', 'Mutation', 'rs1057519783', (62, 68))
39452	27432227	In three patients, both samples were negative for ALK mutations; one patient harbored ALK L1196M in two separate pleural fluid specimens obtained approximately one month apart.	('patients', 'Species', '9606', (9, 17))	('pleural', 'Disease', (113, 120))	('ALK', 'Gene', (86, 89))	('L1196M', 'Mutation', 'rs1057519784', (90, 96))	('L1196M', 'Var', (90, 96))	('pleural fluid', 'Phenotype', 'HP:0002202', (113, 126))	('patient', 'Species', '9606', (69, 76))	('pleural', 'Disease', 'MESH:D010995', (113, 120))	('patient', 'Species', '9606', (9, 16))
39456	27432227	Thus, among 36 crizotinib-resistant specimens tested for both ALK resistance mutations and ALK gene amplification, 31% harbored on-target genetic alterations contributing to resistance.	('harbored', 'Reg', (119, 127))	('ALK', 'Gene', (91, 94))	('contributing', 'Reg', (158, 170))	('mutations', 'Var', (77, 86))	('crizotinib', 'Chemical', 'MESH:D000077547', (15, 25))
39458	27432227	To evaluate whether the scope of ALK resistance mutations changes following treatment with second-generation ALK inhibitors, we assembled cohorts of ALK-positive patients who underwent post-progression biopsies on ceritinib (N=23), alectinib (N=17), or brigatinib (N=6).	('patients', 'Species', '9606', (162, 170))	('ALK-positive', 'Gene', (149, 161))	('ceritinib', 'Chemical', 'MESH:C586847', (214, 223))	('brigatinib', 'Chemical', 'MESH:C000598580', (253, 263))	('alectinib', 'Chemical', 'MESH:C582670', (232, 241))	('mutations', 'Var', (48, 57))
39470	27432227	Over one-half of ceritinib-resistant specimens (13/24; 54%) harbored ALK resistance mutations (Figure 1B), and 17% contained >=2 ALK resistance mutations.	('harbored', 'Reg', (60, 68))	('mutations', 'Var', (84, 93))	('ALK', 'Gene', (69, 72))	('contained', 'Reg', (115, 124))	('ceritinib', 'Chemical', 'MESH:C586847', (17, 26))
39471	27432227	The most common ALK mutations were G1202R (21%) and F1174C/L (16.7%), both of which have been previously described in ALK-positive NSCLC.	('F1174C', 'SUBSTITUTION', 'None', (52, 58))	('G1202R', 'Mutation', 'rs1057519783', (35, 41))	('F1174C', 'Var', (52, 58))	('NSCLC', 'Disease', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('G1202R', 'Var', (35, 41))	('ALK', 'Gene', (16, 19))
39472	27432227	G1202R maps to the solvent-exposed region of the ALK kinase, where the bulkier, charged side chain is thought to lead to steric hindrance of most ALK inhibitors.	('G1202R', 'Var', (0, 6))	('steric', 'MPA', (121, 127))	('G1202R', 'Mutation', 'rs1057519783', (0, 6))
39473	27432227	ALK F1174 mutations map adjacent to the C-terminus of the alphaC helix and may stabilize an active conformation that increases the ATP-binding affinity of ALK.	('F1174 mutations', 'Var', (4, 19))	('ATP-binding', 'molecular_function', 'GO:0005524', ('131', '142'))	('increases', 'PosReg', (117, 126))	('ALK', 'Protein', (155, 158))	('ALK', 'Gene', (0, 3))	('ATP', 'Chemical', 'MESH:D000255', (131, 134))	('active', 'MPA', (92, 98))	('stabilize', 'Reg', (79, 88))	('ATP-binding affinity', 'Interaction', (131, 151))
39474	27432227	In addition to G1202R and F1174C/L, we observed ALK C1156Y mutations in two (8%) specimens.	('C1156Y', 'Mutation', 'rs1057519859', (52, 58))	('G1202R', 'Var', (15, 21))	('G1202R', 'Mutation', 'rs1057519783', (15, 21))	('ALK', 'Gene', (48, 51))	('F1174C', 'SUBSTITUTION', 'None', (26, 32))	('F1174C', 'Var', (26, 32))
39475	27432227	In preclinical models, we previously demonstrated that ceritinib has less activity against ALK C1156Y.	('ALK C1156Y', 'Var', (91, 101))	('ceritinib', 'Chemical', 'MESH:C586847', (55, 64))	('activity', 'MPA', (74, 82))	('C1156Y', 'Mutation', 'rs1057519859', (95, 101))	('less', 'NegReg', (69, 73))
39476	27432227	It should be noted, however, that both C1156Y-containing specimens in this series also harbored additional ALK mutations (MGH084-1: C1156Y and I1171N; MGH932-1: C1156Y, V1180L, and G1202del) that may have contributed to resistance.	('V1180L', 'Var', (169, 175))	('C1156Y-containing', 'Var', (39, 56))	('C1156Y', 'Mutation', 'rs1057519859', (161, 167))	('V1180L', 'Mutation', 'p.V1180L', (169, 175))	('G1202del', 'DELETION', 'None', (181, 189))	('C1156Y', 'Var', (132, 138))	('C1156Y', 'Mutation', 'rs1057519859', (132, 138))	('G1202del', 'Var', (181, 189))	('C1156Y', 'Mutation', 'rs1057519859', (39, 45))	('I1171N', 'Mutation', 'rs1057519698', (143, 149))	('ALK', 'Gene', (107, 110))	('C1156Y', 'Var', (161, 167))	('I1171N', 'Var', (143, 149))
39477	27432227	In this analysis, we also identified a novel ALK G1202del mutation in two (8%) specimens.	('G1202del', 'DELETION', 'None', (49, 57))	('ALK', 'Gene', (45, 48))	('G1202del', 'Var', (49, 57))
39478	27432227	To directly evaluate whether ALK G1202del confers resistance to ceritinib, we engineered Ba/F3 cells to express EML4-ALK (E13;A20) harboring G1202del and examined ALK phosphorylation after treatment with various ALK inhibitors.	('G1202del', 'Var', (141, 149))	('examined', 'Reg', (154, 162))	('G1202del', 'Var', (33, 41))	('G1202del', 'DELETION', 'None', (141, 149))	('EML4-ALK', 'Gene', (112, 120))	('G1202del', 'DELETION', 'None', (33, 41))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('ceritinib', 'Chemical', 'MESH:C586847', (64, 73))
39479	27432227	We observed that G1202del confers moderate levels of resistance to ceritinib, alectinib and brigatinib (Figures S1A-D and S2A-C).	('G1202del', 'DELETION', 'None', (17, 25))	('resistance', 'MPA', (53, 63))	('brigatinib', 'Chemical', 'MESH:C000598580', (92, 102))	('ceritinib', 'Chemical', 'MESH:C586847', (67, 76))	('G1202del', 'Var', (17, 25))	('alectinib', 'Chemical', 'MESH:C582670', (78, 87))
39480	27432227	By contrast, crizotinib potency was less impacted by G1202del.	('G1202del', 'DELETION', 'None', (53, 61))	('G1202del', 'Var', (53, 61))	('crizotinib', 'Chemical', 'MESH:D000077547', (13, 23))	('crizotinib potency', 'MPA', (13, 31))
39482	27432227	Based upon structural modeling studies, however, we speculate that deletion of the glycine at position 1202 could shift the aspartic acid at position 1203 into the 1202 position, leading to disruption of TKI binding (T Johnson, personal communication).	('disruption', 'NegReg', (190, 200))	('glycine', 'Chemical', 'MESH:D005998', (83, 90))	('deletion', 'Var', (67, 75))	('TKI', 'Protein', (204, 207))	('aspartic acid', 'Chemical', 'MESH:D001224', (124, 137))	('aspartic acid', 'MPA', (124, 137))	('binding', 'molecular_function', 'GO:0005488', ('208', '215'))
39483	27432227	Importantly, while our functional models suggest that ALK G1202del may be a novel resistance mutation, G1202del appears to be quite distinct from ALK G1202R.	('G1202R', 'Mutation', 'rs1057519783', (150, 156))	('G1202del', 'DELETION', 'None', (58, 66))	('G1202del', 'DELETION', 'None', (103, 111))	('G1202del', 'Var', (58, 66))	('G1202del', 'Var', (103, 111))
39484	27432227	Indeed, in Ba/F3 models, ALK G1202R results in much higher degrees of resistance to all currently available first- and second-generation ALK inhibitors (Figure S1D).	('G1202R', 'Mutation', 'rs1057519783', (29, 35))	('G1202R', 'Var', (29, 35))	('ALK G1202R', 'Var', (25, 35))	('higher', 'PosReg', (52, 58))	('resistance', 'MPA', (70, 80))
39490	27432227	Moreover, the most common ALK resistance mutation was G1202R, which was found in 29% of cases.	('ALK resistance', 'Gene', (26, 40))	('G1202R', 'Mutation', 'rs1057519783', (54, 60))	('G1202R', 'Var', (54, 60))
39491	27432227	Interestingly, among three patients with RECIST-defined progressive disease on a first repeat tumor assessment (i.e., intrinsic resistance), two harbored G1202R.	('repeat tumor', 'Disease', 'MESH:D000647', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('G1202R', 'Mutation', 'rs1057519783', (154, 160))	('G1202R', 'Var', (154, 160))	('repeat tumor', 'Disease', (87, 99))	('patients', 'Species', '9606', (27, 35))	('harbored', 'Reg', (145, 153))
39492	27432227	Other ALK resistance mutations identified within the complete alectinib-resistant cohort included I1171T/S (12%), V1180L (6%), and L1196M (6%).	('V1180L', 'Mutation', 'p.V1180L', (114, 120))	('V1180L', 'Var', (114, 120))	('alectinib', 'Chemical', 'MESH:C582670', (62, 71))	('I1171T', 'SUBSTITUTION', 'None', (98, 104))	('I1171T', 'Var', (98, 104))	('ALK', 'Gene', (6, 9))	('L1196M', 'Mutation', 'rs1057519784', (131, 137))	('L1196M', 'Var', (131, 137))
39493	27432227	Of note, several different ALK I1171 mutations (e.g., I1171T/N/S) have been reported previously among ALK-positive patients progressing on alectinib.	('patients', 'Species', '9606', (115, 123))	('ALK I1171', 'Gene', (27, 36))	('I1171T', 'SUBSTITUTION', 'None', (54, 60))	('alectinib', 'Chemical', 'MESH:C582670', (139, 148))	('I1171T', 'Var', (54, 60))
39494	27432227	ALK V1180L has also been previously shown to confer resistance to alectinib in vitro, but this represents the first clinical observation of an ALK V1180L mutation in an alectinib-resistant patient.	('alectinib', 'Chemical', 'MESH:C582670', (66, 75))	('alectinib', 'Chemical', 'MESH:C582670', (169, 178))	('ALK', 'Gene', (143, 146))	('patient', 'Species', '9606', (189, 196))	('V1180L', 'Var', (147, 153))	('V1180L', 'Mutation', 'p.V1180L', (147, 153))	('V1180L', 'Mutation', 'p.V1180L', (4, 10))
39495	27432227	Interestingly, alectinib has demonstrated significant activity against the ALK gatekeeper mutation L1196M in preclinical models, yet this was observed in one (6%) post-alectinib biopsy.	('L1196M', 'Mutation', 'rs1057519784', (99, 105))	('alectinib', 'Chemical', 'MESH:C582670', (168, 177))	('ALK', 'Gene', (75, 78))	('L1196M', 'Var', (99, 105))	('alectinib', 'Chemical', 'MESH:C582670', (15, 24))	('gatekeeper', 'Species', '111938', (79, 89))	('activity', 'MPA', (54, 62))
39504	27432227	Like patients progressing on ceritinib and alectinib, the most common ALK resistance mutation was G1202R, which was observed in three specimens.	('patients', 'Species', '9606', (5, 13))	('ceritinib', 'Chemical', 'MESH:C586847', (29, 38))	('G1202R', 'Var', (98, 104))	('G1202R', 'Mutation', 'rs1057519783', (98, 104))	('alectinib', 'Chemical', 'MESH:C582670', (43, 52))	('ALK', 'Gene', (70, 73))
39508	27432227	Collectively, across all three biopsy cohorts (N=48), ALK resistance mutations were present in 56% of ALK-positive patients progressing on second-generation ALK inhibitors (ceritinib 54%, alectinib 53%, and brigatinib 71%).	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (115, 123))	('ALK resistance', 'Gene', (54, 68))	('brigatinib', 'Chemical', 'MESH:C000598580', (207, 217))	('progressing', 'PosReg', (124, 135))	('ALK-positive', 'Gene', (102, 114))	('ceritinib', 'Chemical', 'MESH:C586847', (173, 182))	('alectinib', 'Chemical', 'MESH:C582670', (188, 197))
39510	27432227	Indeed, consistent with preclinical data, ALK G1202R emerged as the most common ALK resistance mutation among patients receiving second-generation ALK inhibitors (Figure 2A-B).	('G1202R', 'Var', (46, 52))	('G1202R', 'Mutation', 'rs1057519783', (46, 52))	('ALK G1202R', 'Var', (42, 52))	('ALK resistance', 'Gene', (80, 94))	('patients', 'Species', '9606', (110, 118))
39511	27432227	Based upon experience from other targeted therapy settings (e.g., chronic myeloid leukemia [CML] and EGFR-mutant lung cancer; ref), we hypothesized that sequential ALK inhibitor therapy may predispose patients to develop compound mutations.	('patients', 'Species', '9606', (201, 209))	('CML', 'Disease', 'MESH:D015464', (92, 95))	('lung cancer', 'Disease', (113, 124))	('ALK', 'Protein', (164, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (74, 90))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('EGFR', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CML', 'Disease', (92, 95))	('compound mutations', 'Var', (221, 239))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (66, 90))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (66, 90))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('chronic myeloid leukemia', 'Disease', (66, 90))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))
39512	27432227	Indeed, we recently described the development of a compound ALK resistance mutation in a patient treated with crizotinib, ceritinib and lorlatinib.	('patient', 'Species', '9606', (89, 96))	('ALK resistance', 'Gene', (60, 74))	('lorlatinib', 'Chemical', 'MESH:C000590786', (136, 146))	('compound', 'Var', (51, 59))	('ceritinib', 'Chemical', 'MESH:C586847', (122, 131))	('crizotinib', 'Chemical', 'MESH:D000077547', (110, 120))
39515	27432227	In three specimens (MGH905-1, MGH086-0, and MGH086-1), ALK resistance mutations were in close enough proximity to confirm that they were present on the same allele or whole-exome sequencing (WES) demonstrated similar cancer cell fractions of each resistance mutation, suggesting that they were present on the same allele of the ALK fusion gene.	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('MGH086-1', 'Var', (44, 52))	('MGH086-0', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
39517	27432227	Following identification of an ALK rearrangement, MGH086 was sequentially treated with crizotinib and brigatinib.	('brigatinib', 'Chemical', 'MESH:C000598580', (102, 112))	('crizotinib', 'Chemical', 'MESH:D000077547', (87, 97))	('ALK', 'Gene', (31, 34))	('rearrangement', 'Var', (35, 48))
39519	27432227	WES of the post-crizotinib specimen (MGH086-00) demonstrated an acquired ALK E1210K mutation.	('E1210K', 'Mutation', 'p.E1210K', (77, 83))	('E1210K', 'Var', (77, 83))	('ALK', 'Gene', (73, 76))	('crizotinib', 'Chemical', 'MESH:D000077547', (16, 26))
39520	27432227	E1210 maps to the ribose-binding pocket of the ALK kinase.	('ribose', 'Chemical', 'MESH:D012266', (18, 24))	('ALK kinase', 'Enzyme', (47, 57))	('E1210', 'Var', (0, 5))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))
39521	27432227	ALK E1210K confers resistance to crizotinib based upon in vitro mutagenesis screens, but this alteration has not been described in clinical NSCLC samples previously.	('crizotinib', 'Chemical', 'MESH:D000077547', (33, 43))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('mutagenesis', 'biological_process', 'GO:0006280', ('64', '75'))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('resistance', 'MPA', (19, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('E1210K', 'Mutation', 'p.E1210K', (4, 10))	('E1210K', 'Var', (4, 10))	('NSCLC', 'Disease', (140, 145))
39524	27432227	Instead, a new ALK D1203N mutation was found.	('ALK', 'Gene', (15, 18))	('D1203N', 'Var', (19, 25))	('D1203N', 'Mutation', 'rs759845895', (19, 25))
39526	27432227	Subsequent treatment with brigatinib enriched for this clone, which eventually acquired a compound ALK S1206C mutation.	('ALK', 'Gene', (99, 102))	('S1206C', 'Var', (103, 109))	('brigatinib', 'Chemical', 'MESH:C000598580', (26, 36))	('S1206C', 'Mutation', 'p.S1206C', (103, 109))
39529	27432227	These data demonstrate that compound ALK resistance mutations can arise in ALK-positive patients treated with sequential ALK inhibitors.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (88, 96))	('compound ALK', 'MPA', (28, 40))	('arise', 'Reg', (66, 71))
39531	27432227	TP53 mutations were the most common, present in 9 (33%) specimens.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
39533	27432227	Missense mutations in DDR2 (L610F), BRAF (G15V), FGFR2 (F645L), MET (T992I), NRAS (A155T) and PIK3CA (G106V) were each identified in one (3.7%) specimen, none of which were overlapping.	('G15V', 'Mutation', 'p.G15V', (42, 46))	('MET', 'Gene', (64, 67))	('G106V', 'Mutation', 'rs1057519930', (102, 107))	('A155T', 'Var', (83, 88))	('NRAS', 'Gene', '4893', (77, 81))	('G106V', 'Var', (102, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('BRAF', 'Gene', '673', (36, 40))	('PIK3CA', 'Gene', '5290', (94, 100))	('BRAF', 'Gene', (36, 40))	('DDR2', 'Gene', '4921', (22, 26))	('FGFR2', 'Gene', (49, 54))	('L610F', 'Mutation', 'p.L610F', (28, 33))	('T992I', 'Mutation', 'rs754384449', (69, 74))	('A155T', 'Mutation', 'c.155A>T', (83, 88))	('FGFR2', 'Gene', '2263', (49, 54))	('NRAS', 'Gene', (77, 81))	('F645L', 'Var', (56, 61))	('DDR2', 'Gene', (22, 26))	('PIK3CA', 'Gene', (94, 100))	('F645L', 'Mutation', 'rs912905439', (56, 61))	('L610F', 'Var', (28, 33))	('Missense mutations', 'Var', (0, 18))
39534	27432227	Mutations in DDR2, BRAF, NRAS and FGFR2 did not occur in known hotspot residues, nor have they been observed in NSCLCs in the COSMIC database (COSMICv76); thus, the impact of these alterations on ALK inhibitor resistance is uncertain.	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '2263', (34, 39))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('DDR2', 'Gene', '4921', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('DDR2', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('SCLC', 'Phenotype', 'HP:0030357', (113, 117))	('NRAS', 'Gene', (25, 29))	('NSCLC', 'Disease', (112, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('NRAS', 'Gene', '4893', (25, 29))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
39536	27432227	MET T992I has been reported at low frequencies in various malignancies, but functional studies have demonstrated that this variant lacks transformative capacity and does not impact MET phosphorylation status.	('T992I', 'Var', (4, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('185', '200'))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('transformative capacity', 'MPA', (137, 160))	('lacks', 'NegReg', (131, 136))	('MET T992I', 'Var', (0, 9))	('T992I', 'Mutation', 'rs754384449', (4, 9))	('malignancies', 'Disease', (58, 70))
39538	27432227	By contrast, the alectinib-resistant specimen MGH074-2 showed no ALK resistance mutations but harbored a PIK3CA G106V mutation.	('PIK3CA', 'Gene', (105, 111))	('alectinib', 'Chemical', 'MESH:C582670', (17, 26))	('G106V', 'Mutation', 'rs1057519930', (112, 117))	('PIK3CA', 'Gene', '5290', (105, 111))	('ALK resistance mutations', 'MPA', (65, 89))	('G106V', 'Var', (112, 117))
39539	27432227	Previous studies have shown that PIK3CA G106V is a gain-of-function mutation that localizes to the p85/adaptor-binding domain of p110alpha and results in increased AKT phosphorylation.	('AKT', 'Gene', (164, 167))	('G106V', 'Mutation', 'rs1057519930', (40, 45))	('PIK3CA', 'Gene', '5290', (33, 39))	('p110alpha', 'Gene', (129, 138))	('p110alpha', 'Gene', '5290', (129, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('G106V', 'Var', (40, 45))	('PIK3CA', 'Gene', (33, 39))	('AKT', 'Gene', '207', (164, 167))	('increased', 'PosReg', (154, 163))
39540	27432227	In addition, PIK3CA mutations have been associated with acquired resistance to EGFR inhibitors in EGFR-mutant NSCLC.	('EGFR', 'Gene', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (79, 83))	('PIK3CA', 'Gene', (13, 19))	('EGFR', 'Gene', (79, 83))	('NSCLC', 'Disease', (110, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('PIK3CA', 'Gene', '5290', (13, 19))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('EGFR', 'Gene', '1956', (98, 102))	('associated', 'Reg', (40, 50))	('mutations', 'Var', (20, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
39541	27432227	Due to tissue availability, we were unable to assess this patient's pre-alectinib specimen for the presence of PI3KCA G106V; thus, it remains unclear when this alteration arose.	('PI3KCA', 'Var', (111, 117))	('alectinib', 'Chemical', 'MESH:C582670', (72, 81))	('patient', 'Species', '9606', (58, 65))	('pre', 'molecular_function', 'GO:0003904', ('68', '71'))	('G106V', 'Var', (118, 123))	('G106V', 'Mutation', 'rs1057519930', (118, 123))
39542	27432227	Among the remaining 26 cases that underwent NGS, no additional PIK3CA mutations were identified; however, we previously reported a PIK3CA H1047R mutation in a ceritinib-resistant specimen (MGH034-2) that was identified by the Snapshot allele-specific assay.	('ceritinib', 'Chemical', 'MESH:C586847', (159, 168))	('H1047R', 'Mutation', 'rs121913279', (138, 144))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (63, 69))	('PIK3CA', 'Gene', '5290', (131, 137))	('H1047R', 'Var', (138, 144))
39544	27432227	All samples underwent targeted NGS of 1000 known cancer genes (Table S11, Figure 4; ref).	('S11', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('NGS', 'Var', (31, 34))	('S11', 'Gene', '6267', (69, 72))	('cancer', 'Disease', (49, 55))
39545	27432227	As we previously reported, MGH034-2A harbored an acquired MAP2K1 K57N mutation.	('MAP2K1', 'Gene', (58, 64))	('MAP2K', 'molecular_function', 'GO:0004708', ('58', '63'))	('K57N', 'Var', (65, 69))	('MAP2K1', 'Gene', '5604', (58, 64))	('K57N', 'Mutation', 'rs869025608', (65, 69))
39546	27432227	Furthermore, treatment with a MEK inhibitor (AZD6244) re-sensitized these cells to ceritinib, suggesting that reactivation of the MAPK pathway promoted resistance in this specimen.	('AZD6244', 'Chemical', 'MESH:C517975', (45, 52))	('reactivation', 'Var', (110, 122))	('ceritinib', 'Chemical', 'MESH:C586847', (83, 92))	('resistance', 'MPA', (152, 162))	('promoted', 'PosReg', (143, 151))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('MAPK pathway', 'Pathway', (130, 142))	('MEK', 'Gene', (30, 33))	('MEK', 'Gene', '5609', (30, 33))
39547	27432227	In addition, for MGH049-1A, we previously observed that agents targeting SRC, EGFR and PI3K re-sensitized cells to ALK inhibition, implicating these signaling pathways as mediators of resistance in this model.	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('ALK inhibition', 'MPA', (115, 129))	('MGH049-1A', 'Var', (17, 26))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('PI3K', 'Gene', (87, 91))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('SRC', 'Gene', '6714', (73, 76))	('SRC', 'Gene', (73, 76))
39552	27432227	While several potential bypass signaling tracts were identified in individual patients, no high frequency, recurring genetic alterations beyond TP53 mutations were observed.	('TP53', 'Gene', '7157', (144, 148))	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('TP53', 'Gene', (144, 148))	('mutations', 'Var', (149, 158))	('patients', 'Species', '9606', (78, 86))
39554	27432227	However, we identified three ALK-positive patients with ALK L1196M following treatment with second-generation ALK inhibitors (ceritinib N=2, alectinib N=1), suggesting that additional resistance mechanisms may be responsible.	('ALK-positive', 'Gene', (29, 41))	('alectinib', 'Chemical', 'MESH:C582670', (141, 150))	('L1196M', 'Mutation', 'rs1057519784', (60, 66))	('L1196M', 'Var', (60, 66))	('ALK', 'Gene', (56, 59))	('patients', 'Species', '9606', (42, 50))	('ceritinib', 'Chemical', 'MESH:C586847', (126, 135))
39557	27432227	Post-crizotinib and/or post-alectinib biopsies were not performed in this patient; thus, we could not determine when the ALK L1196M mutation was acquired.	('patient', 'Species', '9606', (74, 81))	('alectinib', 'Chemical', 'MESH:C582670', (28, 37))	('crizotinib', 'Chemical', 'MESH:D000077547', (5, 15))	('L1196M', 'Mutation', 'rs1057519784', (125, 131))	('L1196M', 'Var', (125, 131))	('ALK', 'Gene', (121, 124))
39559	27432227	Indeed, it is possible that EMT, rather than the ALK L1196M mutation, may have contributed more significantly to ceritinib resistance in this patient.	('contributed', 'Reg', (79, 90))	('ceritinib resistance', 'MPA', (113, 133))	('EMT', 'biological_process', 'GO:0001837', ('28', '31'))	('patient', 'Species', '9606', (142, 149))	('ceritinib', 'Chemical', 'MESH:C586847', (113, 122))	('L1196M', 'Mutation', 'rs1057519784', (53, 59))	('L1196M', 'Var', (53, 59))
39562	27432227	Interestingly, among these five specimens, three harbored ALK resistance mutations, including the two cases with ALK L1196M.	('L1196M', 'Mutation', 'rs1057519784', (117, 123))	('L1196M', 'Var', (117, 123))	('ALK resistance', 'Gene', (58, 72))	('harbored', 'Reg', (49, 57))
39570	27432227	Notably, lorlatinib was the only ALK inhibitor to potently inhibit ALK phosphorylation across all single ALK secondary mutations, including ALK G1202R (IC50 49.9 nM).	('ALK', 'Gene', (105, 108))	('lorlatinib', 'Chemical', 'MESH:C000590786', (9, 19))	('G1202R', 'Var', (144, 150))	('G1202R', 'Mutation', 'rs1057519783', (144, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('ALK phosphorylation', 'MPA', (67, 86))	('inhibit', 'NegReg', (59, 66))
39572	27432227	We found that crizotinib, ceritinib, alectinib and brigatinib were all inactive against D1203N+E1210K and F1174C+D1203N.	('brigatinib', 'Chemical', 'MESH:C000598580', (51, 61))	('F1174C', 'Mutation', 'rs1057519697', (106, 112))	('E1210K', 'Mutation', 'p.E1210K', (95, 101))	('crizotinib', 'Chemical', 'MESH:D000077547', (14, 24))	('D1203N', 'Mutation', 'rs759845895', (88, 94))	('D1203N+E1210K', 'Var', (88, 101))	('alectinib', 'Chemical', 'MESH:C582670', (37, 46))	('ceritinib', 'Chemical', 'MESH:C586847', (26, 35))	('D1203N', 'Mutation', 'rs759845895', (113, 119))	('F1174C+D1203N', 'Var', (106, 119))
39573	27432227	Conversely, lorlatinib retained significant potency against the ALK double-mutant D1203N+E1210K and intermediate potency against D1203N+ F1174C.	('E1210K', 'Mutation', 'p.E1210K', (89, 95))	('D1203N', 'Mutation', 'rs759845895', (82, 88))	('D1203N+E1210K', 'Var', (82, 95))	('lorlatinib', 'Chemical', 'MESH:C000590786', (12, 22))	('D1203N', 'Mutation', 'rs759845895', (129, 135))	('F1174C', 'Mutation', 'rs1057519697', (137, 143))	('D1203N+ F1174C', 'Var', (129, 143))
39578	27432227	These data suggest that in the setting of acquired resistance to second-generation ALK inhibitors, the presence of ALK resistance mutations indicates continued dependency on ALK signaling and susceptibility to the pan-inhibitory ALK inhibitor lorlatinib (Figure 7E-F).	('ALK', 'MPA', (174, 177))	('dependency', 'MPA', (160, 170))	('mutations', 'Var', (130, 139))	('lorlatinib', 'Chemical', 'MESH:C000590786', (243, 253))	('ALK resistance', 'Gene', (115, 129))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))
39579	27432227	In contrast, the absence of ALK resistance mutations after failure of second-generation ALK inhibitors may indicate loss of ALK dependency and resistance to lorlatinib.	('absence', 'NegReg', (17, 24))	('ALK resistance', 'Gene', (28, 42))	('ALK dependency', 'Disease', (124, 138))	('mutations', 'Var', (43, 52))	('loss', 'NegReg', (116, 120))	('resistance', 'MPA', (143, 153))	('ALK dependency', 'Disease', 'MESH:D019966', (124, 138))	('lorlatinib', 'Chemical', 'MESH:C000590786', (157, 167))
39581	27432227	By contrast, ALK resistance mutations were present in over one-half of patients progressing on second-generation ALK inhibitors, likely reflecting the greater potency and selectivity of these agents compared to crizotinib.	('progressing', 'PosReg', (80, 91))	('crizotinib', 'Chemical', 'MESH:D000077547', (211, 221))	('patients', 'Species', '9606', (71, 79))	('ALK resistance', 'Gene', (13, 27))	('ALK', 'Enzyme', (113, 116))	('mutations', 'Var', (28, 37))
39582	27432227	In parallel, we observed that the spectrum of ALK resistance mutations was different following progression on second-generation ALK inhibitors compared to crizotinib.	('crizotinib', 'Chemical', 'MESH:D000077547', (155, 165))	('ALK resistance', 'Gene', (46, 60))	('mutations', 'Var', (61, 70))
39583	27432227	Most notably, ALK G1202R, which was present in only 2% of crizotinib-resistant biopsies, emerged as the most common ALK resistance mutation after treatment with second-generation ALK inhibitors.	('G1202R', 'Mutation', 'rs1057519783', (18, 24))	('ALK', 'Gene', (116, 119))	('crizotinib', 'Chemical', 'MESH:D000077547', (58, 68))	('common', 'Reg', (109, 115))	('ALK G1202R', 'Var', (14, 24))	('G1202R', 'Var', (18, 24))
39584	27432227	These findings are consistent with data from Ba/F3 models, which demonstrate that ALK G1202R confers high levels of resistance to all currently available second-generation ALK inhibitors.	('ALK', 'Gene', (82, 85))	('resistance', 'MPA', (116, 126))	('G1202R', 'Mutation', 'rs1057519783', (86, 92))	('G1202R', 'Var', (86, 92))
39585	27432227	While ALK G1202R was a common shared resistance mutation in each second-generation ALK inhibitor cohort, it is noteworthy that the spectrum of other ALK resistance mutations appeared to differ across agents.	('G1202R', 'Mutation', 'rs1057519783', (10, 16))	('ALK', 'Gene', (6, 9))	('G1202R', 'Var', (10, 16))
39588	27432227	Conversely, several investigators have described ALK I1171 mutations that mediate resistance to alectinib, while conferring sensitivity to ceritinib.	('ALK I1171', 'Gene', (49, 58))	('mediate', 'Reg', (74, 81))	('alectinib', 'Chemical', 'MESH:C582670', (96, 105))	('ceritinib', 'MPA', (139, 148))	('ceritinib', 'Chemical', 'MESH:C586847', (139, 148))	('resistance', 'MPA', (82, 92))	('sensitivity', 'MPA', (124, 135))	('mutations', 'Var', (59, 68))
39591	27432227	Additional biopsies between therapies were unavailable; thus, it is unclear whether the ALK I1171N mutation was acquired as a result of ceritinib or alectinib.	('ALK', 'Gene', (88, 91))	('I1171N', 'Mutation', 'rs1057519698', (92, 98))	('alectinib', 'Chemical', 'MESH:C582670', (149, 158))	('I1171N', 'Var', (92, 98))	('ceritinib', 'Chemical', 'MESH:C586847', (136, 145))
39592	27432227	Tailoring of ALK therapy after failure of crizotinib may also be important in the small proportion of cases with uncommon and refractory mutations like ALK G1202R.	('G1202R', 'Mutation', 'rs1057519783', (156, 162))	('ALK', 'Gene', (152, 155))	('G1202R', 'Var', (156, 162))	('crizotinib', 'Chemical', 'MESH:D000077547', (42, 52))
39595	27432227	Interestingly, ALK L1198F paradoxically re-sensitized cells to crizotinib, again underscoring the importance of serial biopsies in ALK-positive NSCLC.	('NSCLC', 'Disease', (144, 149))	('re-sensitized', 'Reg', (40, 53))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('SCLC', 'Phenotype', 'HP:0030357', (145, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('crizotinib', 'Chemical', 'MESH:D000077547', (63, 73))	('ALK L1198F', 'Var', (15, 25))	('L1198F', 'Mutation', 'rs751306825', (19, 25))
39596	27432227	Of note, the emergence of compound resistance mutations in ALK-positive NSCLC is analogous to the experience with other targeted therapies.	('NSCLC', 'Disease', (72, 77))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('compound resistance mutations', 'Var', (26, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
39597	27432227	For example, in CML, sequential use of different ABL inhibitors has been shown to select for more drug-resistant, compound BCR-ABL mutations.	('ABL', 'Gene', '25', (49, 52))	('ABL', 'Gene', (49, 52))	('mutations', 'Var', (131, 140))	('select', 'Reg', (82, 88))	('CML', 'Disease', (16, 19))	('BCR-ABL', 'Gene', (123, 130))	('BCR-ABL', 'Gene', '25', (123, 130))	('ABL', 'Gene', '25', (127, 130))	('CML', 'Disease', 'MESH:D015464', (16, 19))	('drug-resistant', 'MPA', (98, 112))	('ABL', 'Gene', (127, 130))
39598	27432227	Similarly, in EGFR-mutant NSCLC, compound drug-resistant T790M/C797S mutations have been described following sequential treatment with first- and third-generation EGFR inhibitors.	('SCLC', 'Phenotype', 'HP:0030357', (27, 31))	('EGFR', 'Gene', '1956', (14, 18))	('T790M', 'SUBSTITUTION', 'None', (57, 62))	('EGFR', 'Gene', (14, 18))	('C797S', 'SUBSTITUTION', 'None', (63, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('T790M', 'Var', (57, 62))	('C797S', 'Var', (63, 68))	('EGFR', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('NSCLC', 'Disease', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
39600	27432227	We also observed PIK3CA mutations in two patients.	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))
39601	27432227	PIK3CA mutations have been implicated in resistance to other targeted therapies, such as EGFR inhibitors.	('EGFR', 'Gene', (89, 93))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('implicated', 'Reg', (27, 37))	('EGFR', 'Gene', '1956', (89, 93))	('mutations', 'Var', (7, 16))
39608	27432227	Using a combination of Ba/F3 models and patient-derived cell lines, we demonstrated that lorlatinib was active against all single ALK resistance mutations.	('patient', 'Species', '9606', (40, 47))	('mutations', 'Var', (145, 154))	('lorlatinib', 'Chemical', 'MESH:C000590786', (89, 99))	('ALK resistance', 'Gene', (130, 144))
39609	27432227	Moreover, lorlatinib was the only ALK inhibitor that retained significant activity against ALK G1202R.	('ALK G1202R', 'Var', (91, 101))	('G1202R', 'Mutation', 'rs1057519783', (95, 101))	('lorlatinib', 'Chemical', 'MESH:C000590786', (10, 20))	('activity', 'MPA', (74, 82))
39610	27432227	Such findings are consistent with preliminary phase I data in which lorlatinib has demonstrated an ORR of 44% among ALK-positive patients treated with two or more ALK inhibitors, with responses noted in ALK-positive patients harboring ALK G1202R mutations.	('ALK', 'Gene', (235, 238))	('patients', 'Species', '9606', (129, 137))	('G1202R', 'Var', (239, 245))	('G1202R', 'Mutation', 'rs1057519783', (239, 245))	('patients', 'Species', '9606', (216, 224))	('lorlatinib', 'Chemical', 'MESH:C000590786', (68, 78))
39612	27432227	In particular, we anticipate that repeat biopsies to identify ALK resistance mutations will play a larger role in guiding therapy decisions after progression on second-generation ALK TKIs compared to crizotinib.	('crizotinib', 'Chemical', 'MESH:D000077547', (200, 210))	('mutations', 'Var', (77, 86))	('ALK resistance', 'Gene', (62, 76))
39613	27432227	With respect to the latter, the absence of ALK resistance mutations has not been shown to impact ORRs or PFS to a second-generation ALK inhibitor among crizotinib-resistant patients.	('mutations', 'Var', (58, 67))	('PFS to a second-generation ALK inhibitor', 'MPA', (105, 145))	('crizotinib', 'Chemical', 'MESH:D000077547', (152, 162))	('patients', 'Species', '9606', (173, 181))	('ALK', 'Gene', (43, 46))	('impact', 'Reg', (90, 96))	('ORRs', 'MPA', (97, 101))
39615	27432227	By contrast, data from our patient-derived cell line models suggest that ALK resistance mutation status after disease progression on second-generation ALK inhibitors is likely to be critically important in predicting sensitivity to the third-generation ALK inhibitor lorlatinib.	('mutation', 'Var', (88, 96))	('lorlatinib', 'Chemical', 'MESH:C000590786', (267, 277))	('ALK resistance', 'Gene', (73, 87))	('patient', 'Species', '9606', (27, 34))
39622	27432227	On a practical level, this work will also allow clinicians to personalize ALK-targeted strategies based upon the presence or absence of specific ALK resistance mutations, which may ultimately translate into improved patient outcomes.	('ALK', 'Gene', (145, 148))	('mutations', 'Var', (160, 169))	('patient', 'Species', '9606', (216, 223))	('improved', 'PosReg', (207, 215))
39626	27432227	The MGH NGS platform (v1.1.4) uses anchored multiplex polymerase chain reaction (PCR) to detect single-nucleotide variants (SNVs) and insertions/deletions within 39 cancer-related genes, including ALK (exons 22, 23, and 25; ref).	('insertions/deletions', 'Var', (134, 154))	('ALK', 'Gene', (197, 200))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('single-nucleotide variants', 'Var', (96, 122))
39640	27432227	Cell lines were sequenced to confirm the presence of ALK rearrangements identified by clinical testing of biopsy specimens from the same patients.	('rearrangements', 'Var', (57, 71))	('ALK', 'Gene', (53, 56))	('patients', 'Species', '9606', (137, 145))
39650	27432227	Antibodies against phospho-ALK (Y1282/1283), ALK, phospho-AKT (S473), AKT, Phospho-ERK (T202/Y204), ERK, phospho-S6, and S6 were obtained from Cell Signaling Technology.	('AKT', 'Gene', '207', (70, 73))	('ERK', 'Gene', (83, 86))	('T202/Y204', 'Var', (88, 97))	('AKT', 'Gene', (58, 61))	('ERK', 'molecular_function', 'GO:0004707', ('83', '86'))	('Signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('AKT', 'Gene', (70, 73))	('AKT', 'Gene', '207', (58, 61))	('ERK', 'Gene', (100, 103))	('ERK', 'Gene', '2048', (100, 103))	('Y1282/1283', 'Var', (32, 42))	('ERK', 'molecular_function', 'GO:0004707', ('100', '103'))	('ERK', 'Gene', '2048', (83, 86))	('S473', 'Var', (63, 67))
39654	27432227	Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib.	('lorlatinib', 'Chemical', 'MESH:C000590786', (160, 170))	('mutations', 'Var', (14, 23))	('Secondary ALK', 'Gene', (0, 13))
39765	27594806	It has been shown previously that nucleotide depletion leads to stalled replication forks, which progressively become inactivated and require two different RAD51-mediated pathways for restart and repair.	('stalled replication forks', 'CPA', (64, 89))	('RAD51', 'Gene', (156, 161))	('RAD', 'biological_process', 'GO:1990116', ('156', '159'))	('nucleotide depletion', 'Var', (34, 54))	('RAD51', 'Gene', '5888', (156, 161))
39769	27594806	It has been previously demonstrated that treatment with 5-fluorouracil leads to the incorporation of 5-fluorouracil and uracil during S-phase, generating DNA repair-dependent, persistent DNA strand breaks during the successive G2/M-G1-phase, thereby interfering with the replication machinery in the subsequent S-phase.	('uracil', 'Chemical', 'MESH:D014498', (64, 70))	('uracil', 'Chemical', 'MESH:D014498', (120, 126))	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('S-phase', 'biological_process', 'GO:0051320', ('134', '141'))	('DNA repair', 'biological_process', 'GO:0006281', ('154', '164'))	('S-phase', 'biological_process', 'GO:0051320', ('311', '318'))	('replication machinery', 'MPA', (271, 292))	('DNA', 'Var', (187, 190))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (101, 115))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('G1-phase', 'biological_process', 'GO:0051318', ('232', '240'))	('interfering', 'NegReg', (250, 261))	('uracil', 'Chemical', 'MESH:D014498', (109, 115))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (56, 70))
39775	27594806	In lung adenocarcinoma, oncogenic KRAS mutations are highly prevalent (~25 %) but therapy choices are very limited (reviewed in) suggesting that our findings might be of relevance to advance treatment of a significant fraction of lung adenocarcinoma patients.	('KRAS', 'Gene', '3845', (34, 38))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (230, 249))	('patients', 'Species', '9606', (250, 258))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('mutations', 'Var', (39, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (230, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('lung adenocarcinoma', 'Disease', (230, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('KRAS', 'Gene', (34, 38))	('lung adenocarcinoma', 'Disease', (3, 22))
39784	27594806	NSCLC non-small cell lung cancer RT radiotherapy MTA multitargeted antifolate, commercial name 'Alimta' DSB DNA double strand break IR ionizing radiation SA-beta-Gal senescence-associated beta-galactosidase DDR DNA damage response gammaH2AX phosphorylation of histone variant H2AX	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (6, 32))	('gammaH2AX', 'Gene', '15270', (231, 240))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('H2AX', 'Gene', '3014', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('DNA damage response', 'biological_process', 'GO:0006974', ('211', '230'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (10, 32))	('histone', 'Protein', (260, 267))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (6, 32))	('MTA', 'Chemical', 'MESH:D000068437', (49, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('241', '256'))	('H2AX', 'Gene', (276, 280))	('beta-galactosidase', 'Gene', '2720', (188, 206))	('gammaH2AX', 'Gene', (231, 240))	('beta-galactosidase', 'Gene', (188, 206))	('non-small cell lung cancer', 'Disease', (6, 32))	('senescence', 'biological_process', 'GO:0010149', ('166', '176'))	('variant', 'Var', (268, 275))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('H2AX', 'Gene', '3014', (276, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('phosphorylation', 'MPA', (241, 256))	('H2AX', 'Gene', (236, 240))	('NSCLC', 'Disease', (0, 5))
39785	27485876	Jejunal intussusception caused by metastasis of a giant cell carcinoma of the lung A 55-year-old woman was admitted to our hospital reporting of nausea, vomiting and anorexia.	('giant cell carcinoma of the lung', 'Disease', (50, 82))	('metastasis', 'Var', (34, 44))	('vomiting', 'Disease', (153, 161))	('anorexia', 'Disease', 'MESH:D000855', (166, 174))	('vomiting', 'Disease', 'MESH:D014839', (153, 161))	('intussusception', 'Phenotype', 'HP:0002576', (8, 23))	('anorexia', 'Disease', (166, 174))	('anorexia', 'Phenotype', 'HP:0002039', (166, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (61, 82))	('nausea', 'Phenotype', 'HP:0002018', (145, 151))	('caused by', 'Reg', (24, 33))	('Jejunal intussusception', 'Disease', (0, 23))	('nausea', 'Disease', (145, 151))	('nausea', 'Disease', 'MESH:D009325', (145, 151))	('giant cell carcinoma of the lung', 'Disease', 'MESH:D018286', (50, 82))	('woman', 'Species', '9606', (97, 102))	('vomiting', 'Phenotype', 'HP:0002013', (153, 161))
39934	32562082	Our study demonstrates that AKBA enhances the cisplatin sensitivity of NSCLC cells and that the mechanisms involve G0/G1 phase arrest, apoptosis induction, and autophagy suppression via targeting p21-dependent signaling pathway.	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('arrest', 'Disease', (127, 133))	('AKBA', 'Chemical', 'MESH:C094432', (28, 32))	('autophagy', 'biological_process', 'GO:0006914', ('160', '169'))	('NSCLC', 'Disease', (71, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('enhances', 'PosReg', (33, 41))	('G1 phase', 'biological_process', 'GO:0051318', ('118', '126'))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('arrest', 'Disease', 'MESH:D006323', (127, 133))	('signaling pathway', 'biological_process', 'GO:0007165', ('210', '227'))	('p21', 'Gene', (196, 199))	('suppression', 'NegReg', (170, 181))	('autophagy', 'CPA', (160, 169))	('autophagy', 'biological_process', 'GO:0016236', ('160', '169'))	('cisplatin sensitivity', 'MPA', (46, 67))	('AKBA', 'Var', (28, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('p21', 'Gene', '1026', (196, 199))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
39955	32562082	However, the effects of AKBA on NSCLC cells have rarely been reported, and whether or not AKBA can increase the chemo-sensitivity of CDDP in NSCLC and the underlying mechanisms is still unknown.	('AKBA', 'Var', (90, 94))	('AKBA', 'Chemical', 'MESH:C094432', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('NSCLC', 'Disease', (141, 146))	('AKBA', 'Chemical', 'MESH:C094432', (24, 28))	('CDDP', 'Chemical', '-', (133, 137))	('NSCLC', 'Disease', (32, 37))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('chemo-sensitivity', 'MPA', (112, 129))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('increase', 'PosReg', (99, 107))
40006	32562082	Moreover, we also detected the colony formation of BEAS-2B after cotreatment of AKBA and CDDP, finding that AKBA increased the colony number of BEAS-2B compared to control group (Fig.	('colony number', 'CPA', (127, 140))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('AKBA', 'Chemical', 'MESH:C094432', (108, 112))	('increased', 'PosReg', (113, 122))	('CDDP', 'Chemical', '-', (89, 93))	('AKBA', 'Chemical', 'MESH:C094432', (80, 84))	('AKBA', 'Var', (108, 112))
40015	32562082	Interestingly, after cotreatment of AKBA with CDDP to A549, the percentages of G0/G1 phase were increased and the frequencies of G2/M phase were reduced, compared with CDDP alone.	('increased', 'PosReg', (96, 105))	('reduced', 'NegReg', (145, 152))	('CDDP', 'Chemical', '-', (168, 172))	('G0/G1 phase', 'CPA', (79, 90))	('M phase', 'biological_process', 'GO:0000279', ('132', '139'))	('CDDP', 'Chemical', '-', (46, 50))	('G1 phase', 'biological_process', 'GO:0051318', ('82', '90'))	('G2/M phase', 'CPA', (129, 139))	('AKBA', 'Chemical', 'MESH:C094432', (36, 40))	('CDDP', 'Var', (46, 50))
40022	32562082	Additionally, the expressions of cyclin A2 and p-cdc2 proteins were decreased by treatment of CDDP but were elevated by treatment of AKBA in combination with CDDP (Fig.	('decreased', 'NegReg', (68, 77))	('cdc2', 'Gene', '983', (49, 53))	('AKBA', 'Chemical', 'MESH:C094432', (133, 137))	('cyclin A2', 'Gene', (33, 42))	('CDDP', 'Chemical', '-', (94, 98))	('cdc2', 'Gene', (49, 53))	('cyclin A2', 'Gene', '890', (33, 42))	('cyclin', 'molecular_function', 'GO:0016538', ('33', '39'))	('elevated', 'PosReg', (108, 116))	('expressions', 'MPA', (18, 29))	('CDDP', 'Var', (94, 98))	('CDDP', 'Chemical', '-', (158, 162))
40027	32562082	In addition, we also detected the expression levels of p27 and p21 proteins in BEAS-2B cells, finding that the expressions of p27 and p21 were decreased by treatment of CDDP but were elevated by treatment of AKBA in combination with CDDP (Fig.	('p27', 'Gene', '10671', (126, 129))	('AKBA', 'Chemical', 'MESH:C094432', (208, 212))	('p27', 'Gene', '10671', (55, 58))	('decreased', 'NegReg', (143, 152))	('p27', 'Gene', (126, 129))	('p21', 'Gene', (63, 66))	('CDDP', 'Chemical', '-', (169, 173))	('CDDP', 'Var', (169, 173))	('p21', 'Gene', '1026', (63, 66))	('p27', 'Gene', (55, 58))	('expressions', 'MPA', (111, 122))	('p21', 'Gene', '1026', (134, 137))	('CDDP', 'Chemical', '-', (233, 237))	('p21', 'Gene', (134, 137))	('elevated', 'PosReg', (183, 191))
40029	32562082	7b, the proportions of apoptotic cells were increased by AKBA and CDDP, and they were further elevated by synergetic therapy of AKBA and CDDP.	('CDDP', 'Chemical', '-', (66, 70))	('elevated', 'PosReg', (94, 102))	('AKBA', 'Chemical', 'MESH:C094432', (57, 61))	('CDDP', 'Var', (66, 70))	('CDDP', 'Chemical', '-', (137, 141))	('AKBA', 'Chemical', 'MESH:C094432', (128, 132))	('increased', 'PosReg', (44, 53))	('apoptotic cells', 'CPA', (23, 38))
40047	32562082	In this study, we also investigated the effects of knockdown of p21 on cell regulators in A549 cells treated with two drugs alone or in combination.	('p21', 'Gene', '1026', (64, 67))	('p21', 'Gene', (64, 67))	('knockdown', 'Var', (51, 60))
40059	32562082	10c and d, the expression of Bax of A549 cells transfected by p21 siRNA was decreased after treatment of CDDP alone or AKBA plus CDDP compared with A549 cells transfected by NC siRNA, suggesting that knockdown of p21 decreased the percentages of apoptotic cells and these two drugs exerted anti-cancer effects via p21-depdent signaling pathway.	('knockdown', 'Var', (200, 209))	('decreased', 'NegReg', (217, 226))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('Bax', 'Gene', (29, 32))	('AKBA', 'Chemical', 'MESH:C094432', (119, 123))	('signaling pathway', 'biological_process', 'GO:0007165', ('326', '343'))	('cancer', 'Disease', (295, 301))	('p21', 'Gene', '1026', (314, 317))	('decreased', 'NegReg', (76, 85))	('CDDP', 'Chemical', '-', (129, 133))	('CDDP', 'Chemical', '-', (105, 109))	('p21', 'Gene', (314, 317))	('p21', 'Gene', '1026', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('p21', 'Gene', (213, 216))	('Bax', 'Gene', '581', (29, 32))	('p21', 'Gene', '1026', (62, 65))	('p21', 'Gene', (62, 65))
40062	32562082	Hence, to study deeply the mechanism of chemo-sensitization, we selected A549 cells with knockdown of p21 to detect the expressions of autophagy associated proteins by using western blotting assay.	('sensitization', 'biological_process', 'GO:0046960', ('46', '59'))	('autophagy', 'biological_process', 'GO:0016236', ('135', '144'))	('autophagy', 'biological_process', 'GO:0006914', ('135', '144'))	('detect', 'Reg', (109, 115))	('knockdown', 'Var', (89, 98))	('p21', 'Gene', '1026', (102, 105))	('p21', 'Gene', (102, 105))
40087	32562082	CDDP leaded to cell cycle arrest at G2/M phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (15, 32))	('leaded to', 'Reg', (5, 14))	('arrest', 'Disease', 'MESH:D006323', (26, 32))	('CDDP', 'Var', (0, 4))	('CDDP', 'Chemical', '-', (0, 4))	('M phase', 'biological_process', 'GO:0000279', ('39', '46'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('15', '32'))	('arrest', 'Disease', (26, 32))
40102	32562082	In our study, CDDP significantly increased the number of apoptotic cells in NSCLC cells.	('CDDP', 'Chemical', '-', (14, 18))	('NSCLC', 'Disease', (76, 81))	('CDDP', 'Var', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('increased', 'PosReg', (33, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
40113	32562082	Furthermore, recent studies showed that inhibition of autophagy enhanced the sensitivity of CDDP in numerous cancers, including ovarian cancer (Wan et al.)	('inhibition', 'Var', (40, 50))	('enhanced', 'PosReg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('ovarian cancer', 'Disease', (128, 142))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('autophagy', 'CPA', (54, 63))	('numerous cancers', 'Disease', 'MESH:D009369', (100, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('CDDP', 'Chemical', '-', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))	('numerous cancers', 'Disease', (100, 116))	('sensitivity', 'MPA', (77, 88))
40115	32562082	), which indicated that debilitation of autophagy may be an effective approach to enhancing chemo-sensitivity in NSCLC (Sui et al.).	('chemo-sensitivity', 'CPA', (92, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('debilitation', 'Var', (24, 36))	('autophagy', 'biological_process', 'GO:0016236', ('40', '49'))	('NSCLC', 'Disease', (113, 118))	('enhancing', 'PosReg', (82, 91))	('autophagy', 'biological_process', 'GO:0006914', ('40', '49'))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
40116	32562082	Our results in this study showed that CDDP enhanced autophagy because of the upregulation of LC3A/B protein and the increasing ratio of positive autolysosome in CDDP group, compared with control group.	('autophagy', 'biological_process', 'GO:0016236', ('52', '61'))	('enhanced', 'PosReg', (43, 51))	('autophagy', 'CPA', (52, 61))	('autophagy', 'biological_process', 'GO:0006914', ('52', '61'))	('increasing', 'PosReg', (116, 126))	('autolysosome', 'cellular_component', 'GO:0044754', ('145', '157'))	('LC3A/B protein', 'Protein', (93, 107))	('positive autolysosome', 'CPA', (136, 157))	('CDDP', 'Var', (38, 42))	('upregulation', 'PosReg', (77, 89))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('CDDP', 'Chemical', '-', (161, 165))	('CDDP', 'Chemical', '-', (38, 42))
40117	32562082	In addition, after cotreatment of CDDP and AKBA, the expression level of LC3A/B protein and the ratio of positive autolysosome were decreased in A549 cells, compared with CDDP alone.	('AKBA', 'Chemical', 'MESH:C094432', (43, 47))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('LC3A/B protein', 'Protein', (73, 87))	('CDDP', 'Var', (34, 38))	('expression level', 'MPA', (53, 69))	('ratio of positive autolysosome', 'MPA', (96, 126))	('decreased', 'NegReg', (132, 141))	('autolysosome', 'cellular_component', 'GO:0044754', ('114', '126'))	('CDDP', 'Chemical', '-', (34, 38))	('CDDP', 'Chemical', '-', (171, 175))
40127	32562082	Cell cycle distribution determined by flow cytometry showed that after treatment of AKBA, knockdown of p21 decreased the percentages of G0/G1 phase, negatively controlled the cyclins and proteins, thus to drive cell cycle from G0/G1 to S phase, and increased the proportions of S phase, suggesting that p21 is a promising therapeutic molecular target for cycle arrest treatment with AKBA, and treatment of AKBA further enhanced the chemo-sensitivity of CDDP to NSCLC A549 cells.	('AKBA', 'Chemical', 'MESH:C094432', (84, 88))	('NSCLC', 'Disease', (461, 466))	('p21', 'Gene', (303, 306))	('cyclin', 'Gene', (175, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (461, 466))	('G1 phase', 'biological_process', 'GO:0051318', ('139', '147'))	('CDDP', 'Chemical', '-', (453, 457))	('proportions', 'MPA', (263, 274))	('p21', 'Gene', (103, 106))	('increased', 'PosReg', (249, 258))	('arrest', 'Disease', (361, 367))	('AKBA', 'Chemical', 'MESH:C094432', (406, 410))	('AKBA', 'Chemical', 'MESH:C094432', (383, 387))	('knockdown', 'Var', (90, 99))	('p21', 'Gene', '1026', (303, 306))	('enhanced', 'PosReg', (419, 427))	('percentages', 'MPA', (121, 132))	('chemo-sensitivity', 'CPA', (432, 449))	('cell cycle', 'biological_process', 'GO:0007049', ('211', '221'))	('drive', 'PosReg', (205, 210))	('controlled', 'Reg', (160, 170))	('p21', 'Gene', '1026', (103, 106))	('negatively', 'NegReg', (149, 159))	('arrest', 'Disease', 'MESH:D006323', (361, 367))	('cyclin', 'Gene', '5111', (175, 181))	('NSCLC', 'Disease', 'MESH:D002289', (461, 466))	('decreased', 'NegReg', (107, 116))	('S phase', 'biological_process', 'GO:0051320', ('278', '285'))	('cell cycle', 'CPA', (211, 221))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('S phase', 'biological_process', 'GO:0051320', ('236', '243'))
40128	32562082	We also found that AKBA, CDDP alone, or in combination all increased the apoptotic cells by flow cytometry, but after knockdown of p21, the percentages of apoptotic cells were obviously decreased in A549 cells, which indicated that p21 promoted apoptosis in NSCLC cells.	('NSCLC', 'Disease', (258, 263))	('AKBA', 'Chemical', 'MESH:C094432', (19, 23))	('knockdown', 'Var', (118, 127))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('p21', 'Gene', '1026', (131, 134))	('p21', 'Gene', '1026', (232, 235))	('apoptosis', 'biological_process', 'GO:0097194', ('245', '254'))	('apoptosis', 'biological_process', 'GO:0006915', ('245', '254'))	('p21', 'Gene', (131, 134))	('decreased', 'NegReg', (186, 195))	('p21', 'Gene', (232, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('CDDP', 'Chemical', '-', (25, 29))
40133	32562082	Hence, we downregulated the expression level of p21 in A549 cells, and then investigated whether or not knockdown of p21 exerted the acceleration effects on autophagy.	('p21', 'Gene', '1026', (48, 51))	('autophagy', 'biological_process', 'GO:0016236', ('157', '166'))	('p21', 'Gene', '1026', (117, 120))	('downregulated', 'NegReg', (10, 23))	('p21', 'Gene', (117, 120))	('autophagy', 'biological_process', 'GO:0006914', ('157', '166'))	('p21', 'Gene', (48, 51))	('autophagy', 'CPA', (157, 166))	('expression level', 'MPA', (28, 44))	('knockdown', 'Var', (104, 113))
40141	29135776	Validation of Molecular Pathology Codes for the Identification of Mutational Testing in Lung and Colon Cancer Targeted therapy for patients with lung and colon cancer based on tumor molecular profiles is an important cancer treatment strategy, but the impact of gene mutation tests on cancer treatment and outcomes in large populations is not clear.	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', (176, 181))	('Colon Cancer', 'Phenotype', 'HP:0003003', (97, 109))	('Colon Cancer', 'Disease', (97, 109))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (285, 291))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('patients', 'Species', '9606', (131, 139))	('Mutational', 'Var', (66, 76))	('Colon Cancer', 'Disease', 'MESH:D015179', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
40144	29135776	A combination of CPT laboratory codes ("stacking codes") was used to identify potential tumor mutation testing in the claims data.	('CPT', 'molecular_function', 'GO:0004142', ('17', '20'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CPT', 'molecular_function', 'GO:0004095', ('17', '20'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('mutation', 'Var', (94, 102))
40153	29135776	In patients with lung adenocarcinoma, treatment with epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib, leads to improvements in clinical outcomes for patients harboring specific somatic "oncogenic driver" mutations in the EGFR gene, whereas the presence of a KRAS gene mutation predicts lack of response to EGFR inhibition.	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('KRAS', 'Gene', '3845', (280, 284))	('epidermal growth factor receptor', 'Gene', (53, 85))	('EGFR', 'Gene', (328, 332))	('epidermal growth factor receptor', 'Gene', '1956', (53, 85))	('KRAS', 'Gene', (280, 284))	('patients', 'Species', '9606', (171, 179))	('improvements', 'PosReg', (133, 145))	('erlotinib', 'Chemical', 'MESH:D000069347', (113, 122))	('EGFR', 'Gene', '1956', (243, 247))	('lung adenocarcinoma', 'Disease', (17, 36))	('EGFR', 'Gene', (87, 91))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('53', '76'))	('patients', 'Species', '9606', (3, 11))	('EGFR', 'Gene', '1956', (328, 332))	('mutations', 'Var', (226, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (17, 36))	('clinical outcomes', 'MPA', (149, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (17, 36))	('EGFR', 'Gene', (243, 247))
40154	29135776	Tumors from patients with metastatic lung adenocarcinoma are therefore frequently evaluated to identify EGFR and/or KRAS mutations to guide chemotherapy selection.	('patients', 'Species', '9606', (12, 20))	('mutations', 'Var', (121, 130))	('EGFR', 'Gene', (104, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('Tumors', 'Disease', (0, 6))	('KRAS', 'Gene', (116, 120))	('lung adenocarcinoma', 'Disease', (37, 56))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (37, 56))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('KRAS', 'Gene', '3845', (116, 120))	('EGFR', 'Gene', '1956', (104, 108))
40155	29135776	Similarly, in patients with colon cancer, two anti-EGFR antibody-based therapies, cetuximab and panitumumab, are effective treatments for patients whose tumors do not harbor mutations in the KRAS gene (i.e., wild-type KRAS), but ineffective for patients with mutations in this gene.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (245, 253))	('EGFR', 'Gene', (51, 55))	('antibody', 'molecular_function', 'GO:0003823', ('56', '64'))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('KRAS', 'Gene', '3845', (218, 222))	('antibody', 'cellular_component', 'GO:0042571', ('56', '64'))	('patients', 'Species', '9606', (14, 22))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('KRAS', 'Gene', (218, 222))	('KRAS', 'Gene', '3845', (191, 195))	('mutations', 'Var', (174, 183))	('panitumumab', 'Chemical', 'MESH:D000077544', (96, 107))	('patients', 'Species', '9606', (138, 146))	('EGFR', 'Gene', '1956', (51, 55))	('colon cancer', 'Disease', (28, 40))	('antibody', 'cellular_component', 'GO:0019815', ('56', '64'))	('KRAS', 'Gene', (191, 195))	('cetuximab', 'Chemical', 'MESH:D000068818', (82, 91))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('antibody', 'cellular_component', 'GO:0019814', ('56', '64'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('tumors', 'Disease', (153, 159))
40156	29135776	Thus, tumor mutation testing to identify KRAS gene mutations is necessary to restrict the use of these agents to patients with wild-type KRAS.	('mutations', 'Var', (51, 60))	('KRAS', 'Gene', '3845', (41, 45))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('KRAS', 'Gene', (137, 141))	('KRAS', 'Gene', (41, 45))	('KRAS', 'Gene', '3845', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
40172	29135776	As patients with metastatic disease at presentation (i.e., Stage IV) are much more likely to undergo mutation testing, we selected only patients with metastatic colon cancer (mCC) or lung adenocarcinoma (mLAD) by identifying those with a diagnosis of M1 disease with any T or N designation as reported in PCR enrollment data.	('lung adenocarcinoma', 'Disease', (183, 202))	('mCC', 'biological_process', 'GO:0120197', ('175', '178'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('mCC', 'cellular_component', 'GO:0033597', ('175', '178'))	('undergo', 'Reg', (93, 100))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (3, 11))	('colon cancer', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mutation', 'Var', (101, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
40182	29135776	A laboratory report documenting testing and a result for either KRAS or EGFR mutation testing in lung cancer or KRAS testing only in colon cancer was considered to be positive clinical evidence of molecular testing.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'Gene', '1956', (72, 76))	('mutation', 'Var', (77, 85))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('KRAS', 'Gene', (64, 68))	('colon cancer', 'Disease', (133, 145))	('EGFR', 'Gene', (72, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('KRAS', 'Gene', (112, 116))	('lung cancer', 'Disease', (97, 108))	('KRAS', 'Gene', '3845', (112, 116))	('KRAS', 'Gene', '3845', (64, 68))
40195	29135776	National rates of mutation testing, as identified by stacking code use, in lung and colorectal cancer patients in the 5% random sample of traditional Medicare beneficiaries increased significantly between 2005 and 2012 (Figure 2).	('colorectal cancer', 'Disease', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('patients', 'Species', '9606', (102, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('mutation testing', 'Var', (18, 34))	('lung', 'Disease', (75, 79))
40196	29135776	The annual rate of mutation testing grew from 0.8% to 7.8% for patients with lung cancer (p<0.001), and from 0.7% to 5.2% for patients with colon cancer (p<0.001).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutation testing', 'Var', (19, 35))	('colon cancer', 'Phenotype', 'HP:0003003', (140, 152))	('colon cancer', 'Disease', 'MESH:D015179', (140, 152))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (63, 71))	('colon cancer', 'Disease', (140, 152))	('lung cancer', 'Disease', (77, 88))
40208	29135776	Second, although we show that stacking codes can accurately indicate that mutation testing was performed, these codes do not allow for identification of the specific mutation testing and are thus are context-specific (i.e., we assumed that the appearance of administrative claims with stacking codes in a patient with metastatic lung cancer was an indicator of lung tumor mutational testing).	('lung cancer', 'Disease', (329, 340))	('lung tumor', 'Disease', (361, 371))	('lung cancer', 'Phenotype', 'HP:0100526', (329, 340))	('lung tumor', 'Phenotype', 'HP:0100526', (361, 371))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('lung cancer', 'Disease', 'MESH:D008175', (329, 340))	('stacking codes', 'Var', (285, 299))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('patient', 'Species', '9606', (305, 312))	('lung tumor', 'Disease', 'MESH:D008175', (361, 371))
40216	33649783	RPLP0P2 knockdown significantly decreased cell colony formation, migration and invasion, and arrested CRC cells in the S phase to G2/M phase transition.	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('migration', 'CPA', (65, 74))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('knockdown', 'Var', (8, 17))	('CRC cells in the S phase to G2/M phase transition', 'CPA', (102, 151))	('M phase', 'biological_process', 'GO:0000279', ('133', '140'))	('S phase', 'biological_process', 'GO:0051320', ('119', '126'))	('cell colony formation', 'CPA', (42, 63))	('arrest', 'Disease', (93, 99))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('invasion', 'CPA', (79, 87))	('RPLP0P2', 'Gene', '113157', (0, 7))	('RPLP0P2', 'Gene', (0, 7))	('decreased', 'NegReg', (32, 41))
40223	33649783	In addition, it has been reported that dysregulation of lncRNAs may be involved in the development of human cancer.	('dysregulation', 'Var', (39, 52))	('involved', 'Reg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('lncRNAs', 'Protein', (56, 63))	('cancer', 'Disease', (108, 114))	('human', 'Species', '9606', (102, 107))
40266	33649783	CCK-8 cell proliferation assay revealed that shRNA-RPLP0P2 knockdown significantly decreased proliferation in RKO cells (Fig.	('RPLP0P2', 'Gene', (51, 58))	('proliferation', 'CPA', (93, 106))	('decreased', 'NegReg', (83, 92))	('RKO', 'CellLine', 'CVCL:0504', (110, 113))	('knockdown', 'Var', (59, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('6', '24'))	('RPLP0P2', 'Gene', '113157', (51, 58))	('CCK-8', 'Chemical', '-', (0, 5))
40268	33649783	The results revealed that RPLP0P2 knockdown significantly decreased the number of cell colonies, whereas the control group exhibited a normal ability to pack together and form colonies (Fig.	('decreased', 'NegReg', (58, 67))	('RPLP0P2', 'Gene', '113157', (26, 33))	('RPLP0P2', 'Gene', (26, 33))	('knockdown', 'Var', (34, 43))	('pack', 'CPA', (153, 157))
40275	33649783	The results detected increased accumulation of RKO cells in S phase in the RPLP0P2 knockdown group compared with in the control group, which was evidenced by a significant increase in the number of S phase cells (Fig.	('increase', 'PosReg', (172, 180))	('S phase cells', 'CPA', (198, 211))	('S phase', 'biological_process', 'GO:0051320', ('198', '205'))	('RKO', 'CellLine', 'CVCL:0504', (47, 50))	('RPLP0P2', 'Gene', '113157', (75, 82))	('RPLP0P2', 'Gene', (75, 82))	('accumulation', 'PosReg', (31, 43))	('S phase', 'biological_process', 'GO:0051320', ('60', '67'))	('knockdown', 'Var', (83, 92))	('S phase', 'CPA', (60, 67))
40276	33649783	Meanwhile, there was no significant difference in G2/M cell populations between the RPLP0P2 knockdown and control groups.	('knockdown', 'Var', (92, 101))	('RPLP0P2', 'Gene', '113157', (84, 91))	('RPLP0P2', 'Gene', (84, 91))
40277	33649783	These results revealed that shRNA-mediated RPLP0P2 knockdown arrested RKO cells from S stage to G2/M stage.	('arrest', 'Disease', (61, 67))	('RKO cells', 'CPA', (70, 79))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('RPLP0P2', 'Gene', '113157', (43, 50))	('RPLP0P2', 'Gene', (43, 50))	('RKO', 'CellLine', 'CVCL:0504', (70, 73))	('knockdown', 'Var', (51, 60))
40292	33649783	shRNA-mediated RPLP0P2 knockdown also induced cell cycle arrest of RKO cells in S stage, which confirmed that the RPLP0P2 expression levels were associated with cell proliferation.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('46', '63'))	('RPLP0P2', 'Gene', '113157', (114, 121))	('RPLP0P2', 'Gene', (114, 121))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('knockdown', 'Var', (23, 32))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('RPLP0P2', 'Gene', '113157', (15, 22))	('RPLP0P2', 'Gene', (15, 22))	('induced', 'Reg', (38, 45))	('arrest', 'Disease', (57, 63))	('RKO', 'CellLine', 'CVCL:0504', (67, 70))
40294	33649783	This finding is in agreement with the present experimental results, which revealed that RPLP0P2 knockdown induced cell accumulation in S phase of the cell cycle, suggesting that involvement of RPLP0P2 in CRC may be related to cells arrested from S phase to G2/M phase.	('knockdown', 'Var', (96, 105))	('S phase', 'biological_process', 'GO:0051320', ('246', '253'))	('CRC', 'Disease', (204, 207))	('cell cycle', 'biological_process', 'GO:0007049', ('150', '160'))	('RPLP0P2', 'Gene', '113157', (193, 200))	('arrest', 'Disease', 'MESH:D006323', (232, 238))	('S phase', 'biological_process', 'GO:0051320', ('135', '142'))	('RPLP0P2', 'Gene', (193, 200))	('RPLP0P2', 'Gene', (88, 95))	('RPLP0P2', 'Gene', '113157', (88, 95))	('M phase', 'biological_process', 'GO:0000279', ('260', '267'))	('CRC', 'Phenotype', 'HP:0003003', (204, 207))	('arrest', 'Disease', (232, 238))	('S phase of', 'MPA', (135, 145))
40305	33228475	The study focused on comparison of the COVID-19 infected lung tissue gene expression datasets -GSE155241 and GSE150316 with the GEO2R-limma package.	('COVID-19', 'Disease', 'MESH:C000657245', (39, 47))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('infected', 'Disease', 'MESH:D007239', (48, 56))	('COVID-19', 'Disease', (39, 47))	('infected', 'Disease', (48, 56))	('GSE150316', 'Var', (109, 118))
40309	33228475	Long non-coding RNAs such as C058791.1, TTTY15 and TPTEP1 were predicted to be efficient in regulating the disease mechanisms.	('TPTEP1', 'Gene', '387590', (51, 57))	('C058791.1', 'Var', (29, 38))	('TTTY15', 'Gene', '64595', (40, 46))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('TTTY15', 'Gene', (40, 46))	('TPTEP1', 'Gene', (51, 57))
40330	33228475	The gene expression datasets of COVID-19 were retrieved from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with the accessions GSE150316 (Desai et al.,) and GSE155241 (Han et al.,).	('COVID-19', 'Disease', (32, 40))	('GSE150316', 'Var', (141, 150))	('GSE155241', 'Var', (171, 180))	('Gene Expression', 'biological_process', 'GO:0010467', ('61', '76'))	('COVID-19', 'Disease', 'MESH:C000657245', (32, 40))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
40385	33228475	Long non coding RNAs act as competing endogenous RNA (ceRNA), to inhibit the miRNA expression and regulate the gene expression (Wang,).	('gene expression', 'biological_process', 'GO:0010467', ('111', '126'))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('regulate', 'Reg', (98, 106))	('miRNA expression', 'MPA', (77, 93))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('Long non coding', 'Var', (0, 15))	('inhibit', 'NegReg', (65, 72))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))	('gene expression', 'MPA', (111, 126))	('N', 'Chemical', 'MESH:D009584', (80, 81))
40389	33228475	Three miRNAs - hsa-miR-124-3p, hsa-miR-192-5p and hsa-let-7b-5p were significant with higher degrees of 270, 236 and 187 and a maximum of 69, 55 and 48 target genes, respectively.	('270', 'Var', (104, 107))	('hsa-miR-192', 'Gene', '406967', (31, 42))	('hsa-miR-124-3p', 'Gene', '406909', (15, 29))	('hsa-let-7b', 'Gene', (50, 60))	('hsa-miR-124-3p', 'Gene', (15, 29))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('hsa-let-7b', 'Gene', '406884', (50, 60))	('hsa-miR-192', 'Gene', (31, 42))	('N', 'Chemical', 'MESH:D009584', (9, 10))
40400	33228475	F-1566-0341 was a reported STAT inhibitor with antiviral, antihistamine properties and prescribed to treat neurological disorders (Redell & Tweardy,).	('neurological disorders', 'Disease', (107, 129))	('F-1566-0341', 'Var', (0, 11))	('F-1566-0341', 'Chemical', '-', (0, 11))	('neurological disorders', 'Disease', 'MESH:D009422', (107, 129))	('neurological disorder', 'Phenotype', 'HP:0000707', (107, 128))
40407	33228475	Ligand (Figure 9(A)) exhibited binding energy value of -82.29 Kcal/mol with two hydrogen bond interactions of 2.80 A0 and 3.07 A0 with Gly 143 and His 164 residues, respectively.	('binding', 'Interaction', (31, 38))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('Gly', 'Chemical', 'MESH:D005998', (135, 138))	('3.07', 'Var', (122, 126))	('hydrogen', 'Chemical', 'MESH:D006859', (80, 88))
40412	33228475	Interactions of Glu 290 with 3.59 A0 and Arg 131 at 4.04 A0 were also found but are exceeding the good Hydrogen bond interactions.	('Glu', 'Chemical', 'MESH:D018698', (16, 19))	('Hydrogen', 'Chemical', 'MESH:D006859', (103, 111))	('Arg 131', 'Var', (41, 48))	('Interactions', 'Interaction', (0, 12))	('Glu 290', 'Var', (16, 23))	('Arg', 'Chemical', 'MESH:D001120', (41, 44))
40416	33228475	Interaction of digoxin with residues Glu 127 and Lys 137 were also found at distances of 3.27 A0 and 3.39 A0 respectively.	('Lys', 'Chemical', 'MESH:D008239', (49, 52))	('Interaction', 'Interaction', (0, 11))	('digoxin', 'Chemical', 'MESH:D004077', (15, 22))	('Lys 137', 'Var', (49, 56))	('Glu 127', 'Var', (37, 44))	('Glu', 'Chemical', 'MESH:D018698', (37, 40))
40417	33228475	As seen in Figure 9(D), linifanib showed a slightly higher energy of -74.89 Kcal/mol with interacting residues Arg 105, Gln 110 and Asn 151 at distances of 4.08 A0, 3.63 A0 and 3.14 A0 respectively.	('Gln 110', 'Var', (120, 127))	('linifanib', 'Chemical', 'MESH:C513486', (24, 33))	('Asn 151', 'Var', (132, 139))	('Arg 105', 'Var', (111, 118))	('Arg', 'Chemical', 'MESH:D001120', (111, 114))	('Asn', 'Chemical', 'MESH:D001216', (132, 135))	('energy', 'MPA', (59, 65))	('higher', 'PosReg', (52, 58))	('Gln', 'Chemical', 'MESH:D005973', (120, 123))
40418	33228475	The drug F-1566-0341 (Figure 9(E)) exhibited an energy of -76.89 Kcal/mol and interactions of 3.16 A0 and 3.70 A0 with 5 Lys and 3.15 A0 with 127 Gln.	('Gln', 'Chemical', 'MESH:D005973', (146, 149))	('Lys', 'Chemical', 'MESH:D008239', (121, 124))	('F-1566-0341', 'Var', (9, 20))	('F-1566-0341', 'Chemical', '-', (9, 20))	('interactions', 'Interaction', (78, 90))
40420	33228475	Though Linifanib and F-1566-0341 had slightly higher binding energy values, the interactions were better when compared to the control ligand N3.	('F-1566-0341', 'Var', (21, 32))	('higher', 'PosReg', (46, 52))	('F-1566-0341', 'Chemical', '-', (21, 32))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('ligand', 'molecular_function', 'GO:0005488', ('134', '140'))	('interactions', 'Interaction', (80, 92))	('N', 'Chemical', 'MESH:D009584', (141, 142))	('binding', 'Interaction', (53, 60))	('Linifanib', 'Chemical', 'MESH:C513486', (7, 16))	('Linifanib', 'Gene', (7, 16))
40467	33228475	Originally, F-1566-0341 were reported as antiviral drugs and digoxin to treat heart failure.	('heart failure', 'Disease', 'MESH:D006333', (78, 91))	('F-1566-0341', 'Var', (12, 23))	('digoxin', 'Chemical', 'MESH:D004077', (61, 68))	('F-1566-0341', 'Chemical', '-', (12, 23))	('treat heart failure', 'Phenotype', 'HP:0001635', (72, 91))	('heart failure', 'Disease', (78, 91))
40470	33228475	In conclusion it is reported that there can be severe hypoxia due to failure of iron transport, and imbalance of copper homeostasis (Prohaska,) which leads to severe complications in respiration, liver, blood clotting, and neuroendocrine peptides (Cagliani et al.,).	('failure', 'NegReg', (69, 76))	('hypoxia', 'Disease', (54, 61))	('imbalance', 'Var', (100, 109))	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('imbalance', 'Phenotype', 'HP:0002172', (100, 109))	('copper homeostasis', 'Disease', (113, 131))	('iron transport', 'biological_process', 'GO:0006826', ('80', '94'))	('copper homeostasis', 'biological_process', 'GO:0055070', ('113', '131'))	('respiration', 'biological_process', 'GO:0045333', ('183', '194'))	('respiration', 'biological_process', 'GO:0007585', ('183', '194'))	('respiration', 'MPA', (183, 194))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('copper homeostasis', 'Disease', 'MESH:D007706', (113, 131))	('iron transport', 'MPA', (80, 94))	('copper homeostasis', 'biological_process', 'GO:0006878', ('113', '131'))	('blood clotting', 'biological_process', 'GO:0007596', ('203', '217'))
40478	33228475	Though linifanib and F-1566-0341, showed significant interactions compared to the original control ligand N3, their energy levels were high.	('F-1566-0341', 'Var', (21, 32))	('F-1566-0341', 'Chemical', '-', (21, 32))	('linifanib', 'Chemical', 'MESH:C513486', (7, 16))	('ligand', 'molecular_function', 'GO:0005488', ('99', '105'))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('energy levels', 'MPA', (116, 129))	('interactions', 'Interaction', (53, 65))
40494	32383554	MiR-379-5p and miR-410-3p were significantly up-regulated in metastatic patients (P < .01).	('up-regulated', 'PosReg', (45, 57))	('miR-410-3p', 'Chemical', '-', (15, 25))	('MiR-379', 'Gene', '494328', (0, 7))	('metastatic', 'Disease', (61, 71))	('MiR-379', 'Gene', (0, 7))	('miR-410-3p', 'Var', (15, 25))	('patients', 'Species', '9606', (72, 80))
40495	32383554	Higher expression of exosomal miR-379-5p or miR-410-3p showed shorter progression-free survival of the patients (P < .05).	('miR-410-3p', 'Var', (44, 54))	('shorter', 'NegReg', (62, 69))	('progression-free survival', 'CPA', (70, 95))	('expression', 'MPA', (7, 17))	('miR-379', 'Gene', '494328', (30, 37))	('miR-410-3p', 'Chemical', '-', (44, 54))	('patients', 'Species', '9606', (103, 111))	('miR-379', 'Gene', (30, 37))
40496	32383554	It was also found that miR-379-5p and miR-410-3p were down-regulated in gastric cancer tissue samples, while they were significantly up-regulated in gastric cancer cell culture medium compared with cancer cells.	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('up-regulated', 'PosReg', (133, 145))	('miR-410-3p', 'Chemical', '-', (38, 48))	('cancer', 'Disease', (80, 86))	('gastric cancer', 'Disease', (149, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-379', 'Gene', '494328', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('down-regulated', 'NegReg', (54, 68))	('miR-379', 'Gene', (23, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('miR-410-3p', 'Var', (38, 48))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('gastric cancer', 'Disease', (72, 86))
40521	32383554	Studies have shown that dysregulation of miRNAs was involved in initiation and progression of various malignancies, including gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('gastric cancer', 'Disease', (126, 140))	('dysregulation', 'Var', (24, 37))	('miRNAs', 'Protein', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('malignancies', 'Disease', (102, 114))	('involved', 'Reg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
40541	32383554	The membrane was blocked with 5% no-fat milk, followed by incubation with antibodies specific for anti-CD9 and anti-HSP70 (1:1000; SBI) and anti-beta-actin (1:20 000; Cell Signaling Technology), respectively.	('anti-beta-actin', 'Var', (140, 155))	('HSP70', 'Gene', '3308', (116, 121))	('Signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('CD9', 'Gene', '928', (103, 106))	('CD9', 'Gene', (103, 106))	('HSP70', 'Gene', (116, 121))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))
40568	32383554	From the qPCR array, we found C t values of miR-16-5p, miR-93-5p, miR-486-3p and SNORD38B were more consistent among the six samples.	('miR-486-3p', 'Var', (66, 76))	('SNORD38B', 'Gene', '94163', (81, 89))	('miR-16', 'Gene', '51573', (44, 50))	('SNORD38B', 'Gene', (81, 89))	('miR-93', 'Gene', '407051', (55, 61))	('miR-93', 'Gene', (55, 61))	('miR-16', 'Gene', (44, 50))
40570	32383554	But the expressions of miR-486-3p or SNORD38B were "undetermined" (C t > 40) in some of the samples.	('SNORD38B', 'Gene', (37, 45))	('miR-486-3p', 'Var', (23, 33))	('SNORD38B', 'Gene', '94163', (37, 45))
40571	32383554	It indicated the expressions of miR-486-3p or SNORD38B were too low in some of the samples to be analysed as an internal control.	('SNORD38B', 'Gene', '94163', (46, 54))	('expressions', 'MPA', (17, 28))	('miR-486-3p', 'Var', (32, 42))	('SNORD38B', 'Gene', (46, 54))
40576	32383554	Seven of the dysregulated miRNAs (let-7c-5p, miR-144-5p, miR-379-5p, miR-410-3p, miR-98-5p, miR-505-5p and miR-934) were chosen for further study according to their fold changes and association with cancer development (Table S4).	('let-7c', 'Gene', '406885', (34, 40))	('miR-379', 'Gene', '494328', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-379', 'Gene', (57, 64))	('miR-505', 'Gene', (92, 99))	('miR-98', 'Gene', '407054', (81, 87))	('miR-144', 'Gene', (45, 52))	('miR-934', 'Gene', (107, 114))	('miR-98', 'Gene', (81, 87))	('miR-505', 'Gene', '574508', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('miR-410-3p', 'Var', (69, 79))	('miR-144', 'Gene', '406936', (45, 52))	('cancer', 'Disease', (199, 205))	('let-7c', 'Gene', (34, 40))	('miR-934', 'Gene', '100126324', (107, 114))	('miR-410-3p', 'Chemical', '-', (69, 79))
40578	32383554	Hence, four miRNAs, miR-144-5p, miR-379-5p, miR-410-3p and miR-505-5p, were applied for evaluation in the remaining of the samples.	('miR-410-3p', 'Var', (44, 54))	('miR-379', 'Gene', '494328', (32, 39))	('miR-144', 'Gene', (20, 27))	('miR-410-3p', 'Chemical', '-', (44, 54))	('miR-505', 'Gene', (59, 66))	('miR-505', 'Gene', '574508', (59, 66))	('miR-144', 'Gene', '406936', (20, 27))	('miR-379', 'Gene', (32, 39))
40580	32383554	RT-qPCR indicated that exosomal miR-379-5p and miR-410-3p were significantly up-regulated in the metastasis group (N = 31) comparing with the non-metastasis group (N = 52; Figure 4, ** P < .01).	('miR-410-3p', 'Var', (47, 57))	('miR-379', 'Gene', '494328', (32, 39))	('metastasis', 'CPA', (97, 107))	('miR-410-3p', 'Chemical', '-', (47, 57))	('up-regulated', 'PosReg', (77, 89))	('miR-379', 'Gene', (32, 39))
40581	32383554	Sensitivity and specificity of exosomal miR-379-5p and miR-410-3p were indicated in Figure 5.	('miR-379', 'Gene', '494328', (40, 47))	('miR-379', 'Gene', (40, 47))	('miR-410-3p', 'Var', (55, 65))	('miR-410-3p', 'Chemical', '-', (55, 65))
40582	32383554	Statistical analysis revealed the AUC were 0.6904 for miR-379-5p/miR-16-5p, 0.7016 for miR-379-5p/miR-93-5p, 0.6799 for miR-410-3p/miR-16-5p and 0.7115 for miR-410-3p/miR-93-5p (Figure 5, left side).	('miR-379', 'Gene', '494328', (87, 94))	('0.7115', 'Var', (145, 151))	('miR-93', 'Gene', (98, 104))	('0.7016', 'Var', (76, 82))	('miR-16', 'Gene', (65, 71))	('0.6904', 'Var', (43, 49))	('miR-410-3p', 'Chemical', '-', (156, 166))	('miR-379', 'Gene', '494328', (54, 61))	('miR-16', 'Gene', (131, 137))	('miR-16', 'Gene', '51573', (131, 137))	('miR-16', 'Gene', '51573', (65, 71))	('miR-379', 'Gene', (87, 94))	('miR-410-3p', 'Chemical', '-', (120, 130))	('miR-93', 'Gene', '407051', (167, 173))	('0.6799', 'Var', (109, 115))	('miR-93', 'Gene', (167, 173))	('miR-379', 'Gene', (54, 61))	('miR-93', 'Gene', '407051', (98, 104))
40583	32383554	In addition, the progression-free survival of the patients with higher expression of exosomal miR-379-5p or miR-410-3p was significantly worse than the patients with lower expression (Figure 5, right side).	('progression-free survival', 'CPA', (17, 42))	('expression', 'MPA', (71, 81))	('worse', 'NegReg', (137, 142))	('miR-410-3p', 'Chemical', '-', (108, 118))	('miR-379', 'Gene', '494328', (94, 101))	('patients', 'Species', '9606', (50, 58))	('higher', 'PosReg', (64, 70))	('miR-379', 'Gene', (94, 101))	('miR-410-3p', 'Var', (108, 118))	('exosomal', 'Var', (85, 93))	('patients', 'Species', '9606', (152, 160))
40584	32383554	This suggested that exosomal miR-379-5p and miR-410-3p were associated with gastric cancer progression.	('miR-410-3p', 'Var', (44, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('miR-379', 'Gene', (29, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('miR-379', 'Gene', '494328', (29, 36))	('miR-410-3p', 'Chemical', '-', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('associated', 'Reg', (60, 70))	('gastric cancer', 'Disease', (76, 90))
40586	32383554	To investigate the mechanism of higher expressions of exosomal miR-379-5p and miR-410-3p, the expressions of these two miRNAs were evaluated in gastric cancer paired tumour/ adjacent non-tumour tissue samples (N = 43 pairs) by qPCR.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Disease', (187, 193))	('gastric cancer paired tumour', 'Disease', (144, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('tumour', 'Disease', (166, 172))	('miR-379', 'Gene', '494328', (63, 70))	('miR-410-3p', 'Var', (78, 88))	('miR-379', 'Gene', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('gastric cancer paired tumour', 'Disease', 'MESH:D013274', (144, 172))	('miR-410-3p', 'Chemical', '-', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumour', 'Disease', 'MESH:D009369', (187, 193))
40587	32383554	The result indicated both miR-379-5p and miR-410-3p were significantly down-regulated in gastric cancer tissue samples (*P < .05, 32 out of 43 pairs for miR-379-5p and **P < .01, 33 out of 43 pairs for miR-410-3p) Figure 6A.	('down-regulated', 'NegReg', (71, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('miR-379', 'Gene', (26, 33))	('miR-379', 'Gene', '494328', (153, 160))	('miR-410-3p', 'Var', (41, 51))	('gastric cancer', 'Disease', (89, 103))	('miR-379', 'Gene', '494328', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('miR-379', 'Gene', (153, 160))	('miR-410-3p', 'Chemical', '-', (202, 212))	('miR-410-3p', 'Chemical', '-', (41, 51))
40588	32383554	Expression of miR-379-5p or miR-410-3p was significantly down-regulated in gastric cancer tissue samples, whereas exosomal miR-379-5p or miR-410-3p was up-regulated in serum samples.	('down-regulated', 'NegReg', (57, 71))	('miR-379', 'Gene', '494328', (14, 21))	('miR-379', 'Gene', '494328', (123, 130))	('miR-410-3p', 'Var', (28, 38))	('Expression', 'MPA', (0, 10))	('miR-379', 'Gene', (123, 130))	('miR-410-3p', 'Var', (137, 147))	('up-regulated', 'PosReg', (152, 164))	('gastric cancer', 'Disease', (75, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miR-379', 'Gene', (14, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('miR-410-3p', 'Chemical', '-', (28, 38))	('miR-410-3p', 'Chemical', '-', (137, 147))
40590	32383554	To validate this assumption, expressions of miR-379-5p or miR-410-3p and exosomal miR-379-5p or miR-410-3p were evaluated in gastric cancer cell lines and relevant cell culture medium respectively.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('miR-379', 'Gene', (82, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('miR-410-3p', 'Var', (58, 68))	('miR-410-3p', 'Var', (96, 106))	('miR-379', 'Gene', '494328', (44, 51))	('miR-379', 'Gene', '494328', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('miR-410-3p', 'Chemical', '-', (58, 68))	('gastric cancer', 'Disease', (125, 139))	('miR-410-3p', 'Chemical', '-', (96, 106))	('miR-379', 'Gene', (44, 51))
40595	32383554	The result showed that expressions of exosomal miR-379-5p and miR-410-3p in cancer cell culture medium were significantly higher than the expressions of miR-379-5p and miR-410-3p in gastric cancer cells Figure 6B.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('miR-379', 'Gene', (47, 54))	('miR-379', 'Gene', '494328', (153, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('higher', 'PosReg', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miR-410-3p', 'Var', (62, 72))	('miR-379', 'Gene', '494328', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('miR-410-3p', 'Chemical', '-', (168, 178))	('gastric cancer', 'Disease', (182, 196))	('miR-379', 'Gene', (153, 160))	('cancer', 'Disease', (76, 82))	('miR-410-3p', 'Chemical', '-', (62, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('expressions', 'MPA', (23, 34))
40596	32383554	This suggested that exosomes might translocate miR-379-5p and miR-410-3p from cancer cells to medium.	('miR-379', 'Gene', (47, 54))	('cancer', 'Disease', (78, 84))	('translocate', 'MPA', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('miR-410-3p', 'Var', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR-379', 'Gene', '494328', (47, 54))	('miR-410-3p', 'Chemical', '-', (62, 72))
40602	32383554	By miRNA profiling and qPCR validation, we identify serum exosomal miR-379-5p and miR-410-3p as promising circulating biomarkers for prediction of development of haematogenous metastasis after surgery for stage II/III gastric cancer.	('III gastric cancer', 'Disease', (214, 232))	('miR-410-3p', 'Var', (82, 92))	('miR-410-3p', 'Chemical', '-', (82, 92))	('haematogenous metastasis', 'Disease', 'MESH:D009362', (162, 186))	('miR-379', 'Gene', '494328', (67, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('haematogenous metastasis', 'Disease', (162, 186))	('III gastric cancer', 'Disease', 'MESH:D013274', (214, 232))	('miR-379', 'Gene', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
40603	32383554	Exosomal miR-379-5p and miR-410-3p significantly increased in metastatic patients comparing with non-metastatic ones.	('increased', 'PosReg', (49, 58))	('miR-410-3p', 'Var', (24, 34))	('patients', 'Species', '9606', (73, 81))	('miR-379', 'Gene', '494328', (9, 16))	('Exosomal', 'MPA', (0, 8))	('miR-410-3p', 'Chemical', '-', (24, 34))	('metastatic', 'Disease', (62, 72))	('miR-379', 'Gene', (9, 16))
40604	32383554	Higher expressions of exosomal miR-379-5p or miR-410-3p were associated with worse progression-free survival of the patients.	('miR-379', 'Gene', '494328', (31, 38))	('miR-410-3p', 'Chemical', '-', (45, 55))	('patients', 'Species', '9606', (116, 124))	('progression-free survival', 'CPA', (83, 108))	('miR-379', 'Gene', (31, 38))	('miR-410-3p', 'Var', (45, 55))	('expressions', 'MPA', (7, 18))	('exosomal', 'Protein', (22, 30))
40605	32383554	These results indicated that exosomal miR-379-5p and miR-410-3p might contribute to gastric cancer progression.	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('miR-410-3p', 'Chemical', '-', (53, 63))	('miR-379', 'Gene', (38, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('contribute', 'Reg', (70, 80))	('miR-410-3p', 'Var', (53, 63))	('miR-379', 'Gene', '494328', (38, 45))
40606	32383554	We also found miR-379-5p and miR-410-3p were down-regulated in gastric cancer tissue samples.	('gastric cancer', 'Disease', (63, 77))	('miR-379', 'Gene', '494328', (14, 21))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('miR-410-3p', 'Chemical', '-', (29, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('down-regulated', 'NegReg', (45, 59))	('miR-379', 'Gene', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-410-3p', 'Var', (29, 39))
40607	32383554	As miRNAs could be selectively secreted from their original gastric cancer cells by exosomes, translocation of miR-379-5p and miR-410-3p from cancer cells to circulation might contribute to the down-regulation of miR-379-5p and miR-410-3p in gastric cancer tissue samples.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (242, 256))	('regulation', 'biological_process', 'GO:0065007', ('199', '209'))	('miR-410-3p', 'Chemical', '-', (126, 136))	('miR-379', 'Gene', '494328', (213, 220))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('miR-379', 'Gene', (213, 220))	('miR-410-3p', 'Chemical', '-', (228, 238))	('miR-379', 'Gene', '494328', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('miR-379', 'Gene', (111, 118))	('cancer', 'Disease', (142, 148))	('gastric cancer', 'Disease', (242, 256))	('miR-410-3p', 'Var', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (242, 256))	('down-regulation', 'NegReg', (194, 209))	('cancer', 'Disease', (250, 256))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('translocation', 'MPA', (94, 107))
40608	32383554	This assumption was validated in cell line model that expression levels of exosomal miR-379-5p or miR-410-3p in cell culture medium were much higher than their expression levels in gastric cancer cells.	('miR-379', 'Gene', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('miR-379', 'Gene', '494328', (84, 91))	('miR-410-3p', 'Chemical', '-', (98, 108))	('gastric cancer', 'Disease', (181, 195))	('expression levels', 'MPA', (54, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (181, 195))	('miR-410-3p', 'Var', (98, 108))	('higher', 'PosReg', (142, 148))	('gastric cancer', 'Phenotype', 'HP:0012126', (181, 195))
40610	32383554	29 ,  30  Interestingly, another study indicated exosomal miR-379-5p was higher in plasma samples of lung cancer patients and exosomal miR-379-5p could be circulating biomarkers for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Disease', (182, 193))	('exosomal', 'MPA', (49, 57))	('patients', 'Species', '9606', (113, 121))	('miR-379', 'Gene', (58, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('miR-379', 'Gene', '494328', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('exosomal', 'Var', (126, 134))	('miR-379', 'Gene', '494328', (58, 65))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('lung cancer', 'Disease', (101, 112))	('miR-379', 'Gene', (135, 142))	('higher', 'PosReg', (73, 79))
40617	32383554	Studies reported that miR-410-3p functioned as an oncogene in liver cancer, lung cancer and colorectal cancer, 33 ,  34 ,  35  but as a tumour suppressor in osteosarcoma (bone), glioma (brain) and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('osteosarcoma', 'Disease', (157, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (157, 169))	('liver cancer', 'Phenotype', 'HP:0002896', (62, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('liver cancer', 'Disease', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('glioma', 'Disease', (178, 184))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('miR-410-3p', 'Chemical', '-', (22, 32))	('lung cancer', 'Disease', (76, 87))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('breast cancer', 'Disease', (197, 210))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (136, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('colorectal cancer', 'Disease', (92, 109))	('miR-410-3p', 'Var', (22, 32))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('liver cancer', 'Disease', 'MESH:D006528', (62, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))
40618	32383554	36 ,  37 ,  38  This evidence suggests that the roles of miR-410-3p are cancer-specific and content dependent.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('miR-410-3p', 'Chemical', '-', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('miR-410-3p', 'Var', (57, 67))	('cancer', 'Disease', (72, 78))
40619	32383554	The functions of miR-410-3p are complicated and miR-410-3p is a double-sword in cancer initiation and progression.	('miR-410-3p', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('miR-410-3p', 'Chemical', '-', (17, 27))	('miR-410-3p', 'Chemical', '-', (48, 58))	('cancer', 'Disease', (80, 86))
40620	32383554	39  A study suggested miR-410-3p functioned as a tumour suppressor in gastric cancer.	('miR-410-3p', 'Var', (22, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('miR-410-3p', 'Chemical', '-', (22, 32))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('gastric cancer', 'Disease', (70, 84))	('tumour', 'Disease', (49, 55))
40622	32383554	Secretion of miR-410-3p in exosomes from cancer cells to circulation might contribute to its down-regulation in tissue samples.	('down-regulation', 'NegReg', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('miR-410-3p', 'Var', (13, 23))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('miR-410-3p', 'Chemical', '-', (13, 23))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))
40623	32383554	Exosomal miR-410-3p might enter into distant cells and play oncogenic roles in those cells.	('play', 'Reg', (55, 59))	('miR-410-3p', 'Chemical', '-', (9, 19))	('miR-410-3p', 'Var', (9, 19))
40625	32383554	But this could not explain gastric cancer metastasis to brain, bone or breast (soft tissue), as miR-410-3p executed as a tumour suppressor in these sites.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('miR-410-3p', 'Var', (96, 106))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('gastric cancer metastasis', 'Disease', 'MESH:D013274', (27, 52))	('tumour', 'Disease', (121, 127))	('miR-410-3p', 'Chemical', '-', (96, 106))	('gastric cancer metastasis', 'Disease', (27, 52))
40628	32383554	For example, a study suggested that serum exosomal miR-19b-3p and miR-106a-5 could be potential biomarkers for detection of gastric cancer.	('gastric cancer', 'Disease', (124, 138))	('miR-106a-5', 'Var', (66, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('miR-19b-3p', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))
40629	32383554	41  Another study investigated six serum miRNAs as diagnostic biomarkers for gastric cancer and further indicated four serum exosomal miR-10b-5p, miR-195-5p, miR-20a-3p and miR-296-5p were significantly increased in patients with gastric cancer.	('miR-20a-3p', 'Var', (158, 168))	('gastric cancer', 'Disease', (77, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('miR-195', 'Gene', (146, 153))	('gastric cancer', 'Disease', (230, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('miR-296', 'Gene', (173, 180))	('patients', 'Species', '9606', (216, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (230, 244))	('miR-10b-5p', 'Var', (134, 144))	('miR-195', 'Gene', '406971', (146, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (230, 244))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('miR-296', 'Gene', '407022', (173, 180))	('increased', 'PosReg', (203, 212))
40633	32383554	Exosomal miR-379-5p and miR-410-3p were significantly up-regulated in the serum of gastric cancer patients who would develop haematogenous metastasis.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('develop', 'PosReg', (117, 124))	('haematogenous metastasis', 'Disease', 'MESH:D009362', (125, 149))	('miR-410-3p', 'Var', (24, 34))	('miR-410-3p', 'Chemical', '-', (24, 34))	('patients', 'Species', '9606', (98, 106))	('miR-379', 'Gene', '494328', (9, 16))	('Exosomal', 'MPA', (0, 8))	('up-regulated', 'PosReg', (54, 66))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('haematogenous metastasis', 'Disease', (125, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('miR-379', 'Gene', (9, 16))
40634	32383554	Higher exosomal miR-379-5p or miR-410-3p was associated with worse progression-free survival of the patients.	('miR-410-3p', 'Var', (30, 40))	('exosomal', 'MPA', (7, 15))	('miR-379', 'Gene', '494328', (16, 23))	('patients', 'Species', '9606', (100, 108))	('miR-410-3p', 'Chemical', '-', (30, 40))	('miR-379', 'Gene', (16, 23))	('progression-free survival', 'CPA', (67, 92))	('worse', 'NegReg', (61, 66))
40636	32383554	In conclusion, serum exosomal miR-379-5p and miR-410-3p may be applied as circulating biomarkers for prediction of development of haematogenous metastasis after surgery for patients with stage II/III gastric cancer.	('miR-410-3p', 'Chemical', '-', (45, 55))	('III gastric cancer', 'Disease', (196, 214))	('III gastric cancer', 'Disease', 'MESH:D013274', (196, 214))	('patients', 'Species', '9606', (173, 181))	('haematogenous metastasis', 'Disease', (130, 154))	('miR-410-3p', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('miR-379', 'Gene', '494328', (30, 37))	('haematogenous metastasis', 'Disease', 'MESH:D009362', (130, 154))	('miR-379', 'Gene', (30, 37))
40839	32313071	There were no significant differences in the body weights and in the absolute and relative weights of liver and spleen between the groups, but the rats of groups 52w-quartz and 96w-quartz had generally lower body weights than those of groups 52w-saline and 96w-saline.	('52w', 'Chemical', '-', (242, 245))	('lower body weights', 'Phenotype', 'HP:0004325', (202, 220))	('rats', 'Species', '10116', (147, 151))	('body weights', 'CPA', (208, 220))	('saline', 'Chemical', 'MESH:D012965', (261, 267))	('lower', 'NegReg', (202, 207))	('52w-quartz', 'Var', (162, 172))	('saline', 'Chemical', 'MESH:D012965', (246, 252))	('52w', 'Chemical', '-', (162, 165))	('96w-quartz', 'Var', (177, 187))
40848	32313071	Histopathologically, the lungs of rats from groups 52w-quartz and 96w-quartz showed severe inflammatory changes in the alveolar area and lymph follicle formation around the bronchiole (Fig.	('rats', 'Species', '10116', (34, 38))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('inflammatory changes', 'CPA', (91, 111))	('96w-quartz', 'Var', (66, 76))	('52w', 'Chemical', '-', (51, 54))
40850	32313071	The inflammatory changes in groups 52w-quartz and 96w-quartz were observed in the central and peripheral areas of all lobes of the lungs.	('96w-quartz', 'Var', (50, 60))	('52w', 'Chemical', '-', (35, 38))	('52w-quartz', 'Var', (35, 45))
40851	32313071	The lungs from groups 52w-quartz and 96w-quartz showed neutrophil infiltration in the alveolar walls and in the alveolar space (Fig.	('rat', 'Species', '10116', (72, 75))	('52w', 'Chemical', '-', (22, 25))	('52w-quartz', 'Var', (22, 32))	('neutrophil infiltration', 'CPA', (55, 78))	('96w-quartz', 'Var', (37, 47))
40862	32313071	2l); however, there were no statistical differences in the scores for macrophage and neutrophil infiltration in the alveolar space and for granuloma between groups 96w-quartzand 96w-saline.	('saline', 'Chemical', 'MESH:D012965', (182, 188))	('granuloma', 'Phenotype', 'HP:0032252', (139, 148))	('granuloma', 'Disease', 'MESH:D006099', (139, 148))	('rat', 'Species', '10116', (102, 105))	('96w-quartzand', 'Var', (164, 177))	('granuloma', 'Disease', (139, 148))
40863	32313071	Macrophage infiltration and pulmonary fibrosis in group 96w-quartzwere significantly lower than those in group 52w-quartz (P < 0.01, Fig.	('pulmonary fibrosis', 'Disease', (28, 46))	('52w', 'Chemical', '-', (111, 114))	('lower', 'NegReg', (85, 90))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (28, 46))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (28, 46))	('96w-quartzwere', 'Var', (56, 70))	('rat', 'Species', '10116', (17, 20))
40866	32313071	Groups 52w-quartz and 52w-saline exhibited inflammatory changes (Fig.	('52w', 'Chemical', '-', (22, 25))	('52w', 'Chemical', '-', (7, 10))	('inflammatory changes', 'CPA', (43, 63))	('52w-quartz', 'Var', (7, 17))	('saline', 'Chemical', 'MESH:D012965', (26, 32))
40874	32313071	The numbers of hyperplasia, adenoma, and adenocarcinoma per rat in group 96w-quartz were significantly higher than those in group 96w-saline (P < 0.05, P < 0.01; Fig.	('saline', 'Chemical', 'MESH:D012965', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('rat', 'Species', '10116', (60, 63))	('adenoma', 'Disease', 'MESH:D000236', (28, 35))	('hyperplasia', 'Disease', (15, 26))	('adenocarcinoma', 'Disease', (41, 55))	('adenoma', 'Disease', (28, 35))	('96w-quartz', 'Var', (73, 83))	('higher', 'PosReg', (103, 109))	('hyperplasia', 'Disease', 'MESH:D006965', (15, 26))	('adenocarcinoma', 'Disease', 'MESH:D000230', (41, 55))
40883	32313071	Groups 52w-quartz and 52w-saline exhibited bile duct hyperplasia and lymphocyte infiltration, clear cell foci in the liver, and tubule regeneration and lymphocyte infiltration in the kidney.	('rat', 'Species', '10116', (169, 172))	('rat', 'Species', '10116', (86, 89))	('52w', 'Chemical', '-', (22, 25))	('regeneration', 'biological_process', 'GO:0031099', ('135', '147'))	('bile duct hyperplasia', 'Phenotype', 'HP:0006560', (43, 64))	('tubule regeneration', 'CPA', (128, 147))	('lymphocyte infiltration', 'CPA', (152, 175))	('lymphocyte infiltration', 'CPA', (69, 92))	('bile duct hyperplasia', 'Disease', 'MESH:D001650', (43, 64))	('52w', 'Chemical', '-', (7, 10))	('bile duct hyperplasia', 'Disease', (43, 64))	('52w-quartz', 'Var', (7, 17))	('rat', 'Species', '10116', (141, 144))	('saline', 'Chemical', 'MESH:D012965', (26, 32))	('clear cell foci', 'CPA', (94, 109))
40942	32313071	In our previous study, we reported that high expression of SP-C is a potential marker of proliferative lesions including hyperplasia.	('high', 'Var', (40, 44))	('SP-C', 'Gene', '50683', (59, 63))	('SP-C', 'Gene', (59, 63))	('hyperplasia', 'Disease', 'MESH:D006965', (121, 132))	('rat', 'Species', '10116', (96, 99))	('hyperplasia', 'Disease', (121, 132))
40962	32158261	A ZFPM2-AS1 knockdown significantly reduced cervical cancer cell proliferation, migration, and invasion and increased apoptosis in vitro.	('apoptosis', 'CPA', (118, 127))	('invasion', 'CPA', (95, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('cervical cancer', 'Disease', (44, 59))	('cervical cancer', 'Disease', 'MESH:D002583', (44, 59))	('increased', 'PosReg', (108, 117))	('knockdown', 'Var', (12, 21))	('migration', 'CPA', (80, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('ZFPM2-AS1', 'Gene', '102723356', (2, 11))	('ZFPM2-AS1', 'Gene', (2, 11))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('reduced', 'NegReg', (36, 43))
40963	32158261	The ZFPM2-AS1 knockdown decelerated tumor growth of cervical cancer cells in vivo.	('cervical cancer', 'Disease', (52, 67))	('cervical cancer', 'Disease', 'MESH:D002583', (52, 67))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('decelerated', 'NegReg', (24, 35))	('tumor growth of cervical cancer', 'Phenotype', 'HP:0030159', (36, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('knockdown', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZFPM2-AS1', 'Gene', '102723356', (4, 13))	('ZFPM2-AS1', 'Gene', (4, 13))	('tumor', 'Disease', (36, 41))
40966	32158261	The effects of the ZFPM2-AS1 knockdown on malignant characteristics of cervical cancer cells were greatly attenuated by miR-511-3p inhibition.	('attenuated', 'NegReg', (106, 116))	('knockdown', 'Var', (29, 38))	('cervical cancer', 'Disease', (71, 86))	('miR', 'Gene', '220972', (120, 123))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('miR', 'Gene', (120, 123))	('ZFPM2-AS1', 'Gene', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ZFPM2-AS1', 'Gene', '102723356', (19, 28))
40978	32158261	Functionally, the aberrantly expressed lncRNAs exert cancer-inhibiting or cancer-promoting actions and thereby serve as critical modulators of cervical carcinogenesis by affecting a number of malignant characteristics.	('aberrantly expressed', 'Var', (18, 38))	('lncRNAs', 'Protein', (39, 46))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cervical carcinogenesis', 'Disease', (143, 166))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('affecting', 'Reg', (170, 179))	('cervical carcinogenesis', 'Disease', 'MESH:D063646', (143, 166))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
41024	32158261	FGFR2 3' untranslated region (UTR) fragments containing either the predicted wild-type (WT) miR-511-3p-binding site or a mutant (MUT) binding site were amplified by GenePharma Technology.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('mutant', 'Var', (121, 127))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('binding', 'molecular_function', 'GO:0005488', ('134', '141'))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
41042	32158261	Furthermore, patients with cervical cancer in the ZFPM2-AS1 high-expression group showed shorter overall survival than did the patients in the ZFPM2-AS1 low-expression group (Figure 1C, P = 0.024).	('ZFPM2-AS1', 'Gene', '102723356', (143, 152))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (13, 21))	('ZFPM2-AS1', 'Gene', '102723356', (50, 59))	('ZFPM2-AS1', 'Gene', (50, 59))	('high-expression', 'Var', (60, 75))	('patients', 'Species', '9606', (127, 135))	('cervical cancer', 'Disease', (27, 42))	('cervical cancer', 'Disease', 'MESH:D002583', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('ZFPM2-AS1', 'Gene', (143, 152))	('shorter', 'NegReg', (89, 96))
41048	32158261	In addition, the knockdown of ZFPM2-AS1 strongly promoted the apoptosis of HeLa and SiHa cells, as evidenced by flow-cytometric analysis (Figure 2C and D, P < 0.05).	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('ZFPM2-AS1', 'Gene', '102723356', (30, 39))	('apoptosis', 'CPA', (62, 71))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('promoted', 'PosReg', (49, 57))	('knockdown', 'Var', (17, 26))	('ZFPM2-AS1', 'Gene', (30, 39))	('SiHa', 'CellLine', 'CVCL:0032', (84, 88))
41050	32158261	According to the results, the knockdown of ZFPM2-AS1 significantly reduced the migratory (Figure 2E, P < 0.05) and invasive abilities (Figure 2F, P < 0.05) of HeLa and SiHa cells.	('HeLa', 'CellLine', 'CVCL:0030', (159, 163))	('reduced', 'NegReg', (67, 74))	('SiHa', 'CellLine', 'CVCL:0032', (168, 172))	('ZFPM2-AS1', 'Gene', '102723356', (43, 52))	('ZFPM2-AS1', 'Gene', (43, 52))	('knockdown', 'Var', (30, 39))	('migratory', 'CPA', (79, 88))	('invasive abilities', 'CPA', (115, 133))
41073	32158261	The luciferase activity of HeLa and SiHa cells transfected with WT-FGFR2 was substantially impaired by the miR-511-3p mimic (P < 0.05); however, when the binding sequences of miR-511-3p were mutated in the luciferase reporter plasmid (resulting in plasmid MUT-FGFR2), upregulation of miR-511-3p failed to inhibit the luciferase activity in the transfected HeLa and SiHa cells (Figure 5B).	('FGFR', 'molecular_function', 'GO:0005007', ('260', '264'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('317', '336'))	('miR', 'Gene', (284, 287))	('luciferase activity', 'molecular_function', 'GO:0047712', ('317', '336'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('4', '23'))	('activity', 'MPA', (328, 336))	('luciferase activity', 'molecular_function', 'GO:0045289', ('4', '23'))	('FGFR2', 'Gene', (67, 72))	('luciferase activity', 'molecular_function', 'GO:0047712', ('4', '23'))	('miR', 'Gene', '220972', (107, 110))	('FGFR2', 'Gene', '2263', (260, 265))	('luciferase', 'Enzyme', (317, 327))	('luciferase activity', 'molecular_function', 'GO:0050248', ('317', '336'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('317', '336'))	('FGFR2', 'Gene', '2263', (67, 72))	('luciferase activity', 'molecular_function', 'GO:0050397', ('4', '23'))	('miR', 'Gene', (107, 110))	('luciferase activity', 'molecular_function', 'GO:0050248', ('4', '23'))	('miR', 'Gene', '220972', (175, 178))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('HeLa', 'CellLine', 'CVCL:0030', (356, 360))	('SiHa', 'CellLine', 'CVCL:0032', (365, 369))	('miR', 'Gene', '220972', (284, 287))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('mutated', 'Var', (191, 198))	('miR', 'Gene', (175, 178))	('FGFR2', 'Gene', (260, 265))	('luciferase activity', 'molecular_function', 'GO:0047077', ('317', '336'))	('HeLa', 'CellLine', 'CVCL:0030', (27, 31))	('SiHa', 'CellLine', 'CVCL:0032', (36, 40))
41083	32158261	The downregulation of FGFR2 mRNA (Figure 6E, P < 0.05) and protein (Figure 6F, P < 0.05) mediated by the ZFPM2-AS1 knockdown was found to be greatly recovered by miR-511-3p inhibition in HeLa and SiHa cells.	('HeLa', 'CellLine', 'CVCL:0030', (187, 191))	('SiHa', 'CellLine', 'CVCL:0032', (196, 200))	('knockdown', 'Var', (115, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('FGFR2', 'Gene', (22, 27))	('FGFR2', 'Gene', '2263', (22, 27))	('downregulation', 'NegReg', (4, 18))	('ZFPM2-AS1', 'Gene', '102723356', (105, 114))	('ZFPM2-AS1', 'Gene', (105, 114))	('protein', 'MPA', (59, 66))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))	('mRNA', 'MPA', (28, 32))
41086	32158261	The ZFPM2-AS1 knockdown suppressed HeLa and SiHa cell proliferation (Figure 6G, P < 0.05), promoted their apoptosis (Figure 6H and I, P < 0.05), and decreased their migration (Figure 6J, P < 0.05) and invasiveness (Figure 6K, P < 0.05) in vitro.	('SiHa', 'CellLine', 'CVCL:0032', (44, 48))	('promoted', 'PosReg', (91, 99))	('HeLa', 'CellLine', 'CVCL:0030', (35, 39))	('ZFPM2-AS1', 'Gene', '102723356', (4, 13))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('apoptosis', 'CPA', (106, 115))	('invasiveness', 'Disease', 'MESH:D009361', (201, 213))	('suppressed', 'NegReg', (24, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('invasiveness', 'Disease', (201, 213))	('decreased', 'NegReg', (149, 158))	('knockdown', 'Var', (14, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('migration', 'CPA', (165, 174))	('ZFPM2-AS1', 'Gene', (4, 13))
41092	32158261	The expression levels of ZFPM2-AS1, miR-511-3p, and FGFR2 in the subcutaneous tumors were determined to verify whether the miR-511-3p-FGFR2 axis is responsible for the tumor growth inhibition caused by the ZFPM2-AS1 knockdown.	('FGFR2', 'Gene', (52, 57))	('miR', 'Gene', '220972', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('miR', 'Gene', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('FGFR2', 'Gene', '2263', (52, 57))	('ZFPM2-AS1', 'Gene', (25, 34))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (123, 126))	('knockdown', 'Var', (216, 225))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('tumors', 'Disease', (78, 84))	('ZFPM2-AS1', 'Gene', '102723356', (25, 34))	('ZFPM2-AS1', 'Gene', (206, 215))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('FGFR2', 'Gene', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('ZFPM2-AS1', 'Gene', '102723356', (206, 215))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (65, 84))	('FGFR2', 'Gene', '2263', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
41096	32158261	The dysregulation of lncRNAs has been demonstrated to be crucial for cervical carcinogenesis and cervical cancer progression through the control of a wide range of aggressive characteristics of cancer cells.	('cervical carcinogenesis', 'Disease', 'MESH:D063646', (69, 92))	('cervical cancer', 'Disease', (97, 112))	('cancer', 'Disease', (194, 200))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (106, 112))	('cervical carcinogenesis', 'Disease', (69, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
41108	32158261	In lung adenocarcinoma, resumption of ZFPM2-AS1 expression can increase cancer cell viability and colony-forming ability in vitro.	('cancer', 'Disease', (72, 78))	('increase', 'PosReg', (63, 71))	('resumption', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (3, 22))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('ZFPM2-AS1', 'Gene', '102723356', (38, 47))	('ZFPM2-AS1', 'Gene', (38, 47))	('lung adenocarcinoma', 'Disease', (3, 22))	('colony-forming ability', 'CPA', (98, 120))
41114	32158261	After identifying the expression status and roles of ZFPM2-AS1 in cervical cancer, we next sought to explore the mechanisms of ZFPM2-AS1 knockdown-mediated suppression of the aggressive phenotype of cervical cancer cells in vitro and in vivo.	('aggressive phenotype', 'CPA', (175, 195))	('suppression', 'NegReg', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ZFPM2-AS1', 'Gene', '102723356', (53, 62))	('ZFPM2-AS1', 'Gene', (53, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (199, 214))	('cervical cancer', 'Disease', (66, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cervical cancer', 'Disease', (199, 214))	('ZFPM2-AS1', 'Gene', '102723356', (127, 136))	('ZFPM2-AS1', 'Gene', (127, 136))	('knockdown-mediated', 'Var', (137, 155))
41120	32158261	Fifth, the ZFPM2-AS1 knockdown raised endogenous miR-511-3p expression and decreased the expression of miR-511-3p's target (FGFR2) in cervical cancer cells.	('endogenous', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('expression', 'MPA', (89, 99))	('ZFPM2-AS1', 'Gene', '102723356', (11, 20))	('ZFPM2-AS1', 'Gene', (11, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('FGFR2', 'Gene', (124, 129))	('FGFR2', 'Gene', '2263', (124, 129))	('cervical cancer', 'Disease', (134, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (134, 149))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('raised', 'PosReg', (31, 37))	('knockdown', 'Var', (21, 30))	('decreased', 'NegReg', (75, 84))
41122	32158261	Finally, miR-511-3p inhibition abrogated the regulatory effects of the ZFPM2-AS1 knockdown on FGFR2 expression and on the malignant phenotype of cervical cancer cells.	('abrogated', 'NegReg', (31, 40))	('malignant phenotype of', 'CPA', (122, 144))	('FGFR2', 'Gene', (94, 99))	('FGFR2', 'Gene', '2263', (94, 99))	('regulatory effects', 'MPA', (45, 63))	('ZFPM2-AS1', 'Gene', (71, 80))	('expression', 'MPA', (100, 110))	('cervical cancer', 'Disease', (145, 160))	('knockdown', 'Var', (81, 90))	('ZFPM2-AS1', 'Gene', '102723356', (71, 80))	('cervical cancer', 'Disease', 'MESH:D002583', (145, 160))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
41123	32158261	MiR-511-3p expression is low in prostate cancer and plays an inhibitory part in the aggressiveness of tumor cells in vitro and in vivo.	('prostate cancer', 'Disease', (32, 47))	('MiR-511-3p expression', 'Var', (0, 21))	('aggressiveness of tumor', 'Disease', (84, 107))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('aggressiveness', 'Phenotype', 'HP:0000718', (84, 98))	('low', 'NegReg', (25, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('aggressiveness of tumor', 'Disease', 'MESH:D001523', (84, 107))
41159	31469421	Frequency and Outcomes of Brain Metastases in Patients With HER2-Mutant Lung Cancers Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations are found in approximately 2% of lung adenocarcinomas.	('Brain Metastases', 'Disease', (26, 42))	('HER2', 'Gene', (60, 64))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (183, 203))	('found', 'Reg', (154, 159))	('HER2', 'Gene', '2064', (127, 131))	('epidermal growth factor receptor 2', 'Gene', (91, 125))	('Lung Cancers', 'Disease', 'MESH:D008175', (72, 84))	('Lung Cancers', 'Disease', (72, 84))	('Cancers', 'Phenotype', 'HP:0002664', (77, 84))	('ERBB2', 'Gene', (133, 138))	('lung adenocarcinomas', 'Disease', (183, 203))	('ERBB2', 'Gene', '2064', (133, 138))	('Patients', 'Species', '9606', (46, 54))	('Human', 'Species', '9606', (85, 90))	('HER2', 'Gene', '2064', (60, 64))	('HER2', 'Gene', (127, 131))	('mutations', 'Var', (140, 149))	('Lung Cancers', 'Phenotype', 'HP:0100526', (72, 84))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (183, 203))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('91', '114'))	('Brain Metastases', 'Disease', 'MESH:D009362', (26, 42))	('epidermal growth factor receptor 2', 'Gene', '2064', (91, 125))
41164	31469421	Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS-mutations (HR 5.9, P < .001).	('HER2', 'Gene', '2064', (14, 18))	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('YVMA', 'Gene', (19, 23))	('Patients', 'Species', '9606', (0, 8))	('brain metastases', 'Disease', 'MESH:D009362', (54, 70))	('patients', 'Species', '9606', (89, 97))	('brain metastases', 'Disease', (54, 70))	('mutations', 'Var', (24, 33))	('HER2', 'Gene', (14, 18))
41168	31469421	Oncogenic driver mutations influence the disease course, treatment options, and the development of brain metastases in patients with lung cancers.	('lung cancers', 'Disease', 'MESH:D008175', (133, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('patients', 'Species', '9606', (119, 127))	('lung cancers', 'Phenotype', 'HP:0100526', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('brain metastases', 'Disease', 'MESH:D009362', (99, 115))	('influence', 'Reg', (27, 36))	('brain metastases', 'Disease', (99, 115))	('lung cancers', 'Disease', (133, 145))	('mutations', 'Var', (17, 26))
41170	31469421	Oncogenic mutations in human epidermal growth factor receptor 2 (HER2, also known as ERBB2) occur in 2% of lung adenocarcinomas.	('HER2', 'Gene', '2064', (65, 69))	('lung adenocarcinomas', 'Disease', (107, 127))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (107, 127))	('ERBB2', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (85, 90))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (107, 127))	('epidermal growth factor receptor 2', 'Gene', '2064', (29, 63))	('epidermal growth factor receptor 2', 'Gene', (29, 63))	('human', 'Species', '9606', (23, 28))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('29', '52'))	('mutations', 'Var', (10, 19))	('HER2', 'Gene', (65, 69))
41171	31469421	Partially due to an absence of effective, targeted therapies, HER2 mutations are associated with worse outcomes compared to other oncogenic drivers.	('HER2', 'Gene', '2064', (62, 66))	('HER2', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
41177	31469421	This study aims to characterize the association between brain metastases and HER2-mutant lung cancers, including examination of a 12 base pair, in-frame insertion (p.A775 G776insYVMA) in exon 20 (HER2 YVMA).	('p.A775 G776insYVMA', 'Mutation', 'p.775,776insG,YVMA', (164, 182))	('lung cancers', 'Disease', (89, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('brain metastases', 'Disease', 'MESH:D009362', (56, 72))	('HER2', 'Gene', (77, 81))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('brain metastases', 'Disease', (56, 72))	('HER2', 'Gene', (196, 200))	('HER2', 'Gene', '2064', (77, 81))	('lung cancers', 'Disease', 'MESH:D008175', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancers', 'Phenotype', 'HP:0100526', (89, 101))	('HER2', 'Gene', '2064', (196, 200))	('p.A775 G776insYVMA', 'Var', (164, 182))
41179	31469421	The oncogenic activity of the HER2 YVMA mutation is well described and occurs through downstream activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways.	('protein kinase B', 'Gene', '2185', (148, 164))	('AKT', 'Gene', (166, 169))	('HER2', 'Gene', (30, 34))	('phosphoinositide 3-kinase', 'Gene', '5290', (115, 140))	('protein kinase B', 'Gene', (148, 164))	('MEK', 'Gene', '5609', (209, 212))	('PI3K', 'molecular_function', 'GO:0016303', ('142', '146'))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('extracellular', 'cellular_component', 'GO:0005576', ('214', '227'))	('phosphoinositide 3-kinase', 'Gene', (115, 140))	('mitogen-activated protein kinase', 'Gene', '5609', (175, 207))	('YVMA', 'Gene', (35, 39))	('mutation', 'Var', (40, 48))	('MEK', 'Gene', (209, 212))	('AKT', 'Gene', '207', (166, 169))	('activation', 'PosReg', (97, 107))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('ERK', 'Gene', '5594', (253, 256))	('HER2', 'Gene', '2064', (30, 34))	('oncogenic activity', 'CPA', (4, 22))	('ERK', 'molecular_function', 'GO:0004707', ('253', '256'))	('ERK', 'Gene', (253, 256))	('mitogen-activated protein kinase', 'Gene', (175, 207))
41183	31469421	Unlike the molecularly defined subset of lung cancers harboring an EGFR mutation, HER2- and KRAS-mutant lung cancers do not currently have FDA approved effective targeted therapies available.	('KRAS', 'Gene', (92, 96))	('lung cancers', 'Disease', 'MESH:D008175', (41, 53))	('lung cancers', 'Disease', 'MESH:D008175', (104, 116))	('EGFR', 'Gene', (67, 71))	('lung cancers', 'Disease', (41, 53))	('lung cancers', 'Disease', (104, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('HER2', 'Gene', (82, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancers', 'Phenotype', 'HP:0100526', (41, 53))	('lung cancers', 'Phenotype', 'HP:0100526', (104, 116))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('EGFR', 'Gene', '1956', (67, 71))	('mutation', 'Var', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('HER2', 'Gene', '2064', (82, 86))	('KRAS', 'Gene', '3845', (92, 96))
41184	31469421	The association between HER2 mutations and brain metastasis is important to quantify as it can both describe the clinical course of the disease and help to guide treatment.	('HER2', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('brain metastasis', 'CPA', (43, 59))	('HER2', 'Gene', '2064', (24, 28))
41201	31469421	There were 27 unique HER2 mutations identified, including 14 known to be activating.	('HER2', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('HER2', 'Gene', '2064', (21, 25))
41202	31469421	Most patients with HER2-mutant lung cancer (N = 72) harbored an exon 20 insertion (Supporting Table 2).	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('patients', 'Species', '9606', (5, 13))	('HER2', 'Gene', (19, 23))	('HER2', 'Gene', '2064', (19, 23))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('exon 20', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
41204	31469421	An additional 13 unique HER2 alterations were classified as variants of unknown significance.	('HER2', 'Gene', (24, 28))	('HER2', 'Gene', '2064', (24, 28))	('alterations', 'Var', (29, 40))
41205	31469421	Of the 98 patients in the HER2 cohort, 32 mutations were discovered using the Sequenom platform and the remaining 66 were found with targeted NGS.	('HER2', 'Gene', (26, 30))	('mutations', 'Var', (42, 51))	('HER2', 'Gene', '2064', (26, 30))	('patients', 'Species', '9606', (10, 18))
41211	31469421	Analysis of HER2-mutant subgroups indicated that patients with the HER2 YVMA mutation were significantly more likely to develop brain metastases on treatment than patients in the KRAS-cohort, but not the EGFR-cohort or patients with HER2 non-YVMA mutations (Table 2, Supporting Fig.	('KRAS', 'Gene', '3845', (179, 183))	('develop', 'PosReg', (120, 127))	('patients', 'Species', '9606', (163, 171))	('HER2', 'Gene', (12, 16))	('mutation', 'Var', (77, 85))	('brain metastases', 'Disease', 'MESH:D009362', (128, 144))	('brain metastases', 'Disease', (128, 144))	('HER2', 'Gene', (67, 71))	('HER2', 'Gene', '2064', (12, 16))	('EGFR', 'Gene', '1956', (204, 208))	('HER2', 'Gene', '2064', (67, 71))	('KRAS', 'Gene', (179, 183))	('patients', 'Species', '9606', (219, 227))	('HER2', 'Gene', (233, 237))	('patients', 'Species', '9606', (49, 57))	('EGFR', 'Gene', (204, 208))	('HER2', 'Gene', '2064', (233, 237))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))
41214	31469421	In the HER2 YVMA mutant subgroup, those that ever-had brain metastatic disease had worse OS compared to those without brain metastatic disease (HR 2.8, 95% CI 1.3-6.3, P = .01).	('brain metastatic disease', 'Disease', 'MESH:C538445', (54, 78))	('HER2', 'Gene', '2064', (7, 11))	('brain metastatic disease', 'Disease', (118, 142))	('brain metastatic disease', 'Disease', (54, 78))	('HER2', 'Gene', (7, 11))	('mutant', 'Var', (17, 23))	('brain metastatic disease', 'Disease', 'MESH:C538445', (118, 142))
41217	31469421	Patients with the HER2 YVMA mutation had similar survival (OS 1.3 years, 95% CI 1.2-2.4 years) to patients with KRAS mutations (HR 1.0, 95% CI 0.6-1.5, P = .89), but inferior survival compared to patients with EGFR mutations (HR 1.9, 95% CI 1.2-2.9, P = .005).	('HER2', 'Gene', '2064', (18, 22))	('EGFR', 'Gene', (210, 214))	('YVMA', 'Gene', (23, 27))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (196, 204))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (28, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('KRAS', 'Gene', (112, 116))	('survival', 'MPA', (175, 183))	('KRAS', 'Gene', '3845', (112, 116))	('inferior', 'NegReg', (166, 174))	('HER2', 'Gene', (18, 22))	('EGFR', 'Gene', '1956', (210, 214))
41224	31469421	Fifty four percent (25/46) of patients with HER2 mutations and brain metastases received brain radiotherapy compared to 59% (38/64) of patients with KRAS- and 53% (50/94) of patients with EGFR-mutations.	('brain radiotherapy', 'CPA', (89, 107))	('patients', 'Species', '9606', (135, 143))	('mutations', 'Var', (49, 58))	('brain metastases', 'Disease', 'MESH:D009362', (63, 79))	('KRAS', 'Gene', (149, 153))	('brain metastases', 'Disease', (63, 79))	('HER2', 'Gene', (44, 48))	('KRAS', 'Gene', '3845', (149, 153))	('patients', 'Species', '9606', (174, 182))	('HER2', 'Gene', '2064', (44, 48))	('EGFR', 'Gene', '1956', (188, 192))	('patients', 'Species', '9606', (30, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('EGFR', 'Gene', (188, 192))
41235	31469421	Patients with the HER2 YVMA mutation were significantly more likely to develop brain metastases on treatment compared to patients with KRAS-mutant lung cancers.	('lung cancers', 'Disease', (147, 159))	('HER2', 'Gene', '2064', (18, 22))	('brain metastases', 'Disease', 'MESH:D009362', (79, 95))	('YVMA', 'Gene', (23, 27))	('brain metastases', 'Disease', (79, 95))	('KRAS', 'Gene', (135, 139))	('lung cancers', 'Disease', 'MESH:D008175', (147, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('KRAS', 'Gene', '3845', (135, 139))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (28, 36))	('develop', 'PosReg', (71, 78))	('lung cancers', 'Phenotype', 'HP:0100526', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('patients', 'Species', '9606', (121, 129))	('HER2', 'Gene', (18, 22))
41246	31469421	Divergent co-mutations and variations of driver mutations resulted in population heterogeneities that may have affected the clinical course of the cancers within each cohort.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('variations', 'Var', (27, 37))	('resulted in', 'Reg', (58, 69))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('co-mutations', 'Var', (10, 22))	('affected', 'Reg', (111, 119))	('cancers', 'Disease', (147, 154))
41255	31638194	Alterations in RNA expression (lncRNA, miRNA and mRNA) constitute the largest proportion of the biomarkers of BCR.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('Alterations', 'Var', (0, 11))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))	('BCR', 'Disease', (110, 113))	('RNA expression', 'MPA', (15, 29))
41268	31638194	This capacity of BCR risk stratification is of particular relevance to patients with low- and intermediate-risk PCs; low-risk and intermediate-risk PCs are defined by the European Association of Urology (EAU)-European Society for Radiotherapy and Oncology (ESTRO)-International Society of Geriatric Oncology (SIOG) as PSA <10 ng/ml, Gleason score (GS) <7, cT1-2a, and local-ized (low risk) and PSA levels of 10-20 ng/ml or GS 7 or cT2c and localized (intermediate risk).	('GS', 'Disease', 'MESH:D011125', (348, 350))	('patients', 'Species', '9606', (71, 79))	('PSA', 'Gene', '354', (394, 397))	('Oncology', 'Phenotype', 'HP:0002664', (247, 255))	('Oncology', 'Phenotype', 'HP:0002664', (299, 307))	('cT2c', 'Var', (431, 435))	('PSA', 'Gene', '354', (318, 321))	('PSA', 'Gene', (318, 321))	('PSA', 'Gene', (394, 397))	('GS', 'Disease', 'MESH:D011125', (423, 425))
41278	31638194	Abnormalities in the regulation of cell proliferation are typical of cancer.	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('21', '53'))	('Abnormalities', 'Var', (0, 13))	('regulation of', 'MPA', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
41288	31638194	In a systemic review published in 2018 on the IHC-based detection of BCR, the loss of PTEN was found to be associated with BCR in 8 investigations.	('PTEN', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (86, 90))	('associated', 'Reg', (107, 117))	('BCR', 'Disease', (123, 126))	('loss', 'Var', (78, 82))
41290	31638194	The exception was first observed with BRCA2 germ-line mutations that increase the incidence of PC along with the risk of PC progression; these mutations drive the evolvement of PC by causing genomic instability.	('genomic instability', 'MPA', (191, 210))	('BRCA2', 'Gene', '675', (38, 43))	('mutations', 'Var', (54, 63))	('causing', 'Reg', (183, 190))	('BRCA2', 'Gene', (38, 43))	('drive', 'Reg', (153, 158))	('mutations', 'Var', (143, 152))
41291	31638194	In line with this concept, germline mutations in other factors regulating the DNA damage response (DDR) also increase the risk of PC progression, including ATM, CHEK2, BRCA1, RAD51D and PALB2.	('RAD51D', 'Gene', (175, 181))	('BRCA1', 'Gene', '672', (168, 173))	('PALB2', 'Gene', (186, 191))	('PALB2', 'Gene', '79728', (186, 191))	('RAD', 'biological_process', 'GO:1990116', ('175', '178'))	('increase', 'PosReg', (109, 117))	('BRCA1', 'Gene', (168, 173))	('ATM', 'Gene', '472', (156, 159))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('DNA damage response', 'biological_process', 'GO:0006974', ('78', '97'))	('CHEK2', 'Gene', '11200', (161, 166))	('germline mutations', 'Var', (27, 45))	('RAD51D', 'Gene', '5892', (175, 181))	('ATM', 'Gene', (156, 159))	('CHEK2', 'Gene', (161, 166))
41292	31638194	The observation that BRCA1/2 germline mutations are associated with the risk of PC and PC progression provides additional support for the similarities between PC and breast cancer.	('BRCA1', 'Gene', '672', (21, 26))	('associated', 'Reg', (52, 62))	('BRCA1', 'Gene', (21, 26))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('germline mutations', 'Var', (29, 47))
41294	31638194	It will thus be of interest to investigate the contributions of mutations in BRCA2, ATM, CHEK2, BRCA1, RAD51D and PALB2 in a variety of combinations in the assessment of the risk of BCR.	('CHEK2', 'Gene', (89, 94))	('PALB2', 'Gene', (114, 119))	('ATM', 'Gene', (84, 87))	('RAD', 'biological_process', 'GO:1990116', ('103', '106'))	('BRCA1', 'Gene', '672', (96, 101))	('RAD51D', 'Gene', '5892', (103, 109))	('BRCA2', 'Gene', (77, 82))	('BCR', 'Disease', (182, 185))	('RAD51D', 'Gene', (103, 109))	('ATM', 'Gene', '472', (84, 87))	('BRCA1', 'Gene', (96, 101))	('mutations', 'Var', (64, 73))	('BRCA2', 'Gene', '675', (77, 82))	('CHEK2', 'Gene', '11200', (89, 94))	('PALB2', 'Gene', '79728', (114, 119))
41301	31638194	Alterations in individual miRNAs have been observed to be associated with BCR (Table I).	('miR', 'Gene', '220972', (26, 29))	('associated', 'Reg', (58, 68))	('miR', 'Gene', (26, 29))	('BCR', 'Disease', (74, 77))	('Alterations', 'Var', (0, 11))
41322	31638194	The single nucleotide polymorphism (guanine/adenine) rs2240308 is associated with a decrease in the risk of PC (OR, 0.377; 95% CI, 0.206-0.688; P= 0.001).	('decrease', 'NegReg', (84, 92))	('rs2240308', 'Mutation', 'rs2240308', (53, 62))	('single nucleotide polymorphism', 'Var', (4, 34))	('adenine', 'Chemical', 'MESH:D000225', (44, 51))	('guanine', 'Chemical', 'MESH:D006147', (36, 43))	('rs2240308', 'Var', (53, 62))
41326	31638194	The downregulation of metallothionein 1E (MT1E) is a risk factor for BCR in association with promoter methylation.	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('promoter methylation', 'Var', (93, 113))	('MT1', 'molecular_function', 'GO:0043791', ('42', '45'))	('MT1E', 'Gene', '4493', (42, 46))	('MT1', 'molecular_function', 'GO:0047152', ('42', '45'))	('metallothionein 1E', 'Gene', (22, 40))	('downregulation', 'NegReg', (4, 18))	('BCR', 'Disease', (69, 72))	('metallothionein 1E', 'Gene', '4493', (22, 40))	('MT1', 'molecular_function', 'GO:0043834', ('42', '45'))	('MT1E', 'Gene', (42, 46))
41328	31638194	In addition to PC, MT1E is also downregulated in endometrial carcinoma, intrahepatic cholangiocarcinoma, melanoma, non-small cell lung cancer, papillary thyroid carcinoma and renal cell carcinoma; in the majority of these cancer types, the reductions are associated with hypermethylation.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('non-small cell lung cancer', 'Disease', (115, 141))	('MT1E', 'Gene', (19, 23))	('papillary thyroid carcinoma', 'Disease', 'MESH:C536915', (143, 170))	('cancer', 'Disease', (135, 141))	('MT1', 'molecular_function', 'GO:0047152', ('19', '22'))	('endometrial carcinoma', 'Disease', (49, 70))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (143, 170))	('cancer', 'Disease', (222, 228))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (72, 103))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (115, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MT1', 'molecular_function', 'GO:0043834', ('19', '22'))	('papillary thyroid carcinoma', 'Disease', (143, 170))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (175, 195))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('downregulated', 'NegReg', (32, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('intrahepatic cholangiocarcinoma', 'Disease', (72, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (49, 70))	('renal cell carcinoma', 'Disease', (175, 195))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (175, 195))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (115, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (49, 70))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('melanoma', 'Disease', (105, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (153, 170))	('MT1E', 'Gene', '4493', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('MT1', 'molecular_function', 'GO:0043791', ('19', '22'))	('hypermethylation', 'Var', (271, 287))
41349	31638194	Although the functionality of GLTSCR1 in tumorigenesis remains unclear, recent evidence indicates its role in chromatin remodeling, implying GLTSCR1 may contribute to BCR progression via epigenetic regulations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('epigenetic regulations', 'Var', (187, 209))	('chromatin', 'cellular_component', 'GO:0000785', ('110', '119'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('110', '130'))	('tumor', 'Disease', (41, 46))	('GLTSCR1', 'Gene', (30, 37))	('GLTSCR1', 'Gene', '29998', (141, 148))	('BCR', 'Disease', (167, 170))	('GLTSCR1', 'Gene', '29998', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('GLTSCR1', 'Gene', (141, 148))	('contribute', 'Reg', (153, 163))
41359	31638194	In patients with low-risk (GS 6) or intermediate-risk (GS 3+4) PC, GPS predicts BCR (n=382; HR, 2.73; 95% CI, 1.84-3.96; P<0.001).	('BCR', 'Disease', (80, 83))	('GS', 'Disease', 'MESH:D011125', (55, 57))	('GPS', 'Var', (67, 70))	('patients', 'Species', '9606', (3, 11))	('GS', 'Disease', 'MESH:D011125', (27, 29))
41373	31638194	The biomarker potential of MUC1 alterations in the classification of BCR risk was significantly enhanced in a 9-gene genomic signature.	('enhanced', 'PosReg', (96, 104))	('alterations', 'Var', (32, 43))	('BCR', 'Disease', (69, 72))	('MUC1', 'Gene', (27, 31))	('MUC1', 'Gene', '4582', (27, 31))	('biomarker potential', 'MPA', (4, 23))
41375	31638194	SigMuc1NW is an independent risk factor of BCR (HR, 2.44; 95% CI, 1.53-3.87; P=1.62e-4) after adjusting for age at diagnosis, GS, surgical margin and tumor stage.	('SigMuc1NW', 'Var', (0, 9))	('BCR', 'Disease', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('GS', 'Disease', 'MESH:D011125', (126, 128))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
41386	31638194	Elevations in the levels of lncRNA LOC400891 have been observed in tumors vs. prostate tissue.	('LOC400891', 'Chemical', 'MESH:C492399', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('LOC400891', 'Var', (35, 44))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
41387	31638194	The upregulation increases BCR risk in patients (Table V); its overexpression and knockdown accordingly enhance and inhibit PC cell proliferation in vitro.	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('patients', 'Species', '9606', (39, 47))	('enhance', 'PosReg', (104, 111))	('knockdown', 'Var', (82, 91))	('BCR risk', 'Disease', (27, 35))	('inhibit', 'NegReg', (116, 123))	('upregulation', 'PosReg', (4, 16))	('overexpression', 'PosReg', (63, 77))
41388	31638194	There is evidence to indicate a role of LOC400891 in the activation of the PI3K pathway.	('LOC400891', 'Chemical', 'MESH:C492399', (40, 49))	('LOC400891', 'Var', (40, 49))	('PI3K pathway', 'Pathway', (75, 87))	('PI3K', 'molecular_function', 'GO:0016303', ('75', '79'))
41389	31638194	Nonetheless, the involvement of LOC400891 in PC and other cancer types has yet to be further investigated.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('LOC400891', 'Chemical', 'MESH:C492399', (32, 41))	('cancer', 'Disease', (58, 64))	('LOC400891', 'Var', (32, 41))
41395	31638194	LINC01296 facilitates tumorigenesis in part by sponging miR122-5P in HCC and miR-5059 in cholangiocarcinoma, leading to MYCN activation.	('miR', 'Gene', (77, 80))	('MYCN', 'Gene', (120, 124))	('cholangiocarcinoma', 'Disease', (89, 107))	('MYCN', 'Gene', '4613', (120, 124))	('LINC01296', 'Gene', '642477', (0, 9))	('facilitates', 'PosReg', (10, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('LINC01296', 'Gene', (0, 9))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('miR', 'Gene', '220972', (56, 59))	('tumor', 'Disease', (22, 27))	('miR', 'Gene', (56, 59))	('sponging', 'Var', (47, 55))	('miR', 'Gene', '220972', (77, 80))
41398	31638194	Of note, elevations in SChLAP1 expressoin have been shown to predict PSA relapse (Table V), an event which has also been observed by others, and PC metastasis.	('expressoin', 'Var', (31, 41))	('PSA', 'Gene', (69, 72))	('PSA', 'Gene', '354', (69, 72))	('SChLAP1', 'Gene', '101669767', (23, 30))	('elevations', 'Var', (9, 19))	('predict', 'Reg', (61, 68))	('SChLAP1', 'Gene', (23, 30))
41403	31638194	Mechanistically, UCA1 facilitates PC at least in part through upregulations of ATF2 and CXCR4 by sponging miR-204.	('ATF2', 'Gene', (79, 83))	('miR-204', 'Gene', '406987', (106, 113))	('CXCR4', 'Gene', '7852', (88, 93))	('ATF2', 'Gene', '1386', (79, 83))	('sponging', 'Var', (97, 105))	('miR-204', 'Gene', (106, 113))	('CXCR4', 'Gene', (88, 93))	('UCA1', 'Gene', '652995', (17, 21))	('UCA1', 'Gene', (17, 21))	('facilitates', 'PosReg', (22, 33))	('upregulations', 'PosReg', (62, 75))	('CXCR4', 'molecular_function', 'GO:0038147', ('88', '93'))
41411	31638194	Risk scores of these panels were used to stratify the risk of BCR; the scores were calculated based on the following formula: Risk scores=sum (coefi x DE-lncRNAi), where DE-lncRNAi is the ith DE-lncRNA expression (i=1, ... n) and coefi is the Cox coefficient of DE-lncRNAi.	('Cox', 'Gene', '1351', (243, 246))	('BCR', 'Disease', (62, 65))	('Cox', 'Gene', (243, 246))	('DE-lncRNAi', 'Var', (170, 180))
41442	31638194	In a recent single-arm clinical trial on patients with BCR (n=635) to assess the accuracy of 68Ga-PSMA-11 PET in detecting recurrent PCs, the overall detection rate was 75% (475/635) and the PET-positive rates in different PSA groups were 38% for <0.5 ng/ml, 57% for 0.5-<1.0 ng/ml, 84% for 1.0-<2.0 ng/ml, 86% for 2.0-<5.0 ng/ml, and 97% for >=5.0 ng/ml respectively.	('PSA', 'Gene', (223, 226))	('PSMA', 'Gene', (98, 102))	('PSA', 'Gene', '354', (223, 226))	('patients', 'Species', '9606', (41, 49))	('0.5-<1.0 ng/ml', 'Var', (267, 281))	('PSMA', 'Gene', '2346', (98, 102))	('PSMA', 'molecular_function', 'GO:0043275', ('98', '102'))	('<0.5 ng/ml', 'Var', (247, 257))
41443	31638194	In a recent diagnostic study of 100 patients with BCR using 18F-PSMA-1007 PET/CT, the PET-positive rate was 86, 89, 100 and 100% for patients with PSA levels <=0.5, 0.51-1.0, 1.0-2.0, and >=2.0 ng/ml, respectively.	('patients', 'Species', '9606', (36, 44))	('PSMA', 'Gene', (64, 68))	('<=0.5', 'Var', (158, 163))	('patients', 'Species', '9606', (133, 141))	('0.51-1.0', 'Var', (165, 173))	('PSMA', 'Gene', '2346', (64, 68))	('PSMA', 'molecular_function', 'GO:0043275', ('64', '68'))	('PSA', 'Gene', '354', (147, 150))	('PSA', 'Gene', (147, 150))
41450	31638194	Males with high-risk tumors can be managed with adjuvant therapy following RP; in a small group of patients (n=127) treated with adjuvant hormone therapy, high level of PDL1 expression is an independent risk factor of BCR.	('PDL1', 'Gene', (169, 173))	('high level', 'Var', (155, 165))	('expression', 'MPA', (174, 184))	('tumors', 'Disease', (21, 27))	('BCR', 'Disease', (218, 221))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (99, 107))	('PDL1', 'Gene', '29126', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
41487	31443481	The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development.	('tumour', 'Disease', 'MESH:D009369', (277, 283))	('NENs', 'Disease', (63, 67))	('MEN-1', 'Gene', '4221', (171, 176))	('MEN-1', 'Gene', (171, 176))	('tumour', 'Disease', (277, 283))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (134, 169))	('DAXX', 'Gene', '1616', (40, 44))	('NENs', 'Disease', 'MESH:D018358', (63, 67))	('NENs', 'Phenotype', 'HP:0100634', (63, 67))	('multiple endocrine neoplasia type 1', 'Gene', (134, 169))	('neoplasia', 'Phenotype', 'HP:0002664', (153, 162))	('mutations', 'Var', (22, 31))	('ATRX', 'Gene', (35, 39))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (143, 162))	('tumour', 'Phenotype', 'HP:0002664', (277, 283))	('DAXX', 'Gene', (40, 44))	('ATRX', 'Gene', '546', (35, 39))
41502	31443481	Current advances in genomic analysis techniques have enabled to identify recurrent mutations and chromosomal aberrations at the base of the molecular landscape of NENs.	('mutations', 'Var', (83, 92))	('NENs', 'Disease', 'MESH:D018358', (163, 167))	('NENs', 'Disease', (163, 167))	('chromosomal aberrations', 'Var', (97, 120))	('NENs', 'Phenotype', 'HP:0100634', (163, 167))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (97, 120))
41504	31443481	These mutations can occur in genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1), tuberous sclerosis complex (TSC1/2), neurofibromatosis type 1 (NF1), and von Hippel-Lindau (VHL) syndrome, or in sporadic NENs, and can be germline or somatic mutations.	('NENs', 'Phenotype', 'HP:0100634', (222, 226))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('100', '126'))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (100, 118))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('NENs', 'Disease', (222, 226))	('tuberous sclerosis', 'Disease', (100, 118))	('NF1', 'Gene', '4763', (163, 166))	('MEN1', 'Gene', '4221', (93, 97))	('mutations', 'Var', (6, 15))	('TSC1/2', 'Gene', '7248;7249', (128, 134))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (65, 84))	('NF1', 'Gene', (163, 166))	('multiple endocrine neoplasia type 1', 'Gene', (56, 91))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (56, 91))	('neurofibromatosis type 1', 'Gene', (137, 161))	('MEN1', 'Gene', (93, 97))	('NENs', 'Disease', 'MESH:D018358', (222, 226))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (137, 154))	('occur', 'Reg', (20, 25))	('TSC1/2', 'Gene', (128, 134))	('von Hippel-Lindau (VHL) syndrome', 'Disease', 'MESH:D006623', (173, 205))	('neurofibromatosis type 1', 'Gene', '4763', (137, 161))
41508	31443481	In addition, some mutations, namely mutations in MEN1 and DAXX/ATRX genes, are associated with a better prognosis, and they seem to occur very rarely in poorly differentiated neuroendocrine carcinomas (NECs).	('MEN1', 'Gene', (49, 53))	('NECs', 'Disease', 'MESH:D018278', (202, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('MEN1', 'Gene', '4221', (49, 53))	('ATRX', 'Gene', '546', (63, 67))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (175, 199))	('ATRX', 'Gene', (63, 67))	('DAXX', 'Gene', (58, 62))	('mutations', 'Var', (36, 45))	('NECs', 'Disease', (202, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (190, 200))	('NECs', 'Phenotype', 'HP:0100634', (202, 206))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (175, 200))	('neuroendocrine carcinomas', 'Disease', (175, 200))	('DAXX', 'Gene', '1616', (58, 62))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (175, 200))	('mutations', 'Var', (18, 27))
41509	31443481	On the other hand, mutation in TP53, RB1, PTEN and PIK3CA are more frequent in poorly differentiated NECs.	('NECs', 'Disease', (101, 105))	('PTEN', 'Gene', (42, 46))	('NECs', 'Phenotype', 'HP:0100634', (101, 105))	('mutation', 'Var', (19, 27))	('PTEN', 'Gene', '5728', (42, 46))	('frequent', 'Reg', (67, 75))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('PIK3CA', 'Gene', (51, 57))	('RB1', 'Gene', (37, 40))	('NECs', 'Disease', 'MESH:D018278', (101, 105))	('RB1', 'Gene', '5925', (37, 40))	('PIK3CA', 'Gene', '5290', (51, 57))
41510	31443481	In the following paragraph, we summarise the current knowledge and the clinical significance of the most common genetic alterations in NENs, classifying them according to their hereditary or sporadic condition.	('NENs', 'Phenotype', 'HP:0100634', (135, 139))	('NENs', 'Disease', (135, 139))	('genetic alterations', 'Var', (112, 131))	('NENs', 'Disease', 'MESH:D018358', (135, 139))
41512	31443481	MEN-1 is a rare autosomal dominant syndrome caused by inactivating mutations in the MEN-1 gene, and mostly associated with the appearance of neoplastic lesions in the pancreas and duodenum, as well as in pituitary and parathyroid glands.	('MEN-1', 'Gene', '4221', (84, 89))	('MEN-1', 'Gene', (84, 89))	('associated', 'Reg', (107, 117))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (141, 159))	('MEN-1', 'Gene', '4221', (0, 5))	('MEN-1', 'Gene', (0, 5))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (16, 43))	('caused by', 'Reg', (44, 53))	('autosomal dominant syndrome', 'Disease', (16, 43))	('neoplastic lesions in the pancreas', 'Disease', 'MESH:D010190', (141, 175))	('inactivating mutations', 'Var', (54, 76))	('neoplastic lesions in the pancreas', 'Disease', (141, 175))	('neoplastic lesions in the pancreas', 'Phenotype', 'HP:0002894', (141, 175))
41513	31443481	The majority of germline mutations in the MEN-1 gene cause the truncation or absence of the menin protein in cancer cells.	('cause', 'Reg', (53, 58))	('absence', 'NegReg', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('germline mutations', 'Var', (16, 34))	('menin', 'Gene', '4221', (92, 97))	('MEN-1', 'Gene', '4221', (42, 47))	('MEN-1', 'Gene', (42, 47))	('cancer', 'Disease', (109, 115))	('menin', 'Gene', (92, 97))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('truncation', 'MPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
41514	31443481	Typically, tumour development is associated with the mutation of both MEN-1 alleles, however, an incomplete inactivation of this gene has been observed in thymic and duodenal NETs.	('mutation', 'Var', (53, 61))	('NET', 'Disease', (175, 178))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('associated', 'Reg', (33, 43))	('MEN-1', 'Gene', (70, 75))	('MEN-1', 'Gene', '4221', (70, 75))	('NET', 'Phenotype', 'HP:0100634', (175, 178))	('NET', 'Disease', 'MESH:D018358', (175, 178))	('tumour', 'Disease', (11, 17))
41518	31443481	MEN-2 syndrome is caused by mutations in RET proto-oncogene, encoding a tyrosine kinase receptor.	('MEN-2 syndrome', 'Disease', (0, 14))	('RET', 'Gene', (41, 44))	('MEN', 'Species', '9606', (0, 3))	('tyrosine', 'Chemical', 'None', (72, 80))	('caused by', 'Reg', (18, 27))	('mutations', 'Var', (28, 37))	('RET', 'Gene', '5979', (41, 44))
41519	31443481	These mutations cause activation of RAS/MAPK (mitogen-activated protein kinases) and PI3K/AKT (phosphatidylinositol 3-kinase/Protein Kinase B) signalling pathways and may occur in two different regions of the RET gene, originating two different types of disorders.	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('RET', 'Gene', (209, 212))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('activation', 'PosReg', (22, 32))	('Protein Kinase B', 'Gene', (125, 141))	('signalling', 'biological_process', 'GO:0023052', ('143', '153'))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (95, 115))	('Protein Kinase B', 'Gene', '2185', (125, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('85', '89'))	('RET', 'Gene', '5979', (209, 212))	('mutations', 'Var', (6, 15))
41520	31443481	In addition, the familial MTC (FMTC) syndrome, which is also caused by RET mutations, is only associated with MTC, but is less aggressive than MEN-2 tumours.	('MTC', 'Disease', (32, 35))	('MEN-2 tumours', 'Disease', (143, 156))	('MTC', 'Disease', (26, 29))	('MTC', 'Phenotype', 'HP:0002865', (110, 113))	('MEN-2 tumours', 'Disease', 'MESH:D018813', (143, 156))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('RET', 'Gene', '5979', (71, 74))	('MTC', 'Disease', 'MESH:C536914', (110, 113))	('associated', 'Reg', (94, 104))	('MTC', 'Disease', (110, 113))	('mutations', 'Var', (75, 84))	('MTC', 'Phenotype', 'HP:0002865', (32, 35))	('MTC', 'Disease', 'MESH:C536914', (32, 35))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('MTC', 'Phenotype', 'HP:0002865', (26, 29))	('MTC', 'Disease', 'MESH:C536914', (26, 29))	('RET', 'Gene', (71, 74))
41521	31443481	MEN-4 is a rare autosomal dominant syndrome predisposed to NETs development, such as parathyroid and pituitary adenomas, associated with the germline mutations in CDKN1B genes encoding the p27kip protein.	('NET', 'Disease', 'MESH:D018358', (59, 62))	('CDKN1B', 'Gene', '1027', (163, 169))	('associated', 'Reg', (121, 131))	('MEN-4', 'Gene', (0, 5))	('pituitary adenomas', 'Disease', 'MESH:D010911', (101, 119))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (16, 43))	('parathyroid', 'Disease', (85, 96))	('NET', 'Disease', (59, 62))	('CDKN1B', 'Gene', (163, 169))	('autosomal dominant syndrome', 'Disease', (16, 43))	('mutations', 'Var', (150, 159))	('MEN-4', 'Gene', '1027', (0, 5))	('NET', 'Phenotype', 'HP:0100634', (59, 62))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (101, 119))	('pituitary adenomas', 'Disease', (101, 119))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
41522	31443481	However, more studies are needed to know the penetrance and biological effect of CDKN1B mutations in these patients.	('patients', 'Species', '9606', (107, 115))	('CDKN1B', 'Gene', (81, 87))	('mutations', 'Var', (88, 97))	('CDKN1B', 'Gene', '1027', (81, 87))
41529	31443481	Genetic alterations of the NF1 gene include missense, nonsense and splice site mutations, as well as insertions/deletions (in/dels) and chromosomal rearrangements.	('chromosomal', 'Disease', (136, 147))	('NF1', 'Gene', (27, 30))	('insertions/deletions', 'Var', (101, 121))	('NF1', 'Gene', '4763', (27, 30))	('missense', 'Var', (44, 52))
41532	31443481	Disruption of TSC2 in pancreatic beta cells induces beta cell mass expansion in an mTOR-dependent manner.	('TSC2', 'Gene', '7249', (14, 18))	('mTOR', 'Gene', (83, 87))	('TSC2', 'Gene', (14, 18))	('beta cell mass expansion', 'CPA', (52, 76))	('induces', 'Reg', (44, 51))	('mTOR', 'Gene', '2475', (83, 87))	('Disruption', 'Var', (0, 10))
41533	31443481	Furthermore, it has recently been demonstrated that patients with pancreatic NET (pNET), and loss of PTEN protein, as well as tuberosclerosis 1 protein, show a significantly shorter survival.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('NET', 'Phenotype', 'HP:0100634', (77, 80))	('shorter', 'NegReg', (174, 181))	('NET', 'Disease', 'MESH:D018358', (83, 86))	('tuberosclerosis', 'Disease', (126, 141))	('PTEN', 'Gene', (101, 105))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('loss', 'Var', (93, 97))	('PTEN', 'Gene', '5728', (101, 105))	('NET', 'Disease', (83, 86))	('NET', 'Disease', 'MESH:D018358', (77, 80))	('NET', 'Phenotype', 'HP:0100634', (83, 86))	('tuberosclerosis', 'Disease', 'None', (126, 141))	('survival', 'MPA', (182, 190))	('patients', 'Species', '9606', (52, 60))	('NET', 'Disease', (77, 80))
41534	31443481	Familial pheochromocytoma and paraganglioma syndromes are autosomal-dominant disorders caused mostly by germline mutations in the succinate dehydrogenase subunit (SDH) genes, such as SDHB, SDHC, SDHD, SDHA, and SDHAF2 (succinate dehydrogenase complex assembly factor 2).	('succinate dehydrogenase subunit', 'Gene', (130, 161))	('succinate dehydrogenase complex assembly factor 2', 'Gene', (219, 268))	('SDHB', 'Gene', (183, 187))	('SDHA', 'Gene', '6389', (201, 205))	('SDHC', 'Gene', (189, 193))	('SDH', 'Gene', '6390', (183, 186))	('SDH', 'Gene', (195, 198))	('mutations', 'Var', (113, 122))	('Familial pheochromocytoma and paraganglioma syndromes', 'Disease', 'MESH:C531777', (0, 53))	('SDH', 'Gene', (201, 204))	('autosomal-dominant disorders', 'Disease', (58, 86))	('autosomal-dominant disorders', 'Disease', 'MESH:D030342', (58, 86))	('SDH', 'Gene', (183, 186))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('219', '250'))	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('SDH', 'Gene', '6390', (189, 192))	('SDH', 'Gene', '6390', (163, 166))	('SDHC', 'Gene', '6391', (189, 193))	('caused', 'Reg', (87, 93))	('SDH', 'Gene', '6390', (211, 214))	('SDHD', 'Gene', '6392', (195, 199))	('SDHB', 'Gene', '6390', (183, 187))	('SDHA', 'Gene', (211, 215))	('succinate dehydrogenase complex assembly factor 2', 'Gene', '54949', (219, 268))	('SDH', 'Gene', '6390', (195, 198))	('SDHA', 'Gene', '6389', (211, 215))	('succinate dehydrogenase subunit', 'Gene', '6390', (130, 161))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (9, 25))	('SDH', 'Gene', '6390', (201, 204))	('SDHA', 'Gene', (201, 205))	('SDH', 'Gene', (189, 192))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('219', '250'))	('SDHD', 'Gene', (195, 199))	('SDH', 'Gene', (163, 166))	('SDHAF2', 'Gene', '54949', (211, 217))	('SDHAF2', 'Gene', (211, 217))	('SDH', 'Gene', (211, 214))
41535	31443481	SDH deficiency leads to pseudohypoxic conditions in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SDH', 'Gene', (0, 3))	('pseudohypoxic conditions', 'MPA', (24, 48))	('deficiency', 'Var', (4, 14))	('leads to', 'Reg', (15, 23))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('SDH', 'Gene', '6390', (0, 3))
41537	31443481	SDH mutations are commonly associated with multiple pheochromocytomas and paragangliomas.	('paragangliomas', 'Disease', (74, 88))	('paragangliomas', 'Disease', 'MESH:D010235', (74, 88))	('paragangliomas', 'Phenotype', 'HP:0002668', (74, 88))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (52, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (52, 68))	('SDH', 'Gene', (0, 3))	('multiple pheochromocytomas', 'Disease', (43, 69))	('associated', 'Reg', (27, 37))	('multiple pheochromocytomas', 'Disease', 'MESH:D010673', (43, 69))	('mutations', 'Var', (4, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))	('SDH', 'Gene', '6390', (0, 3))
41538	31443481	However, gastrointestinal stromal tumours, SDH-deficient renal cell carcinoma and pituitary adenomas can also be associated with these mutations.	('gastrointestinal stromal tumours', 'Disease', (9, 41))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (82, 100))	('SDH', 'Gene', (43, 46))	('pituitary adenomas', 'Disease', (82, 100))	('mutations', 'Var', (135, 144))	('renal cell carcinoma', 'Disease', (57, 77))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('SDH', 'Gene', '6390', (43, 46))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (57, 77))	('pituitary adenomas', 'Disease', 'MESH:D010911', (82, 100))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (9, 41))	('associated', 'Reg', (113, 123))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
41540	31443481	In fact, massive parallel sequencing showed that only 24 cancer driver genes are affected by non-synonymous mutations in neuroendocrine neoplasms.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('neoplasm', 'Phenotype', 'HP:0002664', (136, 144))	('cancer', 'Disease', (57, 63))	('neuroendocrine neoplasms', 'Disease', (121, 145))	('non-synonymous mutations', 'Var', (93, 117))	('neoplasms', 'Phenotype', 'HP:0002664', (136, 145))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (121, 145))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (121, 144))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (121, 145))
41543	31443481	Mutations in TP53 and RB1 genes are pivotal drivers in poorly differentiated NECs of any anatomical origin.	('TP53', 'Gene', (13, 17))	('RB1', 'Gene', '5925', (22, 25))	('NECs', 'Disease', (77, 81))	('RB1', 'Gene', (22, 25))	('NECs', 'Phenotype', 'HP:0100634', (77, 81))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('NECs', 'Disease', 'MESH:D018278', (77, 81))
41544	31443481	Mutations in the TP53 gene have been consistently detected in poorly-differentiated GEP-NECs, with a frequency ranging from 20% to 73% of the tested patients.	('NECs', 'Disease', 'MESH:D018278', (88, 92))	('patients', 'Species', '9606', (149, 157))	('NECs', 'Disease', (88, 92))	('NECs', 'Phenotype', 'HP:0100634', (88, 92))	('detected', 'Reg', (50, 58))	('Mutations', 'Var', (0, 9))	('GEP', 'Gene', '2896', (84, 87))	('GEP', 'Gene', (84, 87))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
41545	31443481	The presence of TP53 mutations in GEP-NECs correlates with poor survival, and recently Ali et al.	('GEP', 'Gene', '2896', (34, 37))	('GEP', 'Gene', (34, 37))	('NECs', 'Disease', 'MESH:D018278', (38, 42))	('TP53', 'Gene', '7157', (16, 20))	('poor', 'NegReg', (59, 63))	('NECs', 'Disease', (38, 42))	('NECs', 'Phenotype', 'HP:0100634', (38, 42))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
41546	31443481	have demonstrated that p53 immunoexpression in colorectal NECs correlates with a poorer response to platinum-based chemotherapy and worse prognosis.	('NECs', 'Phenotype', 'HP:0100634', (58, 62))	('immunoexpression', 'Var', (27, 43))	('response to platinum', 'biological_process', 'GO:0070541', ('88', '108'))	('colorectal NECs', 'Disease', 'MESH:D015179', (47, 62))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('colorectal NECs', 'Disease', (47, 62))	('platinum', 'Chemical', 'MESH:D010984', (100, 108))
41548	31443481	The inactivation of RB1 gene product, which occurs mainly by somatic mutations, has been reported in 71% of poorly differentiated pancreatic NECs.	('inactivation', 'Var', (4, 16))	('reported', 'Reg', (89, 97))	('NECs', 'Phenotype', 'HP:0100634', (141, 145))	('RB1', 'Gene', '5925', (20, 23))	('pancreatic NECs', 'Disease', 'MESH:D018278', (130, 145))	('pancreatic NECs', 'Disease', (130, 145))	('RB1', 'Gene', (20, 23))
41549	31443481	KRAS mutations have been identified in gastric, pancreatic and colorectal NECs with frequencies ranging from 8% to 60%.	('colorectal NECs', 'Disease', (63, 78))	('identified', 'Reg', (25, 35))	('gastric', 'Disease', (39, 46))	('NECs', 'Phenotype', 'HP:0100634', (74, 78))	('mutations', 'Var', (5, 14))	('colorectal NECs', 'Disease', 'MESH:D015179', (63, 78))	('KRAS', 'Gene', (0, 4))	('pancreatic', 'Disease', (48, 58))	('KRAS', 'Gene', '3845', (0, 4))
41550	31443481	On the other hand, BRAF mutations were only found in colorectal NECs with a frequency between 13% and 59%, as well as APC affecting some cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('BRAF', 'Gene', '673', (19, 23))	('colorectal NECs', 'Disease', 'MESH:D015179', (53, 68))	('BRAF', 'Gene', (19, 23))	('NECs', 'Phenotype', 'HP:0100634', (64, 68))	('colorectal NECs', 'Disease', (53, 68))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (24, 33))	('APC', 'Disease', 'MESH:D011125', (118, 121))	('APC', 'Disease', (118, 121))	('APC', 'cellular_component', 'GO:0005680', ('118', '121'))
41552	31443481	This subtype presents typical mutations of G1/G2 NETs.	('G1/G2', 'Gene', (43, 48))	('NET', 'Disease', (49, 52))	('mutations', 'Var', (30, 39))	('NET', 'Phenotype', 'HP:0100634', (49, 52))	('NET', 'Disease', 'MESH:D018358', (49, 52))
41553	31443481	For example, G3 pancreatic NETs showed high frequency of MEN1, DAXX, and ATRX mutations or protein loss (31-44%, 9-25% and 18-36%, respectively).	('NET', 'Disease', 'MESH:D018358', (27, 30))	('DAXX', 'Gene', (63, 67))	('NET', 'Disease', (27, 30))	('ATRX', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('ATRX', 'Gene', '546', (73, 77))	('protein', 'Protein', (91, 98))	('NET', 'Phenotype', 'HP:0100634', (27, 30))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('loss', 'NegReg', (99, 103))	('MEN1', 'Gene', (57, 61))	('MEN1', 'Gene', '4221', (57, 61))	('DAXX', 'Gene', '1616', (63, 67))
41554	31443481	DAXX and ATRX mutations also significantly correlate with the presence of mutations in mTOR regulators and were associated with poor prognosis in the G2 NETs.	('mTOR', 'Gene', '2475', (87, 91))	('mutations', 'Var', (14, 23))	('ATRX', 'Gene', '546', (9, 13))	('DAXX', 'Gene', (0, 4))	('NET', 'Phenotype', 'HP:0100634', (153, 156))	('mutations', 'Var', (74, 83))	('NET', 'Disease', 'MESH:D018358', (153, 156))	('DAXX', 'Gene', '1616', (0, 4))	('NET', 'Disease', (153, 156))	('ATRX', 'Gene', (9, 13))	('associated', 'Reg', (112, 122))	('mTOR', 'Gene', (87, 91))
41555	31443481	Therefore, the scientific community is proposing these mutations as possible biomarkers to distinguish G3 pancreatic NETs from NECs.	('NECs', 'Disease', 'MESH:D018278', (127, 131))	('mutations', 'Var', (55, 64))	('NET', 'Disease', 'MESH:D018358', (117, 120))	('NECs', 'Disease', (127, 131))	('NECs', 'Phenotype', 'HP:0100634', (127, 131))	('NET', 'Disease', (117, 120))	('NET', 'Phenotype', 'HP:0100634', (117, 120))
41561	31443481	Mutations in NF1, TSC2 or PTEN-encoding for key suppressor genes of this pathway, and altered expression of the mTOR pathway components, are common hallmarks of a great proportion of NETs, wherein these alterations seem to be directly related with tumour development and progression.	('tumour', 'Disease', (248, 254))	('TSC2', 'Gene', '7249', (18, 22))	('altered', 'Reg', (86, 93))	('related', 'Reg', (235, 242))	('NET', 'Disease', 'MESH:D018358', (183, 186))	('PTEN', 'Gene', '5728', (26, 30))	('TSC2', 'Gene', (18, 22))	('NF1', 'Gene', (13, 16))	('NET', 'Disease', (183, 186))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (13, 16))	('mTOR', 'Gene', '2475', (112, 116))	('PTEN', 'Gene', (26, 30))	('expression', 'MPA', (94, 104))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('mTOR', 'Gene', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('NET', 'Phenotype', 'HP:0100634', (183, 186))
41562	31443481	Loss-of-function mutations in NOTCH family genes, particularly in NOTCH1, have been identified in human and mouse small cell lung cancer (SCLC) and in neuroendocrine pancreatic cells.	('Loss-of-function', 'NegReg', (0, 16))	('neuroendocrine pancreatic', 'Disease', 'MESH:D018358', (151, 176))	('SCLC', 'Gene', '7864', (138, 142))	('SCLC', 'Gene', (138, 142))	('small cell lung cancer', 'Disease', 'MESH:D055752', (114, 136))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (114, 136))	('NOTCH1', 'Gene', (66, 72))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('neuroendocrine pancreatic', 'Disease', (151, 176))	('mouse', 'Species', '10090', (108, 113))	('NOTCH1', 'Gene', '4851', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('small cell lung cancer', 'Disease', (114, 136))	('human', 'Species', '9606', (98, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('mutations', 'Var', (17, 26))
41563	31443481	For a better understanding on how these genetic mutations or genomic alterations could lead to the development of neuroendocrine tumours, in the following section, the composition of NOTCH receptors and the main elements involved in the NOTCH signalling transduction will be explained in detail.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('alterations', 'Var', (69, 80))	('signalling', 'biological_process', 'GO:0023052', ('243', '253'))	('neuroendocrine tumours', 'Disease', (114, 136))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (114, 136))	('neuroendocrine tumour', 'Phenotype', 'HP:0100634', (114, 135))	('lead to', 'Reg', (87, 94))	('transduction', 'biological_process', 'GO:0009293', ('254', '266'))	('mutations', 'Var', (48, 57))
41574	31443481	Pre-clinical studies showed a heterogeneous expression of the NOTCH receptor family in tumoral tissues, and genome sequencing analysis has identified several NOTCH gene mutations in various solid and hematological malignancies.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('mutations', 'Var', (169, 178))	('hematological malignancies', 'Phenotype', 'HP:0004377', (200, 226))	('NOTCH gene', 'Gene', (158, 168))	('tumoral', 'Disease', 'MESH:D009369', (87, 94))	('tumoral', 'Disease', (87, 94))	('hematological malignancies', 'Disease', (200, 226))	('hematological malignancies', 'Disease', 'MESH:D019337', (200, 226))
41576	31443481	In addition, alterations of the NOTCH signalling pathway are responsible for the smooth transition from a non-neuroendocrine to a neuroendocrine phenotype, as a result of a coordinated anti-cancer drug response in pathological cell conditions.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('NOTCH signalling pathway', 'Pathway', (32, 56))	('responsible', 'Reg', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('alterations', 'Var', (13, 24))	('NOTCH signalling pathway', 'biological_process', 'GO:0007219', ('32', '56'))
41580	31443481	Moreover, alterations in Notch signalling were also linked to triple-negative breast cancer (TNBC).	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('linked', 'Reg', (52, 58))	('alterations', 'Var', (10, 21))	('signalling', 'biological_process', 'GO:0023052', ('31', '41'))	('Notch signalling', 'MPA', (25, 41))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
41581	31443481	Mutations were found in NOTCH1-3 at the C-terminal PEST domain, and also in the prolyl-isomerase PIN1 (peptidylprolyl cis/trans isomarase, NIMA-interacting 1), supporting the theory of the involvement of Notch in breast cancer.	('prolyl', 'Chemical', 'MESH:C065612', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('prolyl', 'Chemical', 'MESH:C065612', (80, 86))	('NOTCH1', 'Gene', '4851', (24, 30))	('NOTCH1', 'Gene', (24, 30))	('breast cancer', 'Disease', (213, 226))	('Mutations', 'Var', (0, 9))
41582	31443481	In some neoplasms, mutation can contribute to enhance the physiological function of the pathway, as was described in a previous non-small cell lung carcinoma (NSCLC) analysis.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (128, 157))	('physiological function', 'MPA', (58, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (8, 17))	('mutation', 'Var', (19, 27))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (128, 157))	('NSCLC', 'Disease', (159, 164))	('non-small cell lung carcinoma', 'Disease', (128, 157))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('neoplasm', 'Phenotype', 'HP:0002664', (8, 16))	('neoplasms', 'Disease', 'MESH:D009369', (8, 17))	('SCLC', 'Phenotype', 'HP:0030357', (160, 164))	('neoplasms', 'Disease', (8, 17))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (132, 157))	('enhance', 'PosReg', (46, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
41583	31443481	In this study, it was demonstrated that the presence of a C-terminal mutation in the NOTCH-1 gene confers a gain of function, increasing the receptor signalling transduction in NSCLC cancer.	('cancer', 'Disease', (183, 189))	('C-terminal mutation', 'Var', (58, 77))	('increasing', 'PosReg', (126, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('SCLC', 'Phenotype', 'HP:0030357', (178, 182))	('signalling', 'biological_process', 'GO:0023052', ('150', '160'))	('presence', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('NOTCH-1', 'Gene', (85, 92))	('NSCLC', 'Disease', (177, 182))	('NOTCH-1', 'Gene', '4851', (85, 92))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('transduction', 'biological_process', 'GO:0009293', ('161', '173'))	('receptor signalling transduction', 'MPA', (141, 173))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
41587	31443481	Interestingly, a recent study showed that mutation of NOTCH1 in oral squamous cell carcinoma occurs in 15% of the Caucasian population, whereas in the Asian population the rate of NOTCH1 mutations was about 50%.	('NOTCH1', 'Gene', '4851', (54, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('oral squamous cell carcinoma', 'Disease', (64, 92))	('NOTCH1', 'Gene', (54, 60))	('mutation', 'Var', (42, 50))	('NOTCH1', 'Gene', '4851', (180, 186))	('NOTCH1', 'Gene', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))
41591	31443481	Deyin Xing et al., found oncogenic driver mutations in KRAS, Erb-B2, c-Myc, BCL6 and NOTCH1 in a cohort of 10 small-cell neuroendocrine carcinomas (SCNEC) of the uterine cervix, a rare but extremely aggressive tumour.	('aggressive tumour', 'Disease', (199, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('Erb-B2', 'Gene', (61, 67))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (121, 146))	('neuroendocrine carcinomas', 'Disease', (121, 146))	('NOTCH1', 'Gene', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('aggressive tumour', 'Disease', 'MESH:D001523', (199, 216))	('SCNEC', 'Phenotype', 'HP:0031522', (148, 153))	('uterine cervix', 'Phenotype', 'HP:0030160', (162, 176))	('NOTCH1', 'Gene', '4851', (85, 91))	('Erb-B2', 'Gene', '2064', (61, 67))	('c-Myc', 'Gene', (69, 74))	('BCL6', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (55, 59))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (121, 145))	('c-Myc', 'Gene', '4609', (69, 74))	('KRAS', 'Gene', (55, 59))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (121, 146))	('mutations', 'Var', (42, 51))	('BCL6', 'Gene', '604', (76, 80))
41594	31443481	A separate study conducted whole-genome sequencing of small cell lung cancer (SCLC), identifying inactivating mutations in the NOTCH family genes in 25% of cases.	('small cell lung cancer', 'Disease', (54, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('inactivating mutations', 'Var', (97, 119))	('NOTCH family genes', 'Gene', (127, 145))	('small cell lung cancer', 'Disease', 'MESH:D055752', (54, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('SCLC', 'Gene', '7864', (78, 82))	('SCLC', 'Phenotype', 'HP:0030357', (78, 82))	('SCLC', 'Gene', (78, 82))
41595	31443481	In the following paragraphs, we summarize the current knowledge on the epigenetic modifications and NOTCH signalling pathway alteration in different types of NENs.	('alteration', 'Reg', (125, 135))	('NENs', 'Disease', (158, 162))	('NENs', 'Phenotype', 'HP:0100634', (158, 162))	('NENs', 'Disease', 'MESH:D018358', (158, 162))	('NOTCH signalling pathway', 'Pathway', (100, 124))	('epigenetic modifications', 'Var', (71, 95))	('NOTCH signalling pathway', 'biological_process', 'GO:0007219', ('100', '124'))
41596	31443481	It is conceivable to think of epigenetic changes contributing to the pathological development of tissue and how these alterations could affect gene expression after stem cell differentiation, as happens in other neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (212, 221))	('contributing', 'Reg', (49, 61))	('epigenetic changes', 'Var', (30, 48))	('stem cell differentiation', 'biological_process', 'GO:0048863', ('165', '190'))	('alterations', 'Var', (118, 129))	('neoplasms', 'Phenotype', 'HP:0002664', (212, 221))	('gene expression', 'MPA', (143, 158))	('affect', 'Reg', (136, 142))	('neoplasms', 'Disease', (212, 221))	('gene expression', 'biological_process', 'GO:0010467', ('143', '158'))	('neoplasm', 'Phenotype', 'HP:0002664', (212, 220))
41597	31443481	These alterations not only can occur at the chromatin level and involve acetylation and deacetylation of the histones and the methylation of the cytosine at DNA level, but can also be caused by other molecules, such as non-coding RNAs, for instance, and long non-coding RNAs and microRNAs.	('chromatin', 'cellular_component', 'GO:0000785', ('44', '53'))	('methylation', 'biological_process', 'GO:0032259', ('126', '137'))	('methylation', 'MPA', (126, 137))	('cytosine', 'Chemical', 'MESH:D003596', (145, 153))	('caused', 'Reg', (184, 190))	('histones', 'Protein', (109, 117))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('deacetylation', 'MPA', (88, 101))	('acetylation', 'MPA', (72, 83))	('long non-coding RNAs', 'Var', (254, 274))
41598	31443481	Some pivotal preclinical studies were conducted to explore the role of epigenetic alterations in NETs, obtaining interesting results:silencing regulatory genes (Wnt signaling components) and aberrant mutations in core pathways contributes in NET pathogenesis.	('NET', 'Phenotype', 'HP:0100634', (97, 100))	('aberrant mutations', 'Var', (191, 209))	('NET', 'Phenotype', 'HP:0100634', (242, 245))	('NET', 'Disease', 'MESH:D018358', (97, 100))	('core pathways', 'Pathway', (213, 226))	('NET', 'Disease', 'MESH:D018358', (242, 245))	('silencing regulatory', 'MPA', (133, 153))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('NET', 'Disease', (97, 100))	('pathogenesis', 'biological_process', 'GO:0009405', ('246', '258'))	('NET', 'Disease', (242, 245))	('core', 'cellular_component', 'GO:0019013', ('213', '217'))
41599	31443481	Furthermore, missense mutation in the mixed-lineage leukemia protein 3 (MLL3) often triggers aggressive neuroendocrine tumours, medulloblastomas and Merkel cell carcinoma by means of inducing genomic instability.	('missense mutation', 'Var', (13, 30))	('triggers', 'Reg', (84, 92))	('genomic instability', 'MPA', (192, 211))	('aggressive neuroendocrine tumours', 'Disease', 'MESH:D001523', (93, 126))	('inducing', 'Reg', (183, 191))	('aggressive neuroendocrine tumours', 'Disease', (93, 126))	('MLL3', 'Gene', (72, 76))	('mixed-lineage leukemia protein 3', 'Gene', (38, 70))	('medulloblastomas', 'Disease', (128, 144))	('mixed-lineage leukemia protein 3', 'Gene', '58508', (38, 70))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (149, 170))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('Merkel cell carcinoma', 'Disease', (149, 170))	('MLL3', 'Gene', '58508', (72, 76))	('medulloblastomas', 'Disease', 'MESH:D008527', (128, 144))	('neuroendocrine tumour', 'Phenotype', 'HP:0100634', (104, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
41600	31443481	Moreover, lysine-specific histone demethylase 1A (LSD1) inhibitor ORY-1001 was described in small cell lung cancer (SCLC) because of its anti-tumorigenic role.	('lysine-specific histone demethylase 1A', 'Gene', '23028', (10, 48))	('ORY-1001', 'Var', (66, 74))	('ORY-1001', 'Chemical', 'MESH:C525167', (66, 74))	('lysine-specific histone demethylase 1A', 'Gene', (10, 48))	('LSD1', 'Gene', (50, 54))	('small cell lung cancer', 'Disease', 'MESH:D055752', (92, 114))	('anti-tumorigenic', 'CPA', (137, 153))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))	('LSD1', 'Gene', '23028', (50, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('SCLC', 'Gene', '7864', (116, 120))	('SCLC', 'Phenotype', 'HP:0030357', (116, 120))	('SCLC', 'Gene', (116, 120))	('small cell lung cancer', 'Disease', (92, 114))
41602	31443481	A complete and long-term tumour regression was obtained after treating with ORY-1001 SCLC patient-derived xenograft (PDX) mice models.	('mice', 'Species', '10090', (122, 126))	('ORY-1001', 'Var', (76, 84))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('ORY-1001', 'Chemical', 'MESH:C525167', (76, 84))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('patient', 'Species', '9606', (90, 97))	('SCLC', 'Gene', (85, 89))	('tumour', 'Disease', (25, 31))	('SCLC', 'Gene', '7864', (85, 89))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
41604	31443481	Preliminary research about how aberrant miRNA expression can influence neuroendocrine cell behaviours showed a direct post-transcriptional repression of NOTCH2 and RBPJ proteins operated by miR-375 (microRNA 375) in Merkel cell carcinoma (MCC), a rare cutaneous neuroendocrine malignancy.	('RBPJ', 'Gene', '3516', (164, 168))	('cutaneous neuroendocrine malignancy', 'Disease', 'MESH:D018358', (252, 287))	('neuroendocrine malignancy', 'Phenotype', 'HP:0100634', (262, 287))	('aberrant', 'Var', (31, 39))	('influence', 'Reg', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (216, 237))	('MCC', 'cellular_component', 'GO:0033597', ('239', '242'))	('MCC', 'Disease', 'MESH:D015266', (239, 242))	('miR-375', 'Gene', (190, 197))	('NOTCH2', 'Gene', (153, 159))	('Merkel cell carcinoma', 'Disease', (216, 237))	('cutaneous neuroendocrine malignancy', 'Disease', (252, 287))	('MCC', 'biological_process', 'GO:0120197', ('239', '242'))	('MCC', 'Disease', (239, 242))	('NOTCH2', 'Gene', '4853', (153, 159))	('RBPJ', 'Gene', (164, 168))	('miR-375', 'Gene', '494324', (190, 197))
41611	31443481	Recent findings suggest that the presence of inactivating mutations in NOTCH signalling is involved in the pathogenesis of neuroendocrine neoplasms of the lung, being defined as more than 25% of the cases for small cell lung carcinomas (SCLC).	('SCLC', 'Phenotype', 'HP:0030357', (237, 241))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (209, 234))	('inactivating mutations', 'Var', (45, 67))	('signalling', 'biological_process', 'GO:0023052', ('77', '87'))	('neuroendocrine neoplasms of the lung', 'Disease', 'MESH:D008175', (123, 159))	('small cell lung carcinomas', 'Disease', (209, 235))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('neoplasms', 'Phenotype', 'HP:0002664', (138, 147))	('SCLC', 'Gene', (237, 241))	('SCLC', 'Gene', '7864', (237, 241))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (123, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (138, 146))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (209, 235))	('NOTCH signalling', 'Gene', (71, 87))	('neuroendocrine neoplasms of the lung', 'Disease', (123, 159))	('neoplasms of the lung', 'Phenotype', 'HP:0100526', (138, 159))	('involved', 'Reg', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (209, 235))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (123, 147))	('pathogenesis', 'biological_process', 'GO:0009405', ('107', '119'))
41613	31443481	Moreover, NOTCH signalling is involved in the modulation of the neural and neuroendocrine differentiation process that could mean the implication of mutations in NOTCH in the neuroendocrine features of these tumours, and also in disease progression and relapse.	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('NOTCH', 'Gene', (162, 167))	('neuroendocrine', 'MPA', (175, 189))	('mutations', 'Var', (149, 158))	('involved', 'Reg', (30, 38))	('tumours', 'Disease', 'MESH:D009369', (208, 215))	('tumours', 'Disease', (208, 215))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('signalling', 'biological_process', 'GO:0023052', ('16', '26'))
41614	31443481	NOTCH pathway deregulation has been also pointed out to have a role in chemoresistance in SCLC.	('deregulation', 'Var', (14, 26))	('SCLC', 'Gene', '7864', (90, 94))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('SCLC', 'Gene', (90, 94))	('chemoresistance', 'Disease', (71, 86))	('NOTCH pathway', 'Pathway', (0, 13))
41619	31443481	In the mixed forms of small cell carcinomas, the modulation of the NOTCH system demonstrated the importance of this pathway in tumorigenesis and response to treatment:the activation of NOTCH reduces the particularly aggressive neuroendocrine subtype by increasing the epithelial component with a slower cell proliferation rate whose growth can be controlled with chemotherapy.	('small cell carcinomas', 'Disease', 'MESH:D018288', (22, 43))	('epithelial component', 'CPA', (268, 288))	('cell proliferation', 'biological_process', 'GO:0008283', ('303', '321'))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (22, 43))	('increasing', 'PosReg', (253, 263))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('reduces', 'NegReg', (191, 198))	('NOTCH', 'Gene', (185, 190))	('small cell carcinomas', 'Disease', (22, 43))	('activation', 'Var', (171, 181))
41626	31443481	The majority of the available studies have evaluated the role of NOTCH signalling in pancreatic NENs, thus there is a lack of knowledge on the role of NOTCH signalling in the other GEP-NENs.	('GEP-NENs', 'Disease', (181, 189))	('NOTCH signalling', 'Var', (65, 81))	('signalling', 'biological_process', 'GO:0023052', ('157', '167'))	('NENs', 'Disease', (185, 189))	('NENs', 'Disease', (96, 100))	('NENs', 'Phenotype', 'HP:0100634', (96, 100))	('GEP-NENs', 'Disease', 'MESH:C535650', (181, 189))	('NENs', 'Phenotype', 'HP:0100634', (185, 189))	('NENs', 'Disease', 'MESH:D018358', (185, 189))	('signalling', 'biological_process', 'GO:0023052', ('71', '81'))	('NENs', 'Disease', 'MESH:D018358', (96, 100))
41656	31443481	Overall, there are several approaches to modulate NOTCH signalling that are in different stages of development in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('signalling', 'biological_process', 'GO:0023052', ('56', '66'))	('modulate', 'Var', (41, 49))	('cancer', 'Disease', (114, 120))
41686	31443481	Although several studies have been conducted with the aim of identifying genetic mutations involved in the genesis of neuroendocrine tumours, none of them have shown a substantial mutational percentage in the samples analysed, revealing a low-abundance of consistent mutations in G1/G2 neoplasms compared with other malignancies.	('G1/G2', 'Gene', (280, 285))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('neoplasms', 'Disease', 'MESH:D009369', (286, 295))	('neoplasms', 'Phenotype', 'HP:0002664', (286, 295))	('neoplasms', 'Disease', (286, 295))	('mutations', 'Var', (267, 276))	('neoplasm', 'Phenotype', 'HP:0002664', (286, 294))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (118, 140))	('malignancies', 'Disease', 'MESH:D009369', (316, 328))	('neuroendocrine tumours', 'Disease', (118, 140))	('neuroendocrine tumour', 'Phenotype', 'HP:0100634', (118, 139))	('malignancies', 'Disease', (316, 328))
41737	31040252	Criteria for the reduction of the dose of S-1 and PTX in the next cycle were WBC count <1,000/mm3; neutrophil count <500/mm3; platelet count <25,000/mm3; or occurrence of peripheral neuropathy or toxicities, excluding pigmentation and alopecia of grade 3 or higher, during the previous cycle.	('toxicities', 'Disease', (196, 206))	('<500/mm3', 'Var', (116, 124))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (171, 192))	('pigmentation', 'biological_process', 'GO:0043473', ('218', '230'))	('S-1', 'Gene', '5707', (42, 45))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (171, 192))	('peripheral neuropathy', 'Disease', (171, 192))	('PTX', 'Chemical', 'MESH:D017239', (50, 53))	('toxicities', 'Disease', 'MESH:D064420', (196, 206))	('pigmentation', 'Disease', 'MESH:D010859', (218, 230))	('S-1', 'Gene', (42, 45))	('alopecia', 'Disease', (235, 243))	('reduction', 'NegReg', (17, 26))	('pigmentation', 'Disease', (218, 230))	('alopecia', 'Phenotype', 'HP:0001596', (235, 243))
41803	30653633	These ENM include carbon black (9.6 million t); synthetic amorphous silica (1.5 million t); aluminum oxide (200 000 t); barium titanate (15 000 t); titanium dioxide (10 000 t), cerium dioxide (10 000 t); zinc oxide (8000 t); carbon nanotubes (CNT) and carbon nanofibers (CNF), (100-3000 t); and silver nanoparticles (20 t).	('200 000 t', 'Var', (108, 117))	('10 000 t', 'Var', (193, 201))	('10 000 t', 'Var', (166, 174))	('aluminum oxide', 'Chemical', 'MESH:D000537', (92, 106))	('carbon', 'Chemical', 'MESH:D002244', (225, 231))	('100-3000 t', 'Var', (278, 288))	('titanium dioxide', 'Chemical', 'MESH:C009495', (148, 164))	('8000 t', 'Var', (216, 222))	('cerium dioxide', 'Chemical', 'MESH:C030583', (177, 191))	('zinc oxide', 'Chemical', 'MESH:D015034', (204, 214))	('carbon', 'Chemical', 'MESH:D002244', (18, 24))	('silver', 'Chemical', 'MESH:D012834', (295, 301))	('barium titanate', 'Chemical', '-', (120, 135))	('carbon', 'Chemical', 'MESH:D002244', (252, 258))	('silica', 'Chemical', 'MESH:D012822', (68, 74))	('ENM', 'Chemical', '-', (6, 9))
41843	30653633	Considering the key role of ENM induced reactive oxygen species (ROS) in tissue toxicity, possible biomarkers of early oxidative stress were specifically investigated in a subset of workers (N=37) using SiO2-ENM (12-200 nm).	('ENM', 'Chemical', '-', (28, 31))	('SiO2-ENM', 'Chemical', '-', (203, 211))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (40, 63))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('oxidative stress', 'Phenotype', 'HP:0025464', (119, 135))	('ENM', 'Chemical', '-', (208, 211))	('SiO2-ENM', 'Var', (203, 211))	('toxicity', 'Disease', 'MESH:D064420', (80, 88))	('toxicity', 'Disease', (80, 88))
41845	30653633	When two examinations were performed on workers handling SiO2-ENM at baseline and 6-month follow up, the depression of serum antioxidant enzymes levels, ie, superoxide dismutase and glutathione peroxidase, were significantly greater in exposed groups compared to controls.	('serum antioxidant enzymes levels', 'MPA', (119, 151))	('superoxide dismutase', 'Gene', (157, 177))	('SiO2-ENM', 'Var', (57, 65))	('glutathione', 'Chemical', 'MESH:D005978', (182, 193))	('superoxide dismutase', 'Gene', '6647', (157, 177))	('depression', 'Disease', 'MESH:D000275', (105, 115))	('depression', 'Phenotype', 'HP:0000716', (105, 115))	('SiO2-ENM', 'Chemical', '-', (57, 65))	('glutathione peroxidase', 'MPA', (182, 204))	('depression', 'Disease', (105, 115))
41850	30653633	Overall, epidemiological findings may support that one of the principal mechanisms of SiO2-ENM toxicity is the generation of reactive oxygen species and oxidative injury.	('oxidative injury', 'MPA', (153, 169))	('reactive oxygen species', 'MPA', (125, 148))	('SiO2-ENM', 'Chemical', '-', (86, 94))	('SiO2-ENM', 'Var', (86, 94))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (125, 148))	('toxicity', 'Disease', (95, 103))
41870	30653633	However, lung tumors observed in rats following chronic inhalation of nano-sized TiO2 included squamous cell keratinizing cysts, bronchoalveolar adenocarcinomas, and squamous cell carcinomas.	('TiO2', 'Gene', (81, 85))	('lung tumors', 'Disease', (9, 20))	('keratinizing cysts', 'Phenotype', 'HP:0200040', (109, 127))	('squamous cell keratinizing cysts', 'Disease', (95, 127))	('lung tumors', 'Phenotype', 'HP:0100526', (9, 20))	('rats', 'Species', '10116', (33, 37))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (166, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (166, 190))	('adenocarcinomas', 'Disease', 'MESH:D000230', (145, 160))	('adenocarcinomas', 'Disease', (145, 160))	('squamous cell carcinomas', 'Disease', (166, 190))	('lung tumors', 'Disease', 'MESH:D008175', (9, 20))	('TiO2', 'Chemical', '-', (81, 85))	('nano-sized', 'Var', (70, 80))
41876	30653633	In this study, pulmonary function test alterations were also confirmed by the decrease in serum levels of surfactant protein-D levels, which may be a preclinical lung damage biomarker caused by cell injury and/or decrease in number of type II alveolar epithelial cells.	('decrease', 'NegReg', (78, 86))	('lung damage', 'Disease', 'MESH:D008171', (162, 173))	('decrease', 'NegReg', (213, 221))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('lung damage', 'Disease', (162, 173))	('alterations', 'Var', (39, 50))	('decrease in serum levels of surfactant protein', 'Phenotype', 'HP:0032094', (78, 124))	('serum levels of surfactant protein-D levels', 'MPA', (90, 133))
41880	30653633	Regarding the cardiovascular effects, Ichihara et al demonstrated that exposure to TiO2-ENM was associated with heart rate variabilities in workers involved in processing and handling such nanomaterials.	('TiO2-ENM', 'Var', (83, 91))	('associated', 'Reg', (96, 106))	('TiO2-ENM', 'Chemical', '-', (83, 91))	('heart rate variabilities', 'MPA', (112, 136))
41886	30653633	In a recent investigation, occupational exposure to TiO2-ENM in manufacturing and/or handling facilities resulted in significantly higher oxidative biomarkers, such as urinary 8-OHdG and EBC 8-isoprostane.	('8-isoprostane', 'Chemical', 'MESH:C075750', (191, 204))	('urinary 8-OHdG', 'MPA', (168, 182))	('EBC 8-isoprostane', 'MPA', (187, 204))	('TiO2-ENM', 'Var', (52, 60))	('TiO2-ENM', 'Chemical', '-', (52, 60))	('EBC', 'Chemical', '-', (187, 190))	('oxidative biomarkers', 'MPA', (138, 158))	('8-OHdG', 'Chemical', 'MESH:C067134', (176, 182))	('higher', 'PosReg', (131, 137))
41887	30653633	Such epidemiological findings are supported by extensive animal evidence concerning the deposition and bio persistence of TiO2-ENM in the pulmonary system and the consequent development of inflammatory reactions with possible increased airway responsiveness as well as acute or sub-acute airflow alterations.	('airway', 'CPA', (236, 242))	('TiO2-ENM', 'Var', (122, 130))	('TiO2-ENM', 'Chemical', '-', (122, 130))	('increased', 'PosReg', (226, 235))	('inflammatory reactions', 'CPA', (189, 211))
41889	30653633	Cardiovascular effects have been also reported in animals in which the inhalation of TiO2-ENM enhanced the phosphorylation levels of cardiac proteins and impaired vasodilator response, which may be due to an increase in microvascular oxidative stress.	('TiO2-ENM', 'Var', (85, 93))	('TiO2-ENM', 'Chemical', '-', (85, 93))	('cardiac proteins', 'Disease', 'MESH:D006331', (133, 149))	('vasodilator response', 'MPA', (163, 183))	('increase', 'PosReg', (208, 216))	('oxidative stress', 'Phenotype', 'HP:0025464', (234, 250))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('impaired', 'NegReg', (154, 162))	('cardiac proteins', 'Disease', (133, 149))	('enhanced', 'PosReg', (94, 102))
41894	30653633	Various animal inhalation and intratracheal studies show pulmonary inflammation and fibrosis, from the accumulation of CeO2 ENM in the lung tissue, as well as surface functionalization of the particles.	('CeO2', 'Var', (119, 123))	('pulmonary inflammation', 'Disease', (57, 79))	('inflammation', 'biological_process', 'GO:0006954', ('67', '79'))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (57, 79))	('CeO2 ENM', 'Chemical', '-', (119, 127))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('fibrosis', 'Disease', (84, 92))
41909	30653633	Co-exposure of ZnO-ENM and toluene, at their respective permissible exposure level in the paint industry, was reported to potentially produce a progressive inflammatory and fibrotic response in the alveolar tissues of the lungs of co-exposed rats.	('ZnO-ENM', 'Var', (15, 22))	('produce', 'Reg', (134, 141))	('toluene', 'Chemical', 'MESH:D014050', (27, 34))	('rats', 'Species', '10116', (242, 246))	('ZnO-ENM', 'Chemical', '-', (15, 22))
41935	30653633	The authors identified alterations on CpG sites in the promoter regions of functionally important genes in peripheral blood cells involved in the epigenetic machinery (ie, DNMT1, HDAC4), in the DNA damage response and G1/S transition in the cell cycle (ie, ATM), as well as in oncogenic activity (ie, SKI).	('ATM', 'Gene', '472', (257, 260))	('DNMT1', 'Gene', '1786', (172, 177))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('DNA damage response', 'biological_process', 'GO:0006974', ('194', '213'))	('SKI', 'Gene', (301, 304))	('SKI', 'Gene', '6497', (301, 304))	('oncogenic activity', 'CPA', (277, 295))	('ATM', 'Gene', (257, 260))	('HDAC4', 'Gene', '9759', (179, 184))	('alterations', 'Var', (23, 34))	('HDAC4', 'Gene', (179, 184))	('cell cycle', 'biological_process', 'GO:0007049', ('241', '251'))	('DNMT1', 'Gene', (172, 177))
41977	30653633	Emerging scientific evidence demonstrates that environmentally-induced epigenetic alterations may play a role in the manifestation of a number of human diseases, including cancer, mental disorders, obesity, and other severe conditions.	('mental disorders', 'Disease', (180, 196))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mental disorders', 'Disease', 'MESH:D001523', (180, 196))	('obesity', 'Disease', 'MESH:D009765', (198, 205))	('epigenetic alterations', 'Var', (71, 93))	('obesity', 'Disease', (198, 205))	('play', 'Reg', (98, 102))	('role', 'Reg', (105, 109))	('human', 'Species', '9606', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('obesity', 'Phenotype', 'HP:0001513', (198, 205))
42041	30313027	Moreover, MTA1 may play important role in tumor progression and outcome, and targeting MTA1 may be a new strategy for anti-cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('MTA1', 'Gene', '9112', (10, 14))	('tumor', 'Disease', (42, 47))	('MTA1', 'Gene', '9112', (87, 91))	('targeting', 'Var', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('MTA1', 'Gene', (10, 14))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('MTA1', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
42069	30313027	In accordance with the subgroup analysis according to tumor type, high expression of MTA1 indicated a poor prognosis in NSCLC (n = 5, HR 2.03, 95% CI: 1.40-2.94; P = .000), ESCC (n = 6, HR 1.59, 95% CI: 1.10-2.31; P = .014), and HCC (n = 2, HR 1.90, 95% CI: 1.39-2.59; P = .000), but not in NPC (n = 3, P = 0.118) or breast cancer (n = 2, P = .155) (Fig.	('HCC', 'Disease', (229, 232))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('ESCC', 'Disease', (173, 177))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('NPC', 'cellular_component', 'GO:0005643', ('291', '294'))	('MTA1', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('breast cancer', 'Disease', (317, 330))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('high expression', 'Var', (66, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('tumor', 'Disease', (54, 59))	('MTA1', 'Gene', '9112', (85, 89))	('NSCLC', 'Disease', (120, 125))
42117	30108437	The silver lining is that precision medicine advances quite well in NSCLC, with many targeted therapies currently available for NSCLC harboring specific mutations and rearrangements of oncogenes including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), RET and ROS proto-oncogene 1 (ROS1).	('mutations', 'Var', (153, 162))	('NSCLC', 'Disease', (128, 133))	('ALK', 'Gene', '238', (274, 277))	('epidermal growth factor receptor', 'Gene', (205, 237))	('ROS1', 'Gene', (310, 314))	('RET', 'Gene', (280, 283))	('ALK', 'Gene', (274, 277))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('epidermal growth factor receptor', 'Gene', '1956', (205, 237))	('ROS proto-oncogene 1', 'Gene', '6098', (288, 308))	('EGFR', 'Gene', (239, 243))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (246, 265))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('ROS proto-oncogene 1', 'Gene', (288, 308))	('ROS1', 'Gene', '6098', (310, 314))	('anaplastic lymphoma kinase', 'Gene', '238', (246, 272))	('NSCLC', 'Disease', (68, 73))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('205', '228'))	('anaplastic lymphoma kinase', 'Gene', (246, 272))	('RET', 'Gene', '5979', (280, 283))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('239', '243'))	('lymphoma', 'Phenotype', 'HP:0002665', (257, 265))	('EGFR', 'Gene', '1956', (239, 243))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('rearrangements', 'Var', (167, 181))
42138	30108437	Gefitinib was used at the 8th month of initial treatment since an EGFR mutation (L858R) was reported in the tumor tissue (Table 1).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('EGFR', 'Gene', '1956', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('EGFR', 'Gene', (66, 70))	('L858R', 'Mutation', 'rs121434568', (81, 86))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('tumor', 'Disease', (108, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))	('L858R', 'Var', (81, 86))
42224	30087398	In a previous work, we showed that two mitotic kinase inhibitors namely SP600125 and Reversine reduced the migration of soft tissue sarcoma cell lines.	('Reversine', 'Chemical', 'MESH:C484369', (85, 94))	('rat', 'Species', '10116', (110, 113))	('SP600125', 'Var', (72, 80))	('SP600125', 'Chemical', 'MESH:C432165', (72, 80))	('sarcoma', 'Disease', (132, 139))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (120, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('migration of soft tissue', 'CPA', (107, 131))	('reduced', 'NegReg', (95, 102))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
42225	30087398	SP600125 (anthra[1,9-cd]pyrazol-6-(2H)-one), a reversible ATP-competitive inhibitor of MAPK-JNK, was identified as direct inhibitor of JNK activity in a high throughput screening of a private chemical library held by Celgene.	('Celgene', 'Chemical', 'MESH:D013792', (217, 224))	('anthra[1,9-cd]pyrazol-6-(2H)-one', 'Chemical', 'MESH:C432165', (10, 42))	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('JNK', 'Gene', (135, 138))	('ATP', 'Chemical', 'MESH:D000255', (58, 61))	('JNK', 'molecular_function', 'GO:0004705', ('135', '138'))	('activity', 'MPA', (139, 147))	('JNK', 'Gene', (92, 95))	('JNK', 'Gene', '5599', (135, 138))	('JNK', 'Gene', '5599', (92, 95))	('SP600125', 'Var', (0, 8))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('JNK', 'molecular_function', 'GO:0004705', ('92', '95'))
42226	30087398	SP600125 targets specifically JNK1, JNK2 and JNK3 with an IC50 values of 40 nM for JNK1 and JNK2, as well as 90 nM for JNK3.	('JNK', 'molecular_function', 'GO:0004705', ('83', '86'))	('JNK', 'molecular_function', 'GO:0004705', ('36', '39'))	('JNK3', 'Gene', '5602', (45, 49))	('JNK', 'molecular_function', 'GO:0004705', ('119', '122'))	('JNK', 'molecular_function', 'GO:0004705', ('30', '33'))	('JNK3', 'Gene', (119, 123))	('JNK1', 'Gene', (30, 34))	('JNK2', 'Gene', (36, 40))	('JNK2', 'Gene', '5601', (36, 40))	('JNK', 'molecular_function', 'GO:0004705', ('45', '48'))	('SP600125', 'Var', (0, 8))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('JNK2', 'Gene', (92, 96))	('JNK3', 'Gene', (45, 49))	('JNK2', 'Gene', '5601', (92, 96))	('JNK3', 'Gene', '5602', (119, 123))	('JNK', 'molecular_function', 'GO:0004705', ('92', '95'))
42227	30087398	SP600125 further inhibits the mitotic serine/threonine kinases Aurora kinase A and B and Monopolar spindle 1 kinase (Mps1).	('inhibits', 'NegReg', (17, 25))	('mitotic serine/threonine', 'MPA', (30, 54))	('serine', 'Chemical', 'MESH:D012694', (38, 44))	('spindle', 'cellular_component', 'GO:0005819', ('99', '106'))	('Aurora kinase A and B', 'Gene', '6790;9212', (63, 84))	('Monopolar spindle 1 kinase', 'Gene', (89, 115))	('SP600125', 'Var', (0, 8))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('Monopolar spindle 1 kinase', 'Gene', '7272', (89, 115))	('Mps1', 'Gene', (117, 121))	('Mps1', 'Gene', '7272', (117, 121))
42228	30087398	SP600125 is widely used to disrupt signaling underlying diverse biological processes including inflammation, neurodegeneration, metabolic disease and cancer.	('neurodegeneration', 'Phenotype', 'HP:0002180', (109, 126))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('metabolic disease', 'Disease', (128, 145))	('cancer', 'Disease', (150, 156))	('neurodegeneration', 'Disease', (109, 126))	('inflammation', 'Disease', (95, 107))	('SP600125', 'Var', (0, 8))	('signaling', 'MPA', (35, 44))	('neurodegeneration', 'Disease', 'MESH:D019636', (109, 126))	('metabolic disease', 'Disease', 'MESH:D008659', (128, 145))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('inflammation', 'biological_process', 'GO:0006954', ('95', '107'))	('disrupt', 'Reg', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
42237	30087398	By calculating both the ratio of the field area and cells count of the migration zone it was found that Reversine and SP600125 at 10 muM prevent the migration of sarcoma cells.	('muM', 'Gene', (133, 136))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('rat', 'Species', '10116', (152, 155))	('sarcoma', 'Disease', (162, 169))	('migration', 'CPA', (149, 158))	('prevent', 'NegReg', (137, 144))	('rat', 'Species', '10116', (74, 77))	('SP600125 at', 'Var', (118, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('Reversine', 'Chemical', 'MESH:C484369', (104, 113))	('muM', 'Gene', '56925', (133, 136))	('rat', 'Species', '10116', (24, 27))	('SP600125', 'Chemical', 'MESH:C432165', (118, 126))
42239	30087398	In a first experimental approach, we performed a wound-healing test and found that the decrease of cell free area was significantly delayed in the presence of SP600125 (55 +/- 0.7%) or Reversine (48 +/- 0.1%) (Fig.	('SP600125', 'Chemical', 'MESH:C432165', (159, 167))	('Reversine', 'Chemical', 'MESH:C484369', (185, 194))	('wound-healing', 'biological_process', 'GO:0042060', ('49', '62'))	('decrease', 'NegReg', (87, 95))	('delayed', 'NegReg', (132, 139))	('cell free area', 'CPA', (99, 113))	('SP600125', 'Var', (159, 167))
42240	30087398	The two dimensional OrisTM cell migration assay confirmed the anti-migratory effect of Reversine and SP600125 compared to solvent treated RKO cells (Fig.	('rat', 'Species', '10116', (70, 73))	('SP600125', 'Var', (101, 109))	('SP600125', 'Chemical', 'MESH:C432165', (101, 109))	('cell migration', 'biological_process', 'GO:0016477', ('27', '41'))	('Reversine', 'Chemical', 'MESH:C484369', (87, 96))	('anti-migratory', 'NegReg', (62, 76))	('RKO', 'CellLine', 'CVCL:0504', (138, 141))	('rat', 'Species', '10116', (35, 38))
42241	30087398	1B), Reversine inhibited migration by 40 +/- 0.1% and SP600125 by 37 +/- 0.1%.	('inhibited', 'NegReg', (15, 24))	('SP600125', 'Chemical', 'MESH:C432165', (54, 62))	('migration', 'CPA', (25, 34))	('SP600125', 'Var', (54, 62))	('Reversine', 'Chemical', 'MESH:C484369', (5, 14))	('rat', 'Species', '10116', (28, 31))
42242	30087398	In addition, SP600125 and Reversine reduced individual cell migration, tracked by time laps microscopy (Fig.	('cell migration', 'biological_process', 'GO:0016477', ('55', '69'))	('SP600125', 'Chemical', 'MESH:C432165', (13, 21))	('SP600125', 'Var', (13, 21))	('reduced', 'NegReg', (36, 43))	('rat', 'Species', '10116', (63, 66))	('individual cell migration', 'CPA', (44, 69))	('Reversine', 'Chemical', 'MESH:C484369', (26, 35))
42243	30087398	Moreover, using Boyden chamber assay, cell invasion was completely abolished in cells treated with Reversine and SP600125 for 24 h (Fig.	('Reversine', 'Chemical', 'MESH:C484369', (99, 108))	('cell invasion', 'CPA', (38, 51))	('SP600125', 'Var', (113, 121))	('SP600125', 'Chemical', 'MESH:C432165', (113, 121))	('abolished', 'NegReg', (67, 76))
42249	30087398	Moreover, cell cycle FACS analysis showed that subG1 fraction relative to DNA degradation was not significantly different between SP600125 or Reversine treated cells and DMSO-treated cells (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('Reversine', 'Chemical', 'MESH:C484369', (142, 151))	('DNA degradation', 'biological_process', 'GO:0006308', ('74', '89'))	('SP600125', 'Var', (130, 138))	('DNA degradation', 'MPA', (74, 89))	('SP600125', 'Chemical', 'MESH:C432165', (130, 138))	('cell cycle', 'biological_process', 'GO:0007049', ('10', '20'))	('DMSO', 'Chemical', 'MESH:D004121', (170, 174))
42250	30087398	Together, these results suggest that 24 h treatment of colon cancer cells with Reversine and SP600125 does not affect cell death parameters.	('cell death', 'biological_process', 'GO:0008219', ('118', '128'))	('SP600125', 'Var', (93, 101))	('Reversine', 'Chemical', 'MESH:C484369', (79, 88))	('colon cancer', 'Phenotype', 'HP:0003003', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colon cancer', 'Disease', 'MESH:D015179', (55, 67))	('colon cancer', 'Disease', (55, 67))	('SP600125', 'Chemical', 'MESH:C432165', (93, 101))
42252	30087398	Together, these results suggest that 24 h treatment of non-cancerous cells with Reversine and SP600125 does not affect cell death parameters.	('SP600125', 'Chemical', 'MESH:C432165', (94, 102))	('SP600125', 'Var', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Reversine', 'Chemical', 'MESH:C484369', (80, 89))	('cell death', 'biological_process', 'GO:0008219', ('119', '129'))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
42254	30087398	Crystal violet cell proliferation assay showed that Reversine and SP600125 has no influence in cell proliferation after 24 h of treatment (Fig.	('cell proliferation', 'CPA', (95, 113))	('SP600125', 'Var', (66, 74))	('SP600125', 'Chemical', 'MESH:C432165', (66, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('Reversine', 'Chemical', 'MESH:C484369', (52, 61))	('rat', 'Species', '10116', (27, 30))	('Crystal violet', 'Chemical', 'MESH:D005840', (0, 14))	('rat', 'Species', '10116', (107, 110))
42257	30087398	Treatment of cells Reversine and SP600125 continued to cycle and undergo polyploidy as well as exhibited histone H3 phosphorylation, which is a marker of ongoing cell mitosis (Fig.	('ongoing cell mitosis', 'Disease', 'MESH:C538614', (154, 174))	('SP600125', 'Chemical', 'MESH:C432165', (33, 41))	('polyploidy', 'Disease', (73, 83))	('mitosis', 'biological_process', 'GO:0000278', ('167', '174'))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('SP600125', 'Var', (33, 41))	('histone H3 phosphorylation', 'MPA', (105, 131))	('undergo', 'Reg', (65, 72))	('Reversine', 'Chemical', 'MESH:C484369', (19, 28))	('polyploidy', 'Disease', 'MESH:D011123', (73, 83))	('cycle', 'CPA', (55, 60))	('exhibited', 'Reg', (95, 104))	('ongoing cell mitosis', 'Disease', (154, 174))
42258	30087398	Altogether, this data together with our previous findings demonstrate that SP600125 and Reversine do not influence cancer cells proliferation at 24 h but instead induces cells polyploidization.	('cancer', 'Disease', (115, 121))	('cells polyploidization', 'CPA', (170, 192))	('rat', 'Species', '10116', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SP600125', 'Chemical', 'MESH:C432165', (75, 83))	('SP600125', 'Var', (75, 83))	('induces', 'Reg', (162, 169))	('Reversine', 'Chemical', 'MESH:C484369', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('rat', 'Species', '10116', (65, 68))
42259	30087398	Reversine and SP600125 are reported as broad-spectrum inhibitors of serine/threonine kinases.	('Reversine', 'Chemical', 'MESH:C484369', (0, 9))	('serine', 'Chemical', 'MESH:D012694', (68, 74))	('SP600125', 'Chemical', 'MESH:C432165', (14, 22))	('SP600125', 'Var', (14, 22))	('serine/threonine', 'Enzyme', (68, 84))
42260	30087398	Treatment of RKO cells with 10 microM of Reversine or SP600125 inhibited several kinases with varying efficiency.	('SP600125', 'Chemical', 'MESH:C432165', (54, 62))	('RKO', 'CellLine', 'CVCL:0504', (13, 16))	('SP600125', 'Var', (54, 62))	('Reversine', 'Chemical', 'MESH:C484369', (41, 50))	('kinases', 'Enzyme', (81, 88))	('inhibited', 'NegReg', (63, 72))
42261	30087398	As a result, in a panel of 222 kinases, SP600125 and Reversine inhibited 36 and 93 kinases, respectively.	('SP600125', 'Chemical', 'MESH:C432165', (40, 48))	('SP600125', 'Var', (40, 48))	('Reversine', 'Chemical', 'MESH:C484369', (53, 62))	('inhibited', 'NegReg', (63, 72))
42263	30087398	Regulation of the JNK cascade exhibited the highest enrichment score (Term p-value after correction with Bonferroni = 1,42 x 10-6) for the common SP600125 and Reversine-inhibited kinase (Fig.	('JNK', 'molecular_function', 'GO:0004705', ('18', '21'))	('JNK', 'Gene', '5599', (18, 21))	('SP600125', 'Var', (146, 154))	('JNK cascade', 'biological_process', 'GO:0007254', ('18', '29'))	('Reversine', 'Chemical', 'MESH:C484369', (159, 168))	('JNK', 'Gene', (18, 21))	('SP600125', 'Chemical', 'MESH:C432165', (146, 154))
42268	30087398	Furthermore, Reversine or SP600125 treatment completely abolishes the phosphorylation of JNK1/2.	('JNK1/2', 'Gene', '5599;5601', (89, 95))	('Reversine', 'Chemical', 'MESH:C484369', (13, 22))	('JNK', 'molecular_function', 'GO:0004705', ('89', '92'))	('JNK1/2', 'Gene', (89, 95))	('phosphorylation', 'MPA', (70, 85))	('SP600125', 'Chemical', 'MESH:C432165', (26, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('SP600125', 'Var', (26, 34))	('abolishes', 'NegReg', (56, 65))
42277	30087398	Wound recovering and migration zone invasion were similar after 24h-treatment with the JNK2 inhibitor and control treated cells.	('JNK2', 'Gene', (87, 91))	('JNK2', 'Gene', '5601', (87, 91))	('migration zone invasion', 'CPA', (21, 44))	('JNK', 'molecular_function', 'GO:0004705', ('87', '90'))	('rat', 'Species', '10116', (24, 27))	('inhibitor', 'Var', (92, 101))
42278	30087398	To confirm this data, we treated the cells with small interfering RNAs specific for JNK1 or JNK2.	('JNK1', 'Gene', (84, 88))	('JNK', 'molecular_function', 'GO:0004705', ('84', '87'))	('JNK', 'molecular_function', 'GO:0004705', ('92', '95'))	('JNK2', 'Gene', (92, 96))	('JNK2', 'Gene', '5601', (92, 96))	('small interfering RNAs', 'Var', (48, 70))
42282	30087398	It was evident that the decline of cell free area was significantly delayed following knockdown of JNK1/2 compared to siRNA UNR (74 +/- 0.4% of inhibition) or siJNK2-treated cells (Fig.	('JNK2', 'Gene', '5601', (161, 165))	('UNR', 'Gene', '5030', (124, 127))	('knockdown', 'Var', (86, 95))	('delayed', 'NegReg', (68, 75))	('decline', 'NegReg', (24, 31))	('cell free area', 'CPA', (35, 49))	('JNK', 'molecular_function', 'GO:0004705', ('99', '102'))	('UNR', 'Gene', (124, 127))	('JNK1/2', 'Gene', '5599;5601', (99, 105))	('JNK2', 'Gene', (161, 165))	('JNK1/2', 'Gene', (99, 105))
42283	30087398	To exclude toxic effect of JNK1 and JNK2 knockdown, FACS analyses of the death related parameters were investigated.	('JNK', 'molecular_function', 'GO:0004705', ('36', '39'))	('JNK', 'molecular_function', 'GO:0004705', ('27', '30'))	('JNK1', 'Gene', (27, 31))	('JNK2', 'Gene', (36, 40))	('JNK2', 'Gene', '5601', (36, 40))	('knockdown', 'Var', (41, 50))
42284	30087398	It was found that siRNA transfection of RKO cells with JNK1 or JNK2 did not induce any significant changes in the overall cell survival (Fig.	('RKO', 'CellLine', 'CVCL:0504', (40, 43))	('JNK2', 'Gene', (63, 67))	('JNK', 'molecular_function', 'GO:0004705', ('63', '66'))	('JNK2', 'Gene', '5601', (63, 67))	('JNK1', 'Var', (55, 59))	('JNK', 'molecular_function', 'GO:0004705', ('55', '58'))
42288	30087398	The SP600125-treated mice showed fewer tumor metastases in the liver (Fig.	('tumor metastases', 'Disease', (39, 55))	('mice', 'Species', '10090', (21, 25))	('tumor metastases', 'Disease', 'MESH:D009362', (39, 55))	('fewer', 'NegReg', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SP600125', 'Chemical', 'MESH:C432165', (4, 12))	('SP600125-treated', 'Var', (4, 20))
42292	30087398	Densitometic analysis demonstrated that SP600125 reduces phospho JNK level in treated lung and liver comparatively to control.	('SP600125', 'Chemical', 'MESH:C432165', (40, 48))	('JNK', 'Gene', '5599', (65, 68))	('reduces', 'NegReg', (49, 56))	('SP600125', 'Var', (40, 48))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (106, 109))	('JNK', 'Gene', (65, 68))	('JNK', 'molecular_function', 'GO:0004705', ('65', '68'))
42295	30087398	Here, we report the identification of the small molecules Reversine and SP600125, which can interfere with JNK signaling, as inhibitors of migration and metastasis of colon carcinoma cells.	('SP600125', 'Var', (72, 80))	('JNK', 'Gene', (107, 110))	('SP600125', 'Chemical', 'MESH:C432165', (72, 80))	('metastasis of colon carcinoma', 'Disease', 'MESH:D009362', (153, 182))	('rat', 'Species', '10116', (142, 145))	('inhibitors', 'NegReg', (125, 135))	('migration', 'CPA', (139, 148))	('JNK', 'Gene', '5599', (107, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('Reversine', 'Chemical', 'MESH:C484369', (58, 67))	('JNK', 'molecular_function', 'GO:0004705', ('107', '110'))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('metastasis of colon carcinoma', 'Disease', (153, 182))
42297	30087398	RKO cells harbor mutations in KRAS, BRAF, PIK3CA and PTEN and are considered as one of the most invasive colon cancer cell lines.	('BRAF', 'Gene', (36, 40))	('PIK3CA', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))	('invasive colon cancer', 'Disease', (96, 117))	('RKO', 'CellLine', 'CVCL:0504', (0, 3))	('PTEN', 'Gene', (53, 57))	('PIK3CA', 'Gene', '5290', (42, 48))	('PTEN', 'Gene', '5728', (53, 57))	('invasive colon cancer', 'Disease', 'MESH:D015179', (96, 117))	('KRAS', 'Gene', (30, 34))	('mutations', 'Var', (17, 26))	('BRAF', 'Gene', '673', (36, 40))	('KRAS', 'Gene', '3845', (30, 34))
42299	30087398	The previous test revealed Reversine and SP600125 as potent anti-migratory drugs of invasive sarcoma cells.	('Reversine', 'Chemical', 'MESH:C484369', (27, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('rat', 'Species', '10116', (68, 71))	('SP600125', 'Chemical', 'MESH:C432165', (41, 49))	('invasive sarcoma', 'Disease', 'MESH:D012509', (84, 100))	('SP600125', 'Var', (41, 49))	('invasive sarcoma', 'Disease', (84, 100))
42300	30087398	In the present study, we explored the effect of Reversine and SP600125 on the human colon carcinoma RKO cells.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Reversine', 'Chemical', 'MESH:C484369', (48, 57))	('RKO', 'CellLine', 'CVCL:0504', (100, 103))	('colon carcinoma', 'Disease', 'MESH:D015179', (84, 99))	('SP600125', 'Var', (62, 70))	('SP600125', 'Chemical', 'MESH:C432165', (62, 70))	('human', 'Species', '9606', (78, 83))	('colon carcinoma', 'Disease', (84, 99))
42304	30087398	In this work we could also show that 24 h treatment with Reversine or SP600125 is non-toxic to the non-cancerous cells including non-transformed fibroblast and human colon mucosal epithelial cells.	('Reversine', 'Chemical', 'MESH:C484369', (57, 66))	('colon mucosal epithelial', 'Disease', (166, 190))	('SP600125', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('colon mucosal epithelial', 'Disease', 'MESH:D052016', (166, 190))	('SP600125', 'Chemical', 'MESH:C432165', (70, 78))	('human', 'Species', '9606', (160, 165))
42305	30087398	The kinase profiler screening identified several kinases that were inhibited by both Reversine and SP600125.	('Reversine', 'Chemical', 'MESH:C484369', (85, 94))	('kinases', 'Enzyme', (49, 56))	('inhibited', 'NegReg', (67, 76))	('SP600125', 'Chemical', 'MESH:C432165', (99, 107))	('SP600125', 'Var', (99, 107))
42306	30087398	This result in combination with bio-informatics (GO: gene ontology) approaches identified the JNK family activation as the most significant pathway inhibited by Reversine and SP600125.	('Reversine', 'Chemical', 'MESH:C484369', (161, 170))	('JNK', 'Gene', '5599', (94, 97))	('activation', 'PosReg', (105, 115))	('SP600125', 'Chemical', 'MESH:C432165', (175, 183))	('JNK', 'molecular_function', 'GO:0004705', ('94', '97'))	('SP600125', 'Var', (175, 183))	('gene ontology', 'biological_process', 'GO:0003673', ('53', '66'))	('inhibited', 'NegReg', (148, 157))	('JNK', 'Gene', (94, 97))
42308	30087398	The results demonstrated that only JNK1 inhibition delays the motility of these cells.	('motility of these cells', 'CPA', (62, 85))	('inhibition', 'Var', (40, 50))	('rat', 'Species', '10116', (19, 22))	('delays', 'NegReg', (51, 57))	('JNK', 'molecular_function', 'GO:0004705', ('35', '38'))	('JNK1', 'Gene', (35, 39))
42314	30087398	Reversine inhibits Mps1 in vitro with an IC50 of 63 nM, whereas SP600125 targets Mps1 with an IC50 of 1.95 microM and JNK with an average of 56 nM (JNK1, 2 and 3).	('Mps1', 'Gene', '7272', (19, 23))	('JNK', 'Gene', (118, 121))	('inhibits', 'NegReg', (10, 18))	('Reversine', 'Chemical', 'MESH:C484369', (0, 9))	('Mps1', 'Gene', (19, 23))	('JNK', 'Gene', (148, 151))	('SP600125', 'Chemical', 'MESH:C432165', (64, 72))	('JNK', 'Gene', '5599', (118, 121))	('Mps1', 'Gene', (81, 85))	('JNK', 'molecular_function', 'GO:0004705', ('118', '121'))	('SP600125', 'Var', (64, 72))	('Mps1', 'Gene', '7272', (81, 85))	('JNK', 'Gene', '5599', (148, 151))	('JNK', 'molecular_function', 'GO:0004705', ('148', '151'))	('JNK1, 2 and 3', 'Gene', '5599;5601;5602', (148, 161))
42316	30087398	Mutation of methionine M108 to glutamine in JNK1 renders it insensitive to SP600125 inhibition.	('methionine M108 to glutamine', 'Var', (12, 40))	('JNK1', 'Gene', (44, 48))	('JNK', 'molecular_function', 'GO:0004705', ('44', '47'))	('methionine M108 to glutamine', 'SUBSTITUTION', 'None', (12, 40))	('Mutation', 'Var', (0, 8))	('SP600125', 'Chemical', 'MESH:C432165', (75, 83))
42317	30087398	Moreover, the corresponding mutation in Mps1 (M602Q) also proved significantly less sensitive to SP600125.	('sensitive', 'MPA', (84, 93))	('Mps1', 'Gene', (40, 44))	('SP600125', 'Chemical', 'MESH:C432165', (97, 105))	('Mps1', 'Gene', '7272', (40, 44))	('M602Q', 'SUBSTITUTION', 'None', (46, 51))	('less', 'NegReg', (79, 83))	('M602Q', 'Var', (46, 51))
42318	30087398	These results in combination with our findings suggest that Reversine and SP600125 share the common target kinase JNK.	('Reversine', 'Chemical', 'MESH:C484369', (60, 69))	('SP600125', 'Chemical', 'MESH:C432165', (74, 82))	('JNK', 'Gene', '5599', (114, 117))	('JNK', 'molecular_function', 'GO:0004705', ('114', '117'))	('SP600125', 'Var', (74, 82))	('JNK', 'Gene', (114, 117))
42320	30087398	In the present study, we found that treatment with SP600125 of intravenously injected tumor cells reduces liver and lung tumor metastases.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('lung tumor metastases', 'Disease', (116, 137))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('lung tumor metastases', 'Disease', 'MESH:D009362', (116, 137))	('SP600125', 'Chemical', 'MESH:C432165', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('reduces', 'NegReg', (98, 105))	('lung tumor', 'Phenotype', 'HP:0100526', (116, 126))	('SP600125', 'Var', (51, 59))
42322	30087398	Several studies investigated the effect of JNK1 inhibition by chemicals, small interfering RNA, or dominant-negative mutant, and could confirm the role of JNK-signaling in migration of several different cell types.	('JNK', 'molecular_function', 'GO:0004705', ('43', '46'))	('JNK', 'Gene', '5599', (155, 158))	('mutant', 'Var', (117, 123))	('JNK', 'Gene', (43, 46))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('JNK', 'molecular_function', 'GO:0004705', ('155', '158'))	('rat', 'Species', '10116', (175, 178))	('JNK', 'Gene', '5599', (43, 46))	('inhibition', 'NegReg', (48, 58))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))	('JNK', 'Gene', (155, 158))
42323	30087398	In these studies, the overexpression of a dominant-negative mutant of JNK1 reduced the migration of rat urinary bladder NBT-II cells, cortical neurons, human umbilical vein endothelial cells, and bovine aortic endothelial cells.	('migration', 'CPA', (87, 96))	('bovine', 'Species', '9913', (196, 202))	('overexpression', 'PosReg', (22, 36))	('JNK1', 'Gene', (70, 74))	('reduced', 'NegReg', (75, 82))	('JNK', 'molecular_function', 'GO:0004705', ('70', '73'))	('human', 'Species', '9606', (152, 157))	('cortical neurons', 'CPA', (134, 150))	('mutant', 'Var', (60, 66))	('rat', 'Species', '10116', (100, 103))	('rat', 'Species', '10116', (90, 93))
42324	30087398	Moreover, JNK1 siRNA transfection delays the migration of gastric cancer cells, mouse hepatocellular carcinoma cells, and human melanoma cells.	('human', 'Species', '9606', (122, 127))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (86, 110))	('delays', 'NegReg', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mouse', 'Species', '10090', (80, 85))	('rat', 'Species', '10116', (48, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('hepatocellular carcinoma', 'Disease', (86, 110))	('transfection', 'Var', (21, 33))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('migration', 'CPA', (45, 54))	('gastric cancer', 'Disease', (58, 72))	('JNK1', 'Gene', (10, 14))	('JNK', 'molecular_function', 'GO:0004705', ('10', '13'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
42335	30087398	NCM460 cells were maintained in INCELL's enriched M3:10 medium (M310A; which is M3 Base medium plus supplements with 10% FBS and contains antibiotics).	('M310A', 'SUBSTITUTION', 'None', (64, 69))	('M310A', 'Var', (64, 69))	('FBS', 'Disease', 'MESH:D005198', (121, 124))	('FBS', 'Disease', (121, 124))
42337	30087398	Reversine (BioNordika, Stockholm, Sweden), SP600125 (Sigma-Aldrich), Nocodazole (Sigma-Aldrich) and JNK inhibitor IX (Santa Cruz Biotechnology, Dallas, USA) were stocked as 10 mM solution in DMSO.	('DMSO', 'Chemical', 'MESH:D004121', (191, 195))	('JNK', 'Gene', '5599', (100, 103))	('Reversine', 'Chemical', 'MESH:C484369', (0, 9))	('SP600125', 'Chemical', 'MESH:C432165', (43, 51))	('JNK', 'molecular_function', 'GO:0004705', ('100', '103'))	('SP600125', 'Var', (43, 51))	('Nocodazole', 'Chemical', 'MESH:D015739', (69, 79))	('JNK', 'Gene', (100, 103))
42344	28357677	Identification of a novel somatic mutation leading to allele dropout for EGFR L858R genotyping in non-small cell lung cancer While PCR-based genotyping methods abound in molecular testing for lung cancer therapy, these approaches may not provide the robust sensitivity to detect accurate genotypes in a variable cancer genomic background.	('allele', 'MPA', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (312, 318))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('mutation', 'Var', (34, 42))	('EGFR', 'Gene', (73, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (197, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('L858R', 'Mutation', 'rs121434568', (78, 83))	('lung cancer', 'Disease', (113, 124))	('EGFR', 'Gene', '1956', (73, 77))	('lung cancer', 'Disease', (192, 203))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
42345	28357677	Here, we describe a study of a clinical tumor specimen containing a novel somatic single nucleotide variant that caused allele drop-out in EGFR L858R genotyping, resulting in a false negative interpretation and impacting patient clinical management.	('allele', 'MPA', (120, 126))	('L858R', 'Var', (144, 149))	('single nucleotide variant', 'Var', (82, 107))	('drop-out', 'NegReg', (127, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('false', 'biological_process', 'GO:0071877', ('177', '182'))	('L858R', 'Mutation', 'rs121434568', (144, 149))	('EGFR', 'Gene', '1956', (139, 143))	('patient', 'Species', '9606', (221, 228))	('interpretation', 'MPA', (192, 206))	('false negative', 'NegReg', (177, 191))	('EGFR', 'Gene', (139, 143))	('tumor', 'Disease', (40, 45))	('false', 'biological_process', 'GO:0071878', ('177', '182'))	('impacting', 'Reg', (211, 220))
42349	28357677	However, the use of therapeutic agents targeting the epidermal growth factor receptor (EGFR) have dramatically improved the clinical management of the approximately 15% of patients in the United States and 50% of patients in Asia with lung adenocarcinomas harboring EGFR mutations.	('epidermal growth factor receptor', 'Gene', '1956', (53, 85))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('lung adenocarcinomas', 'Disease', (235, 255))	('improved', 'PosReg', (111, 119))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', '1956', (266, 270))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('53', '76'))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (235, 255))	('clinical management', 'MPA', (124, 143))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (235, 255))	('EGFR', 'Gene', (266, 270))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (172, 180))	('epidermal growth factor receptor', 'Gene', (53, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('266', '270'))	('mutations', 'Var', (271, 280))
42350	28357677	The most common of these mutations are exon 19 deletions and the EGFR L858R mutation.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('common', 'Reg', (9, 15))	('L858R', 'Var', (70, 75))	('L858R', 'Mutation', 'rs121434568', (70, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
42351	28357677	When present, the L858R mutation has been shown to increase patient sensitivity to first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) leading to longer progression-free survival on TKI therapy as compared to those receiving chemotherapy.	('increase', 'PosReg', (51, 59))	('patient', 'Species', '9606', (60, 67))	('progression-free survival', 'CPA', (178, 203))	('EGFR', 'Gene', '1956', (121, 125))	('longer', 'PosReg', (171, 177))	('L858R', 'Var', (18, 23))	('patient sensitivity', 'MPA', (60, 79))	('EGFR', 'Gene', (121, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('L858R', 'Mutation', 'rs121434568', (18, 23))
42352	28357677	As a result, accurate and rapid detection of underlying EGFR mutations in lung cancer specimens is crucial for effective management of patients.	('patients', 'Species', '9606', (135, 143))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('EGFR', 'Gene', '1956', (56, 60))	('mutations', 'Var', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))
42353	28357677	Common molecular diagnostic approaches for genotyping the therapeutically actionable mutations in the EGFR locus include PCR-based methods that utilize specifically designed primers to interrogate the region of interest.	('mutations', 'Var', (85, 94))	('EGFR', 'Gene', (102, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('EGFR', 'Gene', '1956', (102, 106))
42354	28357677	Here we report a specimen that was falsely determined to be negative for the EGFR L858R mutation as a result of allelic dropout caused by a nearby novel silent coding mutation (c.2571G>A, p.G857G), and was subsequently correctly genotyped as an L858R carrier using an unbiased target-capture based sequencing approach.	('negative', 'NegReg', (60, 68))	('L858R', 'Mutation', 'rs121434568', (245, 250))	('L858R', 'Mutation', 'rs121434568', (82, 87))	('p.G857G', 'SUBSTITUTION', 'None', (188, 195))	('allelic', 'MPA', (112, 119))	('carrier', 'molecular_function', 'GO:0005215', ('251', '258'))	('c.2571G>A', 'Var', (177, 186))	('dropout', 'NegReg', (120, 127))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('c.2571G>A', 'Mutation', 'c.2571G>A', (177, 186))	('EGFR', 'Gene', (77, 81))	('p.G857G', 'Var', (188, 195))
42364	28357677	The sensitivity of this assay is approximately 20% EGFR mutation detection in a background of EGFR wild type DNA.	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (94, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('mutation', 'Var', (56, 64))	('EGFR', 'Gene', '1956', (51, 55))
42368	28357677	The specimen was concurrently submitted for testing on a targeted EGFR mutation panel that includes the L858R allele, and a high-throughput 198 gene pan-cancer somatic mutation sequencing panel which includes the entire coding region of the EGFR gene.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('EGFR', 'Gene', '1956', (241, 245))	('mutation', 'Var', (71, 79))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('241', '245'))	('EGFR', 'Gene', (241, 245))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('L858R', 'Mutation', 'rs121434568', (104, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
42369	28357677	Targeted EGFR L858R genotyping results from a dideoxy single-base extension 'SNaPshot' assay is shown in Figure 1.	('L858R', 'Var', (14, 19))	('L858R', 'Mutation', 'rs121434568', (14, 19))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
42371	28357677	The extension primer anneals 5'-adjacent to the L858R causing nucleotide (c.2573) and incorporates a single fluorescently labelled ddNTP.	('L858R', 'Mutation', 'rs121434568', (48, 53))	('ddNTP', 'Chemical', 'MESH:D054306', (131, 136))	('c.2573', 'Var', (74, 80))	('L858R', 'Var', (48, 53))
42374	28357677	Clear absence of any other fragment peaks suggested that the patient specimen was negative for the L858R (c.2573T>G) mutation.	('L858R', 'Var', (99, 104))	('patient', 'Species', '9606', (61, 68))	('c.2573T>G', 'Var', (106, 115))	('L858R', 'Mutation', 'rs121434568', (99, 104))	('c.2573T>G', 'Mutation', 'rs121434568', (106, 115))
42376	28357677	Table 2 shows the variants identified in the EGFR exon 21 region that passed our quality control filtering criteria.	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('variants', 'Var', (18, 26))	('EGFR', 'Gene', (45, 49))
42377	28357677	Following this criteria, we identified the causal L858R c.2573T>G mutation at 23.9% allele frequency within the specimen.	('c.2573T>G', 'SUBSTITUTION', 'None', (56, 65))	('causal', 'Reg', (43, 49))	('c.2573T>G', 'Var', (56, 65))	('L858R', 'SUBSTITUTION', 'None', (50, 55))	('L858R', 'Var', (50, 55))
42379	28357677	Additional bioinformatic analysis identified an adjacent point mutation to the L858 allele causing a silent amino acid change (c.2571G>A, p.G857G) (Figure 2).	('c.2571G>A', 'Mutation', 'c.2571G>A', (127, 136))	('p.G857G', 'Var', (138, 145))	('p.G857G', 'SUBSTITUTION', 'None', (138, 145))	('L858', 'Gene', (79, 83))	('c.2571G>A', 'Var', (127, 136))
42381	28357677	The G857G is in cis with the L858R allele in virtually all reads and is present at a nearly identical depth (2586X, 619 variant supporting reads) and allele frequency (23.2%).	('2586X', 'Var', (109, 114))	('G857G', 'Var', (4, 9))	('L858R', 'Var', (29, 34))	('L858R', 'Mutation', 'rs121434568', (29, 34))
42382	28357677	The presence of the G857G variant disrupted the 3' extension primer binding for the 'SNaPshot' genotyping assay for this patient.	("3' extension primer", 'MPA', (48, 67))	('G857G', 'Var', (20, 25))	('disrupted', 'NegReg', (34, 43))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('patient', 'Species', '9606', (121, 128))
42383	28357677	As the G857G variant was uniquely in cis with the L858R variant on the same somatic allele, the wild type allele was preferentially amplified resulting in a false negative result (Figure 3C).	('false', 'biological_process', 'GO:0071878', ('157', '162'))	('L858R', 'Mutation', 'rs121434568', (50, 55))	('G857G', 'Var', (7, 12))	('false', 'biological_process', 'GO:0071877', ('157', '162'))	('L858R', 'Var', (50, 55))
42384	28357677	This is in contrast to normal specimens harboring two wild type EGFR L858 (c.2573T) alleles producing a single PCR fragment (red) (Figure 3A) and specimens with only the L858R and wild type EGFR alleles producing a mutant PCR fragment (blue) and a wild type PCR fragment (red) (Figure 3B).	('EGFR', 'Gene', '1956', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('L858R', 'Var', (170, 175))	('EGFR', 'Gene', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('L858R', 'Mutation', 'rs121434568', (170, 175))
42385	28357677	The G857G variant appears to represent a novel somatic variant that has not previously been reported in common cancer somatic databases such as COSMIC, cBioPortal, and the ICGC Data Portal.	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('G857G', 'Var', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))
42386	28357677	Thus is it difficult to determine the potential rate of allele dropout in EGFR L858R PCR-based genotyping cases due to synonymous variant reporting bias.	('L858R', 'Var', (79, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('L858R', 'Mutation', 'rs121434568', (79, 84))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (74, 78))
42387	28357677	These findings demonstrate a novel somatic variant (p.G857G, c.2571G>A) resulting in the incorrect genotyping of a lung cancer patient for the EGFR L858R allele using a commonly implemented single base pair extension method.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('EGFR', 'Gene', (143, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))	('patient', 'Species', '9606', (127, 134))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('c.2571G>A', 'Var', (61, 70))	('p.G857G', 'SUBSTITUTION', 'None', (52, 59))	('p.G857G', 'Var', (52, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('L858R', 'Mutation', 'rs121434568', (148, 153))	('EGFR', 'Gene', '1956', (143, 147))	('lung cancer', 'Disease', (115, 126))	('c.2571G>A', 'Mutation', 'c.2571G>A', (61, 70))	('genotyping', 'MPA', (99, 109))
42388	28357677	The presence of these PCR-based genotyping pitfalls has the potential to be exacerbated as continuing molecular testing guidelines suggest EGFR mutation status genotyping as standard of lung cancer care.	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('EGFR', 'Gene', '1956', (139, 143))	('mutation', 'Var', (144, 152))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('EGFR', 'Gene', (139, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))
42391	28357677	Correct EGFR mutation genotyping is critical for the proper therapeutic management of lung cancer patients.	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('mutation', 'Var', (13, 21))	('EGFR', 'Gene', '1956', (8, 12))	('patients', 'Species', '9606', (98, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('EGFR', 'Gene', (8, 12))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
42392	28357677	This study highlights a major pitfall of a common clinical genotyping methodology that results in a false negative result for a clinically actionable EGFR mutation.	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', '1956', (150, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('150', '154'))	('false', 'biological_process', 'GO:0071878', ('100', '105'))	('mutation', 'Var', (155, 163))	('false', 'biological_process', 'GO:0071877', ('100', '105'))
42398	28454391	Scratch and Transwell assays demonstrated that the knockdown of KIN17 inhibited the ability of NSCLC cells to migrate and invade.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('KIN17', 'Gene', '22944', (64, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('KIN17', 'Gene', (64, 69))	('inhibited', 'NegReg', (70, 79))	('NSCLC', 'Disease', (95, 100))	('knockdown', 'Var', (51, 60))
42399	28454391	Furthermore, reverse transcription-quantitative polymerase chain reaction and western blot analyses confirmed that knockdown of KIN17 decreased the expression of matrix metalloproteinase 7, epidermal growth factor receptor and v-myc avian myelocytomatosis viral oncogene homolog.	('decreased', 'NegReg', (134, 143))	('KIN17', 'Gene', '22944', (128, 133))	('KIN17', 'Gene', (128, 133))	('epidermal growth factor receptor', 'Gene', '1956', (190, 222))	('reverse transcription', 'biological_process', 'GO:0001171', ('13', '34'))	('matrix metalloproteinase 7', 'Gene', (162, 188))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('190', '213'))	('expression', 'MPA', (148, 158))	('epidermal growth factor receptor', 'Gene', (190, 222))	('matrix metalloproteinase 7', 'Gene', '4316', (162, 188))	('v-myc avian myelocytomatosis viral oncogene homolog', 'Gene', '4609', (227, 278))	('knockdown', 'Var', (115, 124))
42463	28454391	High Kin17 expression was significantly associated with lymph nodes metastasis (P=0.036) and high tumor grade (grade 2 or 3, P=0.020; Table I).	('lymph nodes metastasis', 'Disease', (56, 78))	('High', 'Var', (0, 4))	('Kin17', 'Gene', (5, 10))	('high tumor', 'Disease', (93, 103))	('expression', 'MPA', (11, 21))	('Kin17', 'Gene', '22944', (5, 10))	('lymph nodes metastasis', 'Disease', 'MESH:D009362', (56, 78))	('high tumor', 'Disease', 'MESH:D009369', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('associated', 'Reg', (40, 50))
42466	28454391	To investigate the role of Kin17 in NSCLC, lentiviral-mediated transfection of siRNA targeting KIN17 mRNA was used to knock down KIN17 expression in A549 cells (Fig.	('KIN17', 'Gene', '22944', (129, 134))	('KIN17', 'Gene', (129, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('KIN17', 'Gene', '22944', (95, 100))	('knock down', 'Var', (118, 128))	('Kin17', 'Gene', '22944', (27, 32))	('KIN17', 'Gene', (95, 100))	('NSCLC', 'Disease', (36, 41))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('Kin17', 'Gene', (27, 32))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))
42468	28454391	Scratch and Transwell assays were conducted in order to investigate the effect of a KIN17 knockdown on the metastasis and invasion abilities of A549 cells, respectively.	('metastasis', 'CPA', (107, 117))	('A549', 'CellLine', 'CVCL:0023', (144, 148))	('KIN17', 'Gene', '22944', (84, 89))	('KIN17', 'Gene', (84, 89))	('knockdown', 'Var', (90, 99))	('invasion abilities', 'CPA', (122, 140))
42469	28454391	In the scratch assay, A549KIN17 KD cells demonstrated a significant reduction in migration 24 h following the scratch compared with A549NC cells (P=0.01; Fig.	('A549NC', 'CellLine', 'CVCL:0023', (132, 138))	('migration', 'CPA', (81, 90))	('reduction', 'NegReg', (68, 77))	('A549KIN17', 'Var', (22, 31))
42471	28454391	Ectopic activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway has been associated with the invasion and metastasis of various types of tumor.	('extracellular', 'cellular_component', 'GO:0005576', ('59', '72'))	('associated', 'Reg', (134, 144))	('MEK', 'Gene', (98, 101))	('MEK', 'Gene', '5609', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('ERK', 'molecular_function', 'GO:0004707', ('102', '105'))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('ERK', 'Gene', '5594', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('invasion', 'CPA', (154, 162))	('signaling pathway', 'biological_process', 'GO:0007165', ('107', '124'))	('Ectopic', 'Var', (0, 7))	('ERK', 'Gene', (102, 105))	('tumor', 'Disease', (198, 203))
42472	28454391	Our previous study of breast cancer revealed that silencing KIN17 may effect this signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('82', '99'))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('effect', 'Reg', (70, 76))	('KIN17', 'Gene', '22944', (60, 65))	('silencing', 'Var', (50, 59))	('KIN17', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('signaling pathway', 'Pathway', (82, 99))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
42473	28454391	In order to explore the role of KIN17 in the MEK/ERK signaling pathway in NSCLC, influencing of KIN17 knockdown on the expression levels of EGFR, MMP7 and MYC, 3 key components of the MEK/ERK signaling pathway, were investigated in A549 cell in the present study.	('EGFR', 'Gene', (140, 144))	('MEK', 'Gene', '5609', (45, 48))	('MYC', 'Gene', '4609', (155, 158))	('A549', 'CellLine', 'CVCL:0023', (232, 236))	('KIN17', 'Gene', (96, 101))	('ERK', 'Gene', '5594', (49, 52))	('ERK', 'molecular_function', 'GO:0004707', ('49', '52'))	('MMP7', 'molecular_function', 'GO:0004235', ('146', '150'))	('signaling pathway', 'biological_process', 'GO:0007165', ('53', '70'))	('KIN17', 'Gene', (32, 37))	('MEK', 'Gene', (45, 48))	('KIN17', 'Gene', '22944', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('MMP7', 'Gene', '4316', (146, 150))	('ERK', 'Gene', (49, 52))	('EGFR', 'Gene', '1956', (140, 144))	('KIN17', 'Gene', '22944', (32, 37))	('ERK', 'Gene', '5594', (188, 191))	('NSCLC', 'Disease', (74, 79))	('ERK', 'molecular_function', 'GO:0004707', ('188', '191'))	('MEK', 'Gene', '5609', (184, 187))	('MYC', 'Gene', (155, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('knockdown', 'Var', (102, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('140', '144'))	('signaling pathway', 'biological_process', 'GO:0007165', ('192', '209'))	('MMP7', 'Gene', (146, 150))	('MEK', 'Gene', (184, 187))	('ERK', 'Gene', (188, 191))
42474	28454391	Western blot analysis revealed that A549KIN17 KD cells expressed markedly lower levels of EGFR, MMP7 and MYC compared with A549NC cells (Fig.	('MMP7', 'molecular_function', 'GO:0004235', ('96', '100'))	('levels', 'MPA', (80, 86))	('MYC', 'Gene', '4609', (105, 108))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('MMP7', 'Gene', (96, 100))	('MYC', 'Gene', (105, 108))	('EGFR', 'Gene', (90, 94))	('MMP7', 'Gene', '4316', (96, 100))	('lower', 'NegReg', (74, 79))	('A549NC', 'CellLine', 'CVCL:0023', (123, 129))	('A549KIN17 KD', 'Var', (36, 48))
42486	28454391	To further determine the role of KIN17 in the invasion and metastasis of NSCLC, siRNA was used to knock down KIN17 expression in A549 cells, and scratch and Transwell assays were used to determine the effects of this.	('metastasis', 'CPA', (59, 69))	('KIN17', 'Gene', (33, 38))	('KIN17', 'Gene', '22944', (33, 38))	('knock', 'Var', (98, 103))	('KIN17', 'Gene', '22944', (109, 114))	('NSCLC', 'Disease', (73, 78))	('KIN17', 'Gene', (109, 114))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('A549', 'CellLine', 'CVCL:0023', (129, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
42491	28454391	This revealed that silencing of KIN17 decreased EGF-stimulated cell proliferation and phosphorylation of ERK in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('decreased', 'NegReg', (38, 47))	('KIN17', 'Gene', '22944', (32, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('breast cancer', 'Disease', (112, 125))	('KIN17', 'Gene', (32, 37))	('ERK', 'Gene', '5594', (105, 108))	('EGF', 'molecular_function', 'GO:0005154', ('48', '51'))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('silencing', 'Var', (19, 28))	('phosphorylation', 'MPA', (86, 101))	('cell proliferation', 'CPA', (63, 81))	('ERK', 'Gene', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
42495	28454391	The phosphorylation of ERK leads to the activation of multiple transcription factors, including activating protein-1 (AP-1) and Myc.	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'molecular_function', 'GO:0004707', ('23', '26'))	('ERK', 'Gene', (23, 26))	('Myc', 'Disease', (128, 131))	('activation', 'PosReg', (40, 50))	('AP-1', 'cellular_component', 'GO:0005907', ('118', '122'))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('phosphorylation', 'Var', (4, 19))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
42499	28454391	Ectopic expression of Myc, a multifunctional transcription factor, results in the altered expression of a variety of genes, including those that are associated with the development and progression of tumors.	('transcription factor', 'molecular_function', 'GO:0000981', ('45', '65'))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Ectopic expression', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('associated', 'Reg', (149, 159))	('expression', 'MPA', (90, 100))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('Myc', 'Gene', (22, 25))	('altered', 'Reg', (82, 89))
42506	28454391	In addition, silencing of KIN17 inhibited NSCLC cell invasion and metastasis.	('NSCLC', 'Disease', (42, 47))	('inhibited', 'NegReg', (32, 41))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('KIN17', 'Gene', '22944', (26, 31))	('KIN17', 'Gene', (26, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('silencing', 'Var', (13, 22))
42567	28358810	EGFR common mutation (Del 19 or L858R) was detected in 20 of 31 (64.5%) patients.	('Del 19', 'Var', (22, 28))	('EGFR', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('L858R', 'Mutation', 'rs121434568', (32, 37))	('L858R', 'Var', (32, 37))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (72, 80))
42573	28358810	The median OS was 49.9 months for patients with nestin-positive tumors and 114.5 months for those with nestin-negative tumors, and nestin expression was significantly associated with a poorer prognosis (P = 0.028, Fig 3B).	('nestin', 'Gene', (103, 109))	('nestin', 'Gene', (131, 137))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('nestin', 'Gene', '10763', (48, 54))	('patients', 'Species', '9606', (34, 42))	('nestin', 'Gene', '10763', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('nestin', 'Gene', (48, 54))	('nestin', 'Gene', '10763', (131, 137))	('expression', 'Var', (138, 148))
42574	28358810	Moreover, we estimated the prognostic impact of nestin expression on survival in 20 patients with EGFR mutations.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('nestin', 'Gene', '10763', (48, 54))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('nestin', 'Gene', (48, 54))
42579	28358810	The results indicated that nestin expression was a significant independent risk factor of poorer survival (HR = 2.56; 95% CI, 1.23-5.30; P = 0.011, Table 3).	('nestin', 'Gene', (27, 33))	('nestin', 'Gene', '10763', (27, 33))	('poorer', 'NegReg', (90, 96))	('expression', 'Var', (34, 44))
42587	28358810	In the treatment of patients with postoperative recurrence, patients with EGFR mutations have a significantly longer survival than those with wild type EGFR when treated with EGFR-TKIs.	('survival', 'MPA', (117, 125))	('EGFR', 'Gene', (175, 179))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', '1956', (175, 179))	('patients', 'Species', '9606', (20, 28))	('EGFR', 'Gene', (152, 156))	('EGFR', 'molecular_function', 'GO:0005006', ('175', '179'))	('longer', 'PosReg', (110, 116))	('EGFR', 'Gene', (74, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))	('mutations', 'Var', (79, 88))
42588	28358810	In the present study, the status of EGFR mutations did not different between nestin-positive and nestin-negative groups.	('mutations', 'Var', (41, 50))	('nestin', 'Gene', (97, 103))	('nestin', 'Gene', '10763', (77, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('nestin', 'Gene', (77, 83))	('EGFR', 'Gene', (36, 40))	('nestin', 'Gene', '10763', (97, 103))
42590	28358810	Thus, in the present study, nestin expression in patients with EGFR mutations did not influence survival.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('nestin', 'Gene', '10763', (28, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('patients', 'Species', '9606', (49, 57))	('mutations', 'Var', (68, 77))	('nestin', 'Gene', (28, 34))
42598	28358810	Therefore, we analyzed E-cadherin and vimentin expression to investigate the relationship between nestin expression and EMT, and demonstrated that nestin expression is significantly associated with loss of E-cadherin expression and gain of vimentin expression, and is significantly associated with the complete type in the EMT phenotype according to expression of E-cadherin and vimentin.	('EMT', 'biological_process', 'GO:0001837', ('323', '326'))	('expression', 'MPA', (217, 227))	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('vimentin', 'Gene', '7431', (240, 248))	('expression', 'MPA', (249, 259))	('vimentin', 'Gene', (240, 248))	('cadherin', 'molecular_function', 'GO:0008014', ('208', '216'))	('vimentin', 'cellular_component', 'GO:0045098', ('38', '46'))	('expression', 'Var', (154, 164))	('vimentin', 'cellular_component', 'GO:0045098', ('379', '387'))	('nestin', 'Gene', '10763', (147, 153))	('vimentin', 'cellular_component', 'GO:0045098', ('240', '248'))	('nestin', 'Gene', (147, 153))	('cadherin', 'molecular_function', 'GO:0008014', ('25', '33'))	('gain', 'PosReg', (232, 236))	('associated', 'Reg', (282, 292))	('nestin', 'Gene', '10763', (98, 104))	('nestin', 'Gene', (98, 104))	('vimentin', 'cellular_component', 'GO:0045099', ('38', '46'))	('vimentin', 'Gene', '7431', (38, 46))	('vimentin', 'Gene', (38, 46))	('vimentin', 'Gene', '7431', (379, 387))	('vimentin', 'cellular_component', 'GO:0045099', ('240', '248'))	('vimentin', 'cellular_component', 'GO:0045099', ('379', '387'))	('loss', 'NegReg', (198, 202))	('vimentin', 'Gene', (379, 387))	('E-cadherin', 'Gene', (364, 374))	('E-cadherin', 'Gene', '999', (364, 374))	('cadherin', 'molecular_function', 'GO:0008014', ('366', '374'))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('E-cadherin', 'Gene', (206, 216))	('E-cadherin', 'Gene', '999', (206, 216))
42672	27895586	The primers of corresponding siRNA are as follows: ERCC1-homo-294 sense 5'-3' GCCAAGCCCUUAUUCCGAUTT, antisense 5'-3' AUCGGAAUAAGGGCUUGGCTT; TOP2A-homo-3522 sense 5'-3' GACCAACCUUCAACUAUCUTT, antisense 5'-3' AGAUAGUUGAAGGUUGGUCTT.	('TOP2A', 'Gene', '21973', (140, 145))	("antisense 5'-3'", 'Var', (191, 206))	('ERCC1', 'Gene', (51, 56))	('ERCC1', 'Gene', '13870', (51, 56))	('TOP2A', 'Gene', (140, 145))
42766	33648534	Single-cell RNA sequencing in cancer research Single-cell RNA sequencing (scRNA-seq), a technology that analyzes transcriptomes of complex tissues at single-cell levels, can identify differential gene expression and epigenetic factors caused by mutations in unicellular genomes, as well as new cell-specific markers and cell types.	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('mutations', 'Var', (245, 254))	('differential gene expression', 'MPA', (183, 211))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('gene expression', 'biological_process', 'GO:0010467', ('196', '211'))	('epigenetic factors', 'Var', (216, 234))
42773	33648534	Malignant tumors are caused by genetic mutations that result from the influence of endogenous and environmental factors, and this challenging aspect of oncology has always been a hot topic in medical research.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Malignant tumors', 'Disease', 'MESH:D009369', (0, 16))	('mutations', 'Var', (39, 48))	('Malignant tumors', 'Disease', (0, 16))	('caused by', 'Reg', (21, 30))	('oncology', 'Phenotype', 'HP:0002664', (152, 160))
42774	33648534	Tumor development is a complex and multi-stage process whereby normal cells develop into malignant tumors, through a series of multiple gene mutations and accumulation in somatic cells.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (141, 150))	('malignant tumors', 'Disease', (89, 105))	('malignant tumors', 'Disease', 'MESH:D009369', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
42775	33648534	During the development of a variety of tumors, several important gene mutations are common which drive the malignant differentiation of cells, as seen by the limitless proliferation, metastasis, and angiogenesis.	('mutations', 'Var', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('metastasis', 'CPA', (183, 193))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('angiogenesis', 'CPA', (199, 211))	('limitless proliferation', 'CPA', (158, 181))	('tumors', 'Disease', (39, 45))	('angiogenesis', 'biological_process', 'GO:0001525', ('199', '211'))	('malignant differentiation', 'CPA', (107, 132))
42793	33648534	scRNA-seq of tumors at different time points can identify key gene mutations, as well as the dynamic change of the tumor heterogeneity over time.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
42815	33648534	These mutations occur randomly in different genomic regions, a few of which may lead to the malignant transformation of normal somatic cells.	('lead to', 'Reg', (80, 87))	('malignant transformation', 'Disease', 'MESH:D009369', (92, 116))	('mutations', 'Var', (6, 15))	('malignant transformation', 'Disease', (92, 116))
42816	33648534	Somatic mutations mainly include gene mutation heterogeneity (base pair replacement, insertion, and deletion) and genomic instability (chromosomal instability, chromosome rearrangement, copy number variations and microsatellite instability).Through next-generation sequencing (NGS), it was found that the occurrence of many tumors, such as breast cancer, hepatoma and lung cancer, were related to the mutation of oncogenes.	('related', 'Reg', (386, 393))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('lung cancer', 'Disease', 'MESH:D008175', (368, 379))	('breast cancer', 'Disease', 'MESH:D001943', (340, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (340, 353))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('hepatoma', 'Disease', (355, 363))	('mutation', 'Var', (401, 409))	('breast cancer', 'Disease', (340, 353))	('hepatoma', 'Disease', 'MESH:D006528', (355, 363))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('chromosome', 'cellular_component', 'GO:0005694', ('160', '170'))	('tumors', 'Disease', (324, 330))	('chromosomal instability', 'Phenotype', 'HP:0040012', (135, 158))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('lung cancer', 'Disease', (368, 379))	('lung cancer', 'Phenotype', 'HP:0100526', (368, 379))	('tumors', 'Disease', 'MESH:D009369', (324, 330))
42820	33648534	scRNA-seq is performed on pancreatic epithelial cells with pancreatic intraepithelial neoplasia (PanIN) to analyze gene mutations related to proliferation, invasion, and metastasis, and to evaluate the risk of malignant transformation, so as to provide the possibility to curb further tumor development.	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('pancreatic intraepithelial neoplasia', 'Disease', (59, 95))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (59, 95))	('neoplasia', 'Phenotype', 'HP:0002664', (86, 95))	('tumor', 'Disease', (285, 290))	('malignant transformation', 'Disease', 'MESH:D009369', (210, 234))	('malignant transformation', 'Disease', (210, 234))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (70, 95))
42828	33648534	These data suggest that analysis of the relationship between metastasis and gene mutation of some tumor cells, may be a new way to control tumor metastasis.	('tumor metastasis', 'Disease', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor metastasis', 'Disease', 'MESH:D009362', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('gene mutation', 'Var', (76, 89))
42829	33648534	scRNA-seq can provide comprehensive information about gene expression and single nucleotide mutations in individual tumor cells and deepen our knowledge in the process of primary tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (179, 195))	('single nucleotide mutations', 'Var', (74, 101))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor metastasis', 'Disease', (179, 195))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (179, 184))
42837	33648534	In addition to the above application in the study of tumorigenesis, scRNA-seq applies in the study of tumor heterogeneity includes cell typing of tumor tissue, and analysis of the characteristic cell state of malignant cells combined with the influence of tumor microenvironment, genetic factors and epigenetic.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('epigenetic', 'Var', (300, 310))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
42842	33648534	In past studies, although the research on heterogeneity of cancer evolution and development mainly focused on genetic changes, the latest cancer research data emphasized the contribution of heritable epigenetic modifications to cancer development.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (228, 234))	('past', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('past', 'Gene', '10938', (3, 7))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('epigenetic modifications', 'Var', (200, 224))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
42843	33648534	In addition to genome-level mutations, epigenetic modification was found to be an important cause of tumor heterogeneity.	('cause', 'Reg', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('epigenetic modification', 'Var', (39, 62))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
42861	33648534	Finally, authors suggested that PARP, PIGF, HDAC2 and FGFR inhibitors that effectively targeted CSCs might be potential therapeutic strategies for CDRCC.	('PIGF', 'Gene', (38, 42))	('HDAC2', 'Gene', (44, 49))	('HDAC2', 'Gene', '3066', (44, 49))	('PIGF', 'Gene', '5281', (38, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('CDRCC', 'Disease', (147, 152))	('PARP', 'Gene', '142', (32, 36))	('inhibitors', 'Var', (59, 69))	('PARP', 'Gene', (32, 36))	('FGFR', 'Gene', (54, 58))
42864	33648534	https://github.com/broadinstitute/inferCNV) is used to explore tumor scRNA-seq data to identify evidence for somatic large-scale chromosomal copy number alterations.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('chromosomal copy number alterations', 'Var', (129, 164))	('tumor', 'Disease', 'MESH:D009369', (63, 68))
42883	33648534	Immune surveillance is one of the most basic functions of the immune system whereby it prevents the occurrence of tumors by recognizing, killing, and eliminating mutant cells in the body.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutant', 'Var', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))
42890	33648534	In the escape stage, the surviving tumor cells that are insensitive to immune attack by genetic variation begin to proliferate in an uncontrolled way, thereby leading to clinically observable malignant diseases.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('leading to', 'Reg', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('malignant diseases', 'Disease', 'MESH:D009369', (192, 210))	('tumor', 'Disease', (35, 40))	('proliferate', 'CPA', (115, 126))	('genetic variation', 'Var', (88, 105))	('malignant diseases', 'Disease', (192, 210))
42910	33648534	The genetic changes and epigenetic variations of malignant cells, which lead to the abnormal expression of protein and the formation of a variety of tumor antigens, are the principal causes of immunogenicity.	('genetic changes', 'Var', (4, 19))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('protein', 'Protein', (107, 114))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (149, 154))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('epigenetic variations', 'Var', (24, 45))	('causes', 'Reg', (183, 189))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
42912	33648534	The NGS technology first detects the abnormal mutation sites in the tumor cells, and then combines the molecular characteristics of Major Histocompatibility Complex (MHC) to screen the mutant proteins with high binding potential to MHC, which can accurately predict the neoantigens that can be used for the reatment (Fig.	('tumor', 'Disease', (68, 73))	('mutant', 'Var', (185, 191))	('binding', 'molecular_function', 'GO:0005488', ('211', '218'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutation', 'Var', (46, 54))	('Major Histocompatibility Complex', 'biological_process', 'GO:0046776', ('132', '164'))
42915	33648534	used the T3 murine methylcholanthrene (MCA)-induced sarcoma line and established T3 tumors in four groups of naive mice, followed by treatment of each group with either control mAb, anti-PD-1, anti-CTLA-4 or anti-PD-1/anti-CTLA-4.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('sarcoma', 'Disease', (52, 59))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (19, 37))	('anti-PD-1', 'Var', (182, 191))	('MCA', 'Chemical', 'MESH:D008748', (39, 42))	('murine', 'Species', '10090', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('anti-PD-1/anti-CTLA-4', 'Var', (208, 229))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mice', 'Species', '10090', (115, 119))	('anti-CTLA-4', 'Var', (193, 204))
42918	33648534	At the same time, monocytes/macrophages also underwent significant remodeling after ICT: macrophages in the Mac_s3, Mac_s4 and Mac_s5 clusters increased dramatically upon ICT and achieved maximal levels in the combination ICT group.Mac_s4 clustersare active in inflammatory responses and hypoxia conditions and have strong glycolytic characteristics.	('active', 'PosReg', (251, 257))	('hypoxia', 'Disease', 'MESH:D000860', (288, 295))	('Mac', 'cellular_component', 'GO:0097423', ('108', '111'))	('Mac', 'cellular_component', 'GO:0097423', ('116', '119'))	('Mac', 'cellular_component', 'GO:0097423', ('232', '235'))	('hypoxia', 'Disease', (288, 295))	('Mac', 'cellular_component', 'GO:0005579', ('127', '130'))	('group.Mac_s4 clustersare', 'Var', (226, 250))	('Mac', 'cellular_component', 'GO:0005579', ('108', '111'))	('Mac', 'cellular_component', 'GO:0005579', ('232', '235'))	('Mac', 'cellular_component', 'GO:0005579', ('116', '119'))	('Mac', 'cellular_component', 'GO:0097423', ('127', '130'))
42920	33648534	In patients with resistance to ICI, this may also be due to mutations in human leukocyte antigen (HLA), an important recognition factor in the immune recognition.	('due', 'Reg', (53, 56))	('human', 'Species', '9606', (73, 78))	('HLA', 'Gene', (98, 101))	('patients', 'Species', '9606', (3, 11))	('resistance', 'Disease', (17, 27))	('mutations', 'Var', (60, 69))
42948	33648534	scRNA-seq shows that one or more important gene mutations occur in a few somatic cells, which indicate a series of processes such as precancerous lesions, in situ tumor formation, metastasis tumor formation, and cancer relapse.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('formation', 'biological_process', 'GO:0009058', ('197', '206'))	('indicate', 'Reg', (94, 102))	('situ tumor', 'Disease', 'MESH:D002278', (158, 168))	('precancerous lesions', 'Disease', 'MESH:D011230', (133, 153))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('precancerous lesions', 'Disease', (133, 153))	('formation', 'biological_process', 'GO:0009058', ('169', '178'))	('metastasis tumor', 'Disease', (180, 196))	('situ tumor', 'Disease', (158, 168))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('metastasis tumor', 'Disease', 'MESH:D009362', (180, 196))
42950	33648534	When combined with genomic methylation and chromatin accessibility analysis, scRNA-seq reveals the impact of epigenetic modification on tumor heterogeneity in cancer patients and provides personalized treatment of patients.	('cancer', 'Disease', (159, 165))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('epigenetic modification', 'Var', (109, 132))	('patients', 'Species', '9606', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('chromatin', 'cellular_component', 'GO:0000785', ('43', '52'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (136, 141))	('patients', 'Species', '9606', (166, 174))
42975	33603033	Flow cytometry indicated the augmentation of cisplatin-induced apoptosis in lung cancer cells pretreated with peptide from L. squarrosulus.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('lung cancer', 'Disease', (76, 87))	('peptide', 'Var', (110, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('augmentation', 'PosReg', (29, 41))	('L. squarrosulus', 'Species', '38802', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('peptide', 'Chemical', 'MESH:D010455', (110, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('cisplatin-induced apoptosis', 'CPA', (45, 72))
42977	33603033	Strong suppression on integrin-mediated survival was evidenced with the diminution of integrins (beta1, beta3, beta5, alpha5, alphaV) and down-stream signals (p-FAK/FAK, p-Src/Src, p-Akt/Akt) consequence with alteration of p53, Bax, Blc-2 and Mcl-1 in cisplatin-treated lung cancer cells preincubated with peptide from L. squarrosulus.	('lung cancer', 'Disease', (270, 281))	('FAK', 'Gene', '5747', (165, 168))	('FAK', 'molecular_function', 'GO:0004717', ('165', '168'))	('integrin-mediated survival', 'CPA', (22, 48))	('Src', 'Gene', '6714', (176, 179))	('suppression', 'NegReg', (7, 18))	('peptide', 'Chemical', 'MESH:D010455', (306, 313))	('p53', 'Gene', '7157', (223, 226))	('Akt', 'Gene', (187, 190))	('Src', 'Gene', (172, 175))	('alteration', 'Var', (209, 219))	('FAK', 'Gene', (161, 164))	('lung cancer', 'Disease', 'MESH:D008175', (270, 281))	('alpha5', 'Gene', '28884', (118, 124))	('Akt', 'Gene', '207', (187, 190))	('integrins (beta1, beta3, beta5', 'Gene', '10312', (86, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (270, 281))	('Bax', 'Gene', (228, 231))	('p53', 'Gene', (223, 226))	('Src', 'Gene', '6714', (172, 175))	('alpha5', 'Gene', (118, 124))	('FAK', 'Gene', '5747', (161, 164))	('Bax', 'Gene', '581', (228, 231))	('L. squarrosulus', 'Species', '38802', (319, 334))	('cisplatin', 'Chemical', 'MESH:D002945', (252, 261))	('down-stream', 'NegReg', (138, 149))	('diminution', 'NegReg', (72, 82))	('Akt', 'Gene', (183, 186))	('FAK', 'molecular_function', 'GO:0004717', ('161', '164'))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('FAK', 'Gene', (165, 168))	('Src', 'Gene', (176, 179))	('Blc-2', 'Gene', (233, 238))	('Akt', 'Gene', '207', (183, 186))
42986	33603033	While the aim is to maximize cisplatin efficacy, evidence shows that cisplatin resistance is associated with reduced apoptosis induction in lung cancer cells.	('apoptosis', 'CPA', (117, 126))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('reduced', 'NegReg', (109, 116))	('cisplatin', 'Var', (69, 78))
42994	33603033	Dysregulation of survival signaling pathways has also been previously linked to cisplatin resistance.	('linked', 'Reg', (70, 76))	('survival signaling pathways', 'Pathway', (17, 44))	('Dysregulation', 'Var', (0, 13))	('cisplatin resistance', 'Disease', (80, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))
43050	33603033	Moreover, the diminished levels of beta1, beta3, beta5, alpha5 and alphaV integrins, which are up-stream regulatory molecules, were time-dependently observed following the treatment of L. squarrosulus peptide (Fig.	('L. squarrosulus', 'Species', '38802', (185, 200))	('alphaV integrins', 'Protein', (67, 83))	('alpha5', 'Gene', (56, 62))	('squarrosulus peptide', 'Chemical', '-', (188, 208))	('alpha5', 'Gene', '28884', (56, 62))	('diminished', 'NegReg', (14, 24))	('L. squarrosulus', 'Var', (185, 200))	('beta1, beta3, beta5', 'Gene', '597;10312', (35, 54))	('levels', 'MPA', (25, 31))
43057	33603033	The decreased levels of integrin beta1, beta3, beta5 and alpha5 and the corresponding diminution of survival signaling proteins including FAK, p-FAK, Src, p-Src, Akt and p-Akt were more pronounced in the cisplatin treated-H460 cells that were precultured with 0.4 M NaCl peptide compared with the cells treated with only cisplatin (Fig.	('Src', 'Gene', (150, 153))	('diminution', 'NegReg', (86, 96))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('FAK', 'Gene', (145, 148))	('Akt', 'Gene', (172, 175))	('FAK', 'Gene', (138, 141))	('Src', 'Gene', '6714', (150, 153))	('survival signaling proteins', 'MPA', (100, 127))	('Src', 'Gene', (157, 160))	('Akt', 'Gene', '207', (172, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (321, 330))	('integrin beta1', 'Gene', (24, 38))	('FAK', 'Gene', '5747', (145, 148))	('FAK', 'Gene', '5747', (138, 141))	('FAK', 'molecular_function', 'GO:0004717', ('138', '141'))	('cisplatin', 'Var', (204, 213))	('beta5 and alpha5', 'Gene', '28884', (47, 63))	('levels', 'MPA', (14, 20))	('Akt', 'Gene', (162, 165))	('Src', 'Gene', '6714', (157, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (204, 213))	('Akt', 'Gene', '207', (162, 165))	('decreased', 'NegReg', (4, 13))	('NaCl peptide', 'Chemical', '-', (266, 278))	('FAK', 'molecular_function', 'GO:0004717', ('145', '148'))	('beta1, beta3, beta5', 'Gene', '597;10312', (33, 52))	('integrin beta1', 'Gene', '3688', (24, 38))	('H460', 'CellLine', 'CVCL:0459', (222, 226))
43059	33603033	To further assess the chemosensitizing effect previously observed in H460 (p53 and KRas wild-type) (Fig.	('H460', 'Var', (69, 73))	('H460', 'CellLine', 'CVCL:0459', (69, 73))	('KRas', 'Gene', '3845', (83, 87))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('KRas', 'Gene', (83, 87))
43079	33603033	Time-dependent chemosensitizing activity was evidenced by the augmentation of cisplatin-induced apoptosis detected with Hoechst33342/PI costaining (Fig.	('augmentation', 'PosReg', (62, 74))	('cisplatin-induced apoptosis', 'CPA', (78, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('Hoechst33342/PI', 'Var', (120, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('Hoechst33342', 'Chemical', 'MESH:C017807', (120, 132))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
43091	33603033	Integrins, especially the beta1, beta3, beta5, alpha5 and alphaV subunit, and the related survival proteins have been shown to contribute to uncontrollable lung cancer progression and chemotherapeutic failure, as their dysregulation could promote rapid cloning of cancer cells and increase cell survival against various stresses such as cisplatin toxicity.	('dysregulation', 'Var', (219, 232))	('cancer', 'Disease', (161, 167))	('alpha5', 'Gene', '28884', (47, 53))	('cancer', 'Disease', (264, 270))	('promote', 'PosReg', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('toxicity', 'Disease', 'MESH:D064420', (347, 355))	('alpha5', 'Gene', (47, 53))	('lung cancer', 'Disease', (156, 167))	('beta1, beta3, beta5', 'Gene', '597;10312', (26, 45))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('toxicity', 'Disease', (347, 355))	('increase', 'PosReg', (281, 289))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cisplatin', 'Chemical', 'MESH:D002945', (337, 346))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('contribute', 'Reg', (127, 137))	('cell survival', 'CPA', (290, 303))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
43092	33603033	Coinciding with decreased survival signaling, the capability of individual cells to generate new cancer colonies was clearly more suppressed in cisplatin-treated lung cancer cells which were then preincubated with L. squarrosulus peptide as compared to both untreated control and cisplatin-treated groups (Fig.	('squarrosulus peptide', 'Chemical', '-', (217, 237))	('cisplatin-treated', 'Var', (144, 161))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('suppressed', 'NegReg', (130, 140))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('L. squarrosulus', 'Species', '38802', (214, 229))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('cancer', 'Disease', (167, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (280, 289))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
43096	33603033	Downregulation of integrins and associated survival signals induces apoptosis and suppresses survival in diverse lung cancer cell, as observed in both p53 wild-type and mutants lung cancer cells.	('Downregulation', 'NegReg', (0, 14))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('p53', 'Gene', '7157', (151, 154))	('integrins', 'Protein', (18, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('suppresses', 'NegReg', (82, 92))	('mutants', 'Var', (169, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('survival', 'CPA', (93, 101))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('p53', 'Gene', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('induces', 'Reg', (60, 67))	('apoptosis', 'CPA', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', (177, 188))	('lung cancer', 'Disease', (113, 124))
43097	33603033	Moreover, activation of integrins (beta1, beta3, alphaV) is also associated with aggressive features of oncogenic KRas dependent lung cancer cells and antagonizing these integrins has been shown to sensitize the resistant lung cancer cells to chemotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('lung cancer', 'Disease', (222, 233))	('KRas dependent lung cancer', 'Disease', 'MESH:D008175', (114, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('integrins (beta1, beta3', 'Gene', '597', (24, 47))	('antagonizing', 'Var', (151, 163))	('KRas dependent lung cancer', 'Disease', (114, 140))	('associated', 'Reg', (65, 75))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('alphaV', 'Protein', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('activation', 'PosReg', (10, 20))
43098	33603033	The presented results indicate that L. squarrosulus peptide may provide chemosensitizing activity against wild-type and mutant lung cancer cells through inhibition of integrins as demonstrated by the peptide's effects on H460 (p53 and KRas wild-type), H292 (p53 wild-type), H23 (p53 and KRas mutant) and A549 (KRas mutant) (Figs.	('p53', 'Gene', '7157', (279, 282))	('p53', 'Gene', (227, 230))	('lung cancer', 'Disease', (127, 138))	('p53', 'Gene', (258, 261))	('KRas', 'Gene', (287, 291))	('squarrosulus peptide', 'Chemical', '-', (39, 59))	('H292', 'CellLine', 'CVCL:0455', (252, 256))	('KRas', 'Gene', (310, 314))	('peptide', 'Chemical', 'MESH:D010455', (52, 59))	('mutant', 'Var', (120, 126))	('p53', 'Gene', (279, 282))	('KRas', 'Gene', '3845', (287, 291))	('L. squarrosulus', 'Species', '38802', (36, 51))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('KRas', 'Gene', '3845', (310, 314))	('integrins', 'Protein', (167, 176))	('chemosensitizing activity', 'MPA', (72, 97))	('KRas', 'Gene', (235, 239))	('peptide', 'Chemical', 'MESH:D010455', (200, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('KRas', 'Gene', '3845', (235, 239))	('p53', 'Gene', '7157', (258, 261))	('inhibition', 'NegReg', (153, 163))	('p53', 'Gene', '7157', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('H460', 'CellLine', 'CVCL:0459', (221, 225))	('A549', 'CellLine', 'CVCL:0023', (304, 308))
43121	33603033	Next, centrifugation at 6,500 rpm for 1 h (4  C) was performed to acquire crude protein pellets which were re-solubilized with phosphate buffer solution (PBS; pH 7.4) containing Na2HPO4 and KH2PO4 on ice.	('Na2HPO4', 'Var', (178, 185))	('KH2PO4', 'Var', (190, 196))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('Na2HPO4', 'Chemical', '-', (178, 185))	('PBS', 'Chemical', '-', (154, 157))	('KH2PO4', 'Chemical', '-', (190, 196))	('phosphate', 'Chemical', 'MESH:D010710', (127, 136))
43145	33603033	Prigrow III medium (Applied Biological Materials Inc., Richmond, BC, Canada) was used for the culture of human dermal papilla cells DPCs obtained from Applied Biological Materials Inc. (Richmond, BC, Canada).	('dermal papilla', 'Disease', 'MESH:D010211', (111, 125))	('dermal papilla', 'Disease', (111, 125))	('DPCs', 'Chemical', 'MESH:C000607942', (132, 136))	('Prigrow III medium', 'Chemical', '-', (0, 18))	('human', 'Species', '9606', (105, 110))	('Richmond', 'Var', (186, 194))
43193	33115309	Immunohistochemistry showed that Ki67, CK5/6 and P40 were expressed (Figure 1b-d).	('P40', 'cellular_component', 'GO:0043514', ('49', '52'))	('P40', 'cellular_component', 'GO:0070743', ('49', '52'))	('CK5/6', 'Gene', '3852', (39, 44))	('P40', 'Gene', (49, 52))	('CK5/6', 'Gene', (39, 44))	('P40', 'Gene', '3578', (49, 52))	('Ki67', 'Var', (33, 37))
43223	33115309	Moreover, in patients with advanced NSCLC harbouring epidermal growth factor (EGFR) mutations, median PFS following first-line afatinib treatment was 11.0 to 13.6 months.	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('patients', 'Species', '9606', (13, 21))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('53', '76'))	('mutations', 'Var', (84, 93))	('EGFR', 'Gene', '1950', (78, 82))	('epidermal growth factor', 'Gene', (53, 76))	('NSCLC', 'Disease', (36, 41))	('epidermal growth factor', 'Gene', '1950', (53, 76))	('EGFR', 'Gene', (78, 82))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('afatinib', 'Chemical', 'MESH:D000077716', (127, 135))
43224	33115309	In patients with exon 19 deletions in EGFR, prolonged OS of 31.7 months has been observed.	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', (38, 42))	('deletions', 'Var', (25, 34))	('patients', 'Species', '9606', (3, 11))	('exon 19 deletions', 'Var', (17, 34))	('EGFR', 'Gene', '1950', (38, 42))
43227	33115309	In SqCC, multiple genetic mutations have been identified in various downstream signalling molecules of the ErbB receptors, while EGFR mutations are rare (<5%).	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('ErbB', 'Gene', (107, 111))	('signalling', 'biological_process', 'GO:0023052', ('79', '89'))	('EGFR', 'Gene', '1950', (129, 133))	('SqCC', 'Phenotype', 'HP:0002860', (3, 7))	('mutations', 'Var', (26, 35))	('identified', 'Reg', (46, 56))	('SqCC', 'Disease', (3, 7))	('EGFR', 'Gene', (129, 133))	('ErbB', 'Gene', '1956', (107, 111))
43232	33115309	In addition, patients with ErbB mutations in the afatinib-treated group had longer PFS and OS than those with non-ErbB mutations (4.9 months vs 3.0 months and 10.6 months vs 8.1 months, respectively).	('ErbB', 'Gene', (114, 118))	('ErbB', 'Gene', '1956', (114, 118))	('patients', 'Species', '9606', (13, 21))	('afatinib', 'Chemical', 'MESH:D000077716', (49, 57))	('mutations', 'Var', (32, 41))	('longer', 'PosReg', (76, 82))	('ErbB', 'Gene', '1956', (27, 31))	('PFS', 'CPA', (83, 86))	('ErbB', 'Gene', (27, 31))
43236	33115309	Tumour mutation profiling of patients in the LUX-Lung 8 study revealed that benefit from afatinib therapy was predominantly associated with mutations in HER3 and HER4, and particularly HER2.	('patients', 'Species', '9606', (29, 37))	('afatinib', 'Chemical', 'MESH:D000077716', (89, 97))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('HER3', 'Gene', (153, 157))	('benefit', 'PosReg', (76, 83))	('HER3', 'Gene', '2065', (153, 157))	('mutations', 'Var', (140, 149))	('HER4', 'Gene', '2066', (162, 166))	('HER4', 'Gene', (162, 166))	('HER2', 'Gene', (185, 189))	('HER2', 'Gene', '2064', (185, 189))
43238	33115309	It seems conceivable that an alternative pathway may exist that could be strongly inhibited by afatinib, for example, one enabled by mutations in HER2.	('HER2', 'Gene', '2064', (146, 150))	('inhibited', 'NegReg', (82, 91))	('mutations', 'Var', (133, 142))	('afatinib', 'Chemical', 'MESH:D000077716', (95, 103))	('HER2', 'Gene', (146, 150))
43239	33115309	Moreover, it is also possible that the wide and sustained inhibition seen with afatinib therapy in these cases is related to the presence of co-expressed mutations in multiple ErbB family members.	('ErbB', 'Gene', (176, 180))	('ErbB', 'Gene', '1956', (176, 180))	('afatinib', 'Chemical', 'MESH:D000077716', (79, 87))	('inhibition', 'NegReg', (58, 68))	('mutations', 'Var', (154, 163))
43287	33023150	This confirmed the association between high NfL (N = 12) and inferior survival (crude HR: 2.43 (95% CI: 1.03-5.69)).	('NfL', 'Gene', (44, 47))	('high', 'Var', (39, 43))	('NfL', 'Gene', '4747', (44, 47))	('inferior survival', 'CPA', (61, 78))
43372	31835038	By enhancing the tumor cell fluorescence with anti-mCherry or anti-GFP nanobodies conjugated to Atto-594 or Atto-647N dyes, we found that nanobodies can increase the signal strength of cancer cells over 100 times compared to imaging the endogenous mCherry signal after clearing (Figure S1).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('nanobodies', 'Var', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('enhancing', 'PosReg', (3, 12))	('Atto-647N', 'Chemical', '-', (108, 117))	('increase', 'PosReg', (153, 161))	('Atto-594', 'Chemical', '-', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('signal strength', 'MPA', (166, 181))	('cancer', 'Disease', (185, 191))
43497	31835038	Furthermore, heterogeneity of antigen expression on the surface of tumor cells and internalization and degradation of antigen/antibody complexes might also affect therapeutic antibody targeting efficiency.	('antibody', 'cellular_component', 'GO:0019815', ('126', '134'))	('antibody', 'cellular_component', 'GO:0019814', ('175', '183'))	('degradation', 'MPA', (103, 114))	('antibody', 'molecular_function', 'GO:0003823', ('175', '183'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('antibody', 'cellular_component', 'GO:0019814', ('126', '134'))	('affect', 'Reg', (156, 162))	('heterogeneity', 'Var', (13, 26))	('therapeutic', 'MPA', (163, 174))	('internalization', 'MPA', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('antibody', 'molecular_function', 'GO:0003823', ('126', '134'))	('antibody', 'cellular_component', 'GO:0042571', ('175', '183'))	('antibody', 'cellular_component', 'GO:0042571', ('126', '134'))	('tumor', 'Disease', (67, 72))	('antigen', 'Protein', (30, 37))	('degradation', 'biological_process', 'GO:0009056', ('103', '114'))	('antibody', 'cellular_component', 'GO:0019815', ('175', '183'))
43502	31835038	MDA-MB-231 breast cancer cells transduced with a lentivirus expressing mCherry and enhanced firefly luciferase were counted, filtered through a 100 mum filter and resuspended in RPMI 1640 medium (Gibco, 11875093).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (0, 10))	('firefly luciferase', 'Enzyme', (92, 110))	('enhanced', 'PosReg', (83, 91))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('RPMI 1640 medium', 'Chemical', '-', (178, 194))	('breast cancer', 'Disease', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('mCherry', 'Var', (71, 78))
43557	31835038	Atto647N conjugated anti-RFP/mCherry signal-enhancing nanobodies was diluted 1:500 in the staining solution and the lungs sections were incubated overnight at 4 C. After the treatment with nanobodies, the lungs sections were washed 3 times with PBS for 5 minutes with gentle shaking.	('RFP', 'Gene', (25, 28))	('Atto647N', 'Chemical', '-', (0, 8))	('for 5', 'Gene', (249, 254))	('RFP', 'Gene', '19720', (25, 28))	('for 5', 'Gene', '109647', (249, 254))	('Atto647N', 'Var', (0, 8))	('PBS', 'Chemical', 'MESH:D007854', (245, 248))
43613	32709240	miR-541 serves as a prognostic biomarker of osteosarcoma and its regulatory effect on tumor cell proliferation, migration and invasion by targeting TGIF2 Several studies reported the dysregulation of miR-541 in the progression of some human malignancies.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-541', 'Gene', (200, 207))	('TGIF2', 'Gene', (148, 153))	('miR-541', 'Gene', '100126308', (200, 207))	('tumor', 'Disease', (86, 91))	('miR-541', 'Gene', '100126308', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('miR-541', 'Gene', (0, 7))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('targeting', 'Reg', (138, 147))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('human', 'Species', '9606', (235, 240))	('osteosarcoma', 'Disease', (44, 56))	('osteosarcoma', 'Disease', 'MESH:D012516', (44, 56))	('malignancies', 'Disease', (241, 253))	('dysregulation', 'Var', (183, 196))
43629	32709240	In addition, numerous studies have found a number of miRNAs with aberrant expression in cancer tissues and cells, indicating their association with the development of cancers.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('aberrant', 'Var', (65, 73))	('association', 'Reg', (131, 142))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
43648	32709240	To regulate the expression of miR-541 in U2OS and HOS cells, the cells were transfected with miR-541 mimic or mimic negative control (NC) (RiboBio, Guangzhou, China by Lipofectamine 2000 reagent (Invitrogen, Carlsbad, 125 CA, USA) according to the manufacturer's instruction.	('miR-541', 'Gene', '100126308', (30, 37))	('miR-541', 'Gene', (30, 37))	('HOS', 'Gene', (50, 53))	('U2OS', 'CellLine', 'CVCL:0042', (41, 45))	('HOS', 'Gene', '23291', (50, 53))	('miR-541', 'Gene', '100126308', (93, 100))	('Lipofectamine 2000 reagent', 'Chemical', '-', (168, 194))	('miR-541', 'Gene', (93, 100))	('mimic', 'Var', (101, 106))
43661	32709240	U2OS and HOS cells were seeded in 6-well plates and cultured for 24 h. Then the cells were co-transfected with miR-NC or miR-541 and luciferase reporter containing the wild type (WT) or mutant type (MT) of TGIF2 3'-UTR by Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instruction.	('HOS', 'Gene', (9, 12))	('HOS', 'Gene', '23291', (9, 12))	('TGIF2', 'Gene', (206, 211))	('U2OS', 'CellLine', 'CVCL:0042', (0, 4))	('miR-NC', 'Disease', (111, 117))	('mutant', 'Var', (186, 192))	('Lipofectamine 2000 reagent', 'Chemical', '-', (222, 248))	('TGIF2', 'Gene', '60436', (206, 211))	('miR-NC', 'Disease', 'OMIM:617025', (111, 117))	('miR-541', 'Gene', '100126308', (121, 128))	('miR-541', 'Gene', (121, 128))
43666	32709240	In addition, the expression of miR-541 was lower in patients with poor differentiation tumors than those with well/moderate differentiation tumors (P < 0.001, Fig.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('miR-541', 'Gene', '100126308', (31, 38))	('expression', 'MPA', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('poor', 'Var', (66, 70))	('miR-541', 'Gene', (31, 38))	('patients', 'Species', '9606', (52, 60))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('lower', 'NegReg', (43, 48))
43679	32709240	3a and b, the expression of miR-541 was significantly upregulated in both two cell lines transfected with miR-541 mimic (both P < 0.001).	('upregulated', 'PosReg', (54, 65))	('miR-541', 'Gene', '100126308', (106, 113))	('miR-541', 'Gene', (106, 113))	('miR-541', 'Gene', '100126308', (28, 35))	('expression', 'MPA', (14, 24))	('miR-541', 'Gene', (28, 35))	('mimic', 'Var', (114, 119))
43695	32709240	These results indicated that the aberrant expression of miR-541 might be involved in the development of OS.	('miR-541', 'Gene', (56, 63))	('aberrant', 'Var', (33, 41))	('miR-541', 'Gene', '100126308', (56, 63))	('involved', 'Reg', (73, 81))
43733	32560530	RNAi (RNA interference)-mediated depletion of ANLN causes furrow instability in D. melanogaster S2 cells.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('depletion', 'Var', (33, 42))	('furrow instability', 'CPA', (58, 76))	('D. melanogaster', 'Species', '7227', (80, 95))	('ANLN', 'Gene', (46, 50))	('furrow', 'cellular_component', 'GO:0097610', ('58', '64'))	('causes', 'Reg', (51, 57))	('RNA interference', 'biological_process', 'GO:0016246', ('6', '22'))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))
43734	32560530	The loss of ANLN also promotes membrane blebbing and, in cases where a relatively stable furrow forms, a loss of stability of the midbody structure that forms after furrowing in D. melanogaster.	('midbody', 'cellular_component', 'GO:0030496', ('130', '137'))	('promotes', 'PosReg', (22, 30))	('D. melanogaster', 'Species', '7227', (178, 193))	('loss', 'NegReg', (105, 109))	('stability', 'CPA', (113, 122))	('membrane', 'cellular_component', 'GO:0016020', ('31', '39'))	('furrow', 'cellular_component', 'GO:0097610', ('89', '95'))	('ANLN', 'Gene', (12, 16))	('membrane blebbing', 'CPA', (31, 48))	('membrane blebbing', 'biological_process', 'GO:0032060', ('31', '48'))	('loss', 'Var', (4, 8))
43746	32560530	ANLN was characterized as a molecule that is specifically associated with F-actin.	('F-actin', 'cellular_component', 'GO:0031941', ('74', '81'))	('F-actin', 'Gene', (74, 81))	('F-actin', 'Gene', '40444', (74, 81))	('ANLN', 'Var', (0, 4))
43748	32560530	ANLN was also described as a binding site for F-actin and amino acids 246-371 bundle actin filaments.	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('amino acids 246-371', 'Var', (58, 77))	('F-actin', 'cellular_component', 'GO:0031941', ('46', '53'))	('binding', 'Interaction', (29, 36))	('F-actin', 'Gene', '40444', (46, 53))	('F-actin', 'Gene', (46, 53))
43755	32560530	Taken together, this suggests that ANLN could have a direct or indirect impact on actin activities both outside and inside cytokinesis events, which could be related to cancer progression.	('cancer', 'Disease', (169, 175))	('actin activities', 'MPA', (82, 98))	('ANLN', 'Var', (35, 39))	('cytokinesis', 'biological_process', 'GO:0000910', ('123', '134'))	('related', 'Reg', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('impact', 'Reg', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
43757	32560530	ANLN may indirectly impact myosin through F-actin.	('myosin', 'MPA', (27, 33))	('F-actin', 'Gene', '40444', (42, 49))	('impact', 'Reg', (20, 26))	('F-actin', 'Gene', (42, 49))	('F-actin', 'cellular_component', 'GO:0031941', ('42', '49'))	('ANLN', 'Var', (0, 4))
43768	32560530	ANLN truncation occurs in human cells without the AH domain, which was considered as a factor mediating the interaction of septins, and showed the mislocalization of the poles in the span of oscillation like the event witnessed as a lack of myosin.	('human', 'Species', '9606', (26, 31))	('ANLN truncation', 'Var', (0, 15))	('mislocalization of the poles', 'MPA', (147, 175))
43778	32560530	The half of the ANLN N-terminal of ANLN was observed not to interact with any RacGAP constructs.	('RacGAP', 'Gene', '36538', (78, 84))	('RacGAP', 'Gene', (78, 84))	('ANLN', 'Var', (35, 39))
43779	32560530	Specific RacGAP deletions to abolish Pebble or MKLP1 binding was documented without any effect on the interaction with ANLN.	('deletions', 'Var', (16, 25))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('MKLP1', 'Gene', (47, 52))	('RacGAP', 'Gene', (9, 15))	('Pebble', 'Gene', (37, 43))	('RacGAP', 'Gene', '36538', (9, 15))	('Pebble', 'Gene', '38879', (37, 43))	('abolish', 'NegReg', (29, 36))	('binding', 'Interaction', (53, 60))
43780	32560530	The absence of ANLN leads to a loss of connection between the spindle-associated RacGAP and the equatorial cortex and to cytokinesis failure.	('cytokinesis', 'biological_process', 'GO:0000910', ('121', '132'))	('loss', 'NegReg', (31, 35))	('spindle', 'cellular_component', 'GO:0005819', ('62', '69'))	('RacGAP', 'Gene', (81, 87))	('cytokinesis failure', 'Disease', (121, 140))	('cytokinesis failure', 'Disease', 'MESH:D006333', (121, 140))	('absence', 'Var', (4, 11))	('ANLN', 'Gene', (15, 19))	('RacGAP', 'Gene', '36538', (81, 87))	('connection', 'Interaction', (39, 49))
43782	32560530	This was also underpinned by the evidence of phosphomimetic-mutant S635D, the negative charge of D at the 635 residues which partially recovered the localization.	('S635D', 'Var', (67, 72))	('negative charge', 'MPA', (78, 93))	('S635D', 'Mutation', 'p.S635D', (67, 72))	('localization', 'MPA', (149, 161))	('localization', 'biological_process', 'GO:0051179', ('149', '161'))
43783	32560530	S635 phosphorylation helps ANLN improve the efficacy of the Rho integration with its upstream and downstream regulators, which contributes to the success of cytokinesis.	('Rho', 'Protein', (60, 63))	('reg', 'Gene', (109, 112))	('efficacy', 'MPA', (44, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('cytokinesis', 'biological_process', 'GO:0000910', ('157', '168'))	('phosphorylation', 'Var', (5, 20))	('S635 phosphorylation', 'Var', (0, 20))	('improve', 'PosReg', (32, 39))	('reg', 'Gene', '5967', (109, 112))
43803	32560530	The observations have suggested that ANLN acts as the intrinsic connection between PI3K/PTEN and KDR signaling, which represents two critical transitions in carcinogenesis.	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('KDR', 'Gene', (97, 100))	('PTEN', 'Gene', (88, 92))	('ANLN', 'Var', (37, 41))	('PTEN', 'Gene', '5728', (88, 92))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('KDR', 'Gene', '3791', (97, 100))
43804	32560530	The interaction between ANLN and KDR could act as ANLN and KDR jointly as a prognostic in cancer survival, which could be applied to control triple negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('KDR', 'Gene', (59, 62))	('interaction', 'Interaction', (4, 15))	('KDR', 'Gene', '3791', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ANLN', 'Var', (50, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('KDR', 'Gene', (33, 36))	('KDR', 'Gene', '3791', (59, 62))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
43813	32560530	TAF10 inactivation in liver tissue was observed to dissociate TFIID complexes individually, but genes affected by TAF10 inactivation were less than 5% of the active genes.	('TFIID', 'Gene', '6908', (62, 67))	('inactivation', 'Var', (120, 132))	('TFIID', 'Gene', (62, 67))
43815	32560530	Loss of function mutations decrease the repair of DNA double-strand breaks and thereby increases the mutation frequency and the risk of cancer.	('mutation', 'CPA', (101, 109))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('increases', 'PosReg', (87, 96))	('decrease', 'NegReg', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('Loss of function', 'NegReg', (0, 16))	('cancer', 'Disease', (136, 142))	('repair', 'MPA', (40, 46))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
43817	32560530	The BRCA1 mutation is found in breast cancer in young women, which is a triple negative breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BRCA1', 'Gene', (4, 9))	('women', 'Species', '9606', (54, 59))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('mutation', 'Var', (10, 18))	('breast cancer', 'Disease', (31, 44))	('BRCA1', 'Gene', '672', (4, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
43819	32560530	Therefore, there is a possibility that ANLN modulates DNA repair by interacting with BRCA1 in the nucleus.	('DNA repair', 'MPA', (54, 64))	('modulates', 'Reg', (44, 53))	('DNA repair', 'biological_process', 'GO:0006281', ('54', '64'))	('BRCA1', 'Gene', (85, 90))	('interacting', 'Interaction', (68, 79))	('ANLN', 'Var', (39, 43))	('nucleus', 'cellular_component', 'GO:0005634', ('98', '105'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('BRCA1', 'Gene', '672', (85, 90))
43825	32560530	Onset of cytokinesis (metaphase): When nuclear envelopes are broken down, ANLN moves from the nuclei to peripheral stress fibers in mammalian cells, at which ANLN might mediate these fibers' disassembly and increase the round cortex of Drosophila cells.	('broken down', 'Phenotype', 'HP:0001061', (61, 72))	('Drosophila', 'Species', '7227', (236, 246))	('increase', 'PosReg', (207, 215))	('mammalian', 'Species', '9606', (132, 141))	('metaphase', 'biological_process', 'GO:0051323', ('22', '31'))	('cytokinesis', 'biological_process', 'GO:0000910', ('9', '20'))	('ANLN', 'Var', (158, 162))	('round cortex of Drosophila cells', 'CPA', (220, 252))
43827	32560530	ANLN depletion leads to a mislocalization of F-actin, like myosin, out of the equator in Drosophila spermatocytes, which could lead to a failure in cytokinesis.	('depletion', 'Var', (5, 14))	('mislocalization', 'MPA', (26, 41))	('F-actin', 'cellular_component', 'GO:0031941', ('45', '52'))	('ANLN depletion', 'Var', (0, 14))	('Drosophila', 'Species', '7227', (89, 99))	('cytokinesis', 'biological_process', 'GO:0000910', ('148', '159'))	('cytokinesis', 'MPA', (148, 159))	('F-actin', 'Gene', (45, 52))	('lead to', 'Reg', (127, 134))	('failure', 'NegReg', (137, 144))	('F-actin', 'Gene', '40444', (45, 52))
43828	32560530	In C. elegans, ANLN (ANI-1) is associated with an asymmetry of the division plane, which plays an important role in the perturbations of contractility during cytokinesis.	('ANI-1', 'Gene', (21, 26))	('cytokinesis', 'biological_process', 'GO:0000910', ('158', '169'))	('C. elegans', 'Species', '6239', (3, 13))	('ANI-1', 'Gene', '176672', (21, 26))	('ANLN', 'Var', (15, 19))	('asymmetry of the division plane', 'CPA', (50, 81))	('associated', 'Reg', (31, 41))
43829	32560530	Metazoan ANLN coordinates contractile ring assembly and organization by crosslinking with myosin septins and F-actin in the actin-myosin ring.	('F-actin', 'Gene', '40444', (109, 116))	('F-actin', 'Gene', (109, 116))	('actin-myosin ring', 'Phenotype', 'HP:0025200', (124, 141))	('contractile ring assembly', 'biological_process', 'GO:0000915', ('26', '51'))	('F-actin', 'cellular_component', 'GO:0031941', ('109', '116'))	('crosslinking', 'Var', (72, 84))	('myosin septins', 'Protein', (90, 104))	('contractile ring', 'cellular_component', 'GO:0070938', ('26', '42'))
43830	32560530	Although actin-myosin contractility still happens in both human and Drosophila cultured cells that have been depleted of ANLN, the depletion of ANLN leads to the lateral oscillation of cleavage furrow, or its failure cannot accurately maintain at the division plane.	('lateral oscillation', 'CPA', (162, 181))	('human', 'Species', '9606', (58, 63))	('ANLN', 'Gene', (144, 148))	('Drosophila', 'Species', '7227', (68, 78))	('cleavage furrow', 'cellular_component', 'GO:0032154', ('185', '200'))	('depletion', 'Var', (131, 140))	('leads to', 'Reg', (149, 157))	('cleavage furrow', 'CPA', (185, 200))
43831	32560530	The knockdown of ANLN in human cells and Drosophila ANLN mutants caused slow and abortive furrowing as well as slow ingression.	('slow ingression', 'CPA', (111, 126))	('abortive furrowing', 'CPA', (81, 99))	('ANLN', 'Gene', (52, 56))	('human', 'Species', '9606', (25, 30))	('Drosophila', 'Species', '7227', (41, 51))	('mutants', 'Var', (57, 64))
43853	32560530	Evidence has shown an association between poor tumour prognosis and highly expressed ANLN in the nucleus.	('highly', 'Var', (68, 74))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('nucleus', 'cellular_component', 'GO:0005634', ('97', '104'))	('tumour', 'Disease', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
43867	32560530	For example, mutations in the ANLN gene cause kidney disease and focal segmental glomerulosclerosis, which indicate a defect in podosomal matrix adhesions.	('kidney disease', 'Phenotype', 'HP:0000112', (46, 60))	('ANLN', 'Gene', (30, 34))	('cause', 'Reg', (40, 45))	('focal segmental glomerulosclerosis', 'Disease', 'MESH:D005923', (65, 99))	('focal segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (65, 99))	('kidney disease', 'Disease', (46, 60))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (81, 99))	('mutations', 'Var', (13, 22))	('focal segmental glomerulosclerosis', 'Disease', (65, 99))	('kidney disease', 'Disease', 'MESH:D007674', (46, 60))
43869	32560530	ANLN knockdown results in abnormal adherens junctions and tight junctions in Xenopus embryos.	('adherens', 'MPA', (35, 43))	('ANLN', 'Gene', (0, 4))	('results in', 'Reg', (15, 25))	('knockdown', 'Var', (5, 14))	('tight junctions', 'CPA', (58, 73))	('Xenopus', 'Species', '8355', (77, 84))
43874	32560530	Indeed, the overexpression of ANLN in the colon cancer cell lines SW480 and HT29 actually increased cell migration and invasion, which seems to be partly related to a decrease in the expression of E-cadherin.	('cell migration', 'biological_process', 'GO:0016477', ('100', '114'))	('E-cadherin', 'Gene', (197, 207))	('cell migration', 'CPA', (100, 114))	('E-cadherin', 'Gene', '37386', (197, 207))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('overexpression', 'PosReg', (12, 26))	('HT29', 'CellLine', 'CVCL:0320', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('199', '207'))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('expression', 'MPA', (183, 193))	('ANLN', 'Var', (30, 34))	('invasion', 'CPA', (119, 127))	('increased', 'PosReg', (90, 99))	('SW480', 'CellLine', 'CVCL:0546', (66, 71))	('colon cancer', 'Disease', (42, 54))	('decrease', 'NegReg', (167, 175))	('expression', 'Species', '29278', (183, 193))	('expression', 'Species', '29278', (16, 26))
43883	32560530	Hence, we highlight the hallmarks of cancer that are impacted by ANLN (Figure 5) and discuss them as follows.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ANLN', 'Var', (65, 69))
43884	32560530	There is evidence showing that ANLN plays a critical role in driving cell proliferation, and the absence of ANLN could hinder cancer cells from division.	('hinder', 'NegReg', (119, 125))	('absence', 'Var', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('ANLN', 'Gene', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cell proliferation', 'CPA', (69, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
43886	32560530	The analysis with flow cytometry indicated that ANLN knockdown in MDA-MB-231 cells inhibited the cell cycle progression, with an increasing amount of cells stuck at the G2/M phase because of phosphorylation of Cdc2 and an inhibition of Cyclin D1.	('Cyclin', 'molecular_function', 'GO:0016538', ('236', '242'))	('M phase', 'biological_process', 'GO:0000279', ('172', '179'))	('phosphorylation', 'biological_process', 'GO:0016310', ('191', '206'))	('increasing', 'PosReg', (129, 139))	('inhibition', 'NegReg', (222, 232))	('Cdc2', 'Gene', (210, 214))	('cell cycle progression', 'CPA', (97, 119))	('Cyclin D1', 'Gene', '595', (236, 245))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('inhibited', 'NegReg', (83, 92))	('Cyclin D1', 'Gene', (236, 245))	('ANLN knockdown', 'Var', (48, 62))	('Cdc2', 'Gene', '983', (210, 214))	('phosphorylation', 'MPA', (191, 206))
43889	32560530	ANLN deletion led to an increase in polyploidy cells along with the activation of apoptosis and DNA damage.	('increase', 'PosReg', (24, 32))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('68', '91'))	('apoptosis', 'CPA', (82, 91))	('activation', 'PosReg', (68, 78))	('DNA damage', 'CPA', (96, 106))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('68', '91'))	('polyploidy', 'Disease', (36, 46))	('ANLN deletion', 'Var', (0, 13))	('polyploidy', 'Disease', 'MESH:D011123', (36, 46))
43890	32560530	In pancreatic cancer, ANLN deficiency led to the expression of miR218-5p while mir-218 caused the apoptosis of pancreatic cancer cells.	('pancreatic cancer', 'Disease', (3, 20))	('apoptosis', 'CPA', (98, 107))	('expression', 'Species', '29278', (49, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('expression', 'MPA', (49, 59))	('mir-218', 'Var', (79, 86))	('pancreatic cancer', 'Disease', (111, 128))	('caused', 'Reg', (87, 93))	('miR218-5p', 'Var', (63, 72))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('ANLN deficiency', 'Disease', (22, 37))	('ANLN deficiency', 'Disease', 'MESH:D007153', (22, 37))
43891	32560530	ANLN was known to be involved in PI3K/PTEN signaling.	('PTEN', 'Gene', '5728', (38, 42))	('PTEN', 'Gene', (38, 42))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('ANLN', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
43900	32560530	In addition, the incidence of metastasis in patients with a high ANLN expression was substantially higher than that in patients with low expression.	('patients', 'Species', '9606', (44, 52))	('ANLN', 'Protein', (65, 69))	('higher', 'PosReg', (99, 105))	('high', 'Var', (60, 64))	('patients', 'Species', '9606', (119, 127))	('expression', 'Species', '29278', (70, 80))	('metastasis', 'CPA', (30, 40))	('expression', 'Species', '29278', (137, 147))
43903	32560530	ANLN may be involved in the metastasis of lung adenocarcinoma by promoting the epithelial mesenchymal transformation of tumour cells.	('promoting', 'PosReg', (65, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (42, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('tumour', 'Disease', (120, 126))	('involved', 'Reg', (12, 20))	('ANLN', 'Var', (0, 4))	('lung adenocarcinoma', 'Disease', (42, 61))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
43916	32560530	The deficiency of ANLN in U2OS cells progressively induced an increase in the number and intensity of 53BP1 foci in G1 nuclei, a phenomenon that could act as a marker for an increased number of DNA damage events.	('53BP1', 'Gene', (102, 107))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('ANLN', 'Gene', (18, 22))	('deficiency', 'Var', (4, 14))	('U2OS', 'CellLine', 'CVCL:0042', (26, 30))	('increase', 'PosReg', (62, 70))
43917	32560530	ANLN interacts with BRCA1, so aberrant ANLN expression might affect genome instability and mutation.	('BRCA1', 'Gene', (20, 25))	('aberrant', 'Var', (30, 38))	('mutation', 'CPA', (91, 99))	('genome instability', 'CPA', (68, 86))	('affect', 'Reg', (61, 67))	('expression', 'Species', '29278', (44, 54))	('BRCA1', 'Gene', '672', (20, 25))	('ANLN', 'Gene', (39, 43))
43919	32560530	ANLN knockdown was documented to induce polyploid hepatocytes, which induce an upregulation of the genes controlling lipid metabolism and a downregulation of the genes controlling mitochondrial oxidation.	('genes', 'MPA', (99, 104))	('ANLN', 'Gene', (0, 4))	('lipid metabolism', 'biological_process', 'GO:0006629', ('117', '133'))	('knockdown', 'Var', (5, 14))	('reg', 'Gene', (144, 147))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('reg', 'Gene', '5967', (144, 147))	('mitochondrial oxidation', 'MPA', (180, 203))	('lipid metabolism', 'MPA', (117, 133))	('reg', 'Gene', (81, 84))	('reg', 'Gene', '5967', (81, 84))	('induce', 'Reg', (33, 39))
43934	32560530	In a study on Dalmatian dogs, the loss of ANLN caused a familial fatal acute respiratory distress syndrome, which is a disease where inflammatory mediators such as IL-8, IL-6 are suggested as the potential culprits.	('acute respiratory distress syndrome', 'Phenotype', 'HP:0011948', (71, 106))	('loss', 'Var', (34, 38))	('IL-8', 'molecular_function', 'GO:0005153', ('164', '168'))	('familial fatal acute respiratory distress syndrome', 'Disease', (56, 106))	('ANLN', 'Gene', (42, 46))	('dogs', 'Species', '9615', (24, 28))	('IL-6', 'Gene', '403985', (170, 174))	('IL-8', 'Gene', (164, 168))	('familial fatal acute respiratory distress syndrome', 'Disease', 'MESH:D012128', (56, 106))	('respiratory distress', 'Phenotype', 'HP:0002098', (77, 97))	('caused', 'Reg', (47, 53))	('IL-8', 'Gene', '403850', (164, 168))	('IL-6', 'molecular_function', 'GO:0005138', ('170', '174'))	('IL-6', 'Gene', (170, 174))
43945	32560530	Another study also suggests a critical role in the immune response through a synergy between ANLN and KDR, which have prognostic value in breast cancer survival.	('synergy', 'Var', (77, 84))	('KDR', 'Gene', '3791', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ANLN', 'Gene', (93, 97))	('immune response', 'biological_process', 'GO:0006955', ('51', '66'))	('breast cancer', 'Disease', (138, 151))	('KDR', 'Gene', (102, 105))
43950	32560530	ANLN facilitates septin assembly to prevent pathological outfoldings of central nervous system myelin.	('central nervous system myelin', 'Disease', 'MESH:D020278', (72, 101))	('central nervous system myelin', 'Disease', (72, 101))	('septin', 'Protein', (17, 23))	('facilitates', 'PosReg', (5, 16))	('ANLN', 'Var', (0, 4))
43968	32560530	In other research, there is evidence showing that ANLN is also related to metastasis in lung adenocarcinoma (A549, PC9).	('ANLN', 'Var', (50, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('PC9', 'Gene', '255738', (115, 118))	('metastasis', 'CPA', (74, 84))	('lung adenocarcinoma', 'Disease', (88, 107))	('PC9', 'Gene', (115, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('related', 'Reg', (63, 70))
43971	32560530	The Cancer Genome Atlas data analysis revealed 27 mutations in 446 patients with lung adenocarcinoma, with five mutations affecting the conserved amino acids of ANLN.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (50, 59))	('lung adenocarcinoma', 'Disease', (81, 100))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
43975	32560530	Based on the analysis of colorectal cancer tissues, ANLN is supposed to be associated with colorectal cancer development and with a poor prognosis.	('associated with', 'Reg', (75, 90))	('ANLN', 'Var', (52, 56))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('colorectal cancer', 'Disease', (25, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (25, 42))
43977	32560530	An integrated bioinformatics analysis showed that ANLN could play a role as a key candidate in cervical cancer.	('ANLN', 'Var', (50, 54))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
43983	32560530	However, some studies have shown that both total ANLN and p-ANLN expression decreased by LY294002 (Sigma-Aldrich; 20 mumol/L for 16 h), a specific inhibitor of the catalytic subunit of PI3K, which is directed at the ATP-binding site of the kinase.	('ANLN', 'MPA', (49, 53))	('LY294002', 'Var', (89, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('ATP-binding', 'molecular_function', 'GO:0005524', ('216', '227'))	('p-ANLN expression', 'MPA', (58, 75))	('expression', 'Species', '29278', (65, 75))	('decreased', 'NegReg', (76, 85))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))	('ATP', 'Chemical', 'MESH:D000255', (216, 219))
43992	32560530	The mechanism of the cytotoxicity of 5-FU has been depicted to cause the misincorporation of fluoronucleotides in RNA and DNA, and the suppression of the nucleotide synthetic enzyme thymidylate synthase.	('5-FU', 'Chemical', 'MESH:D005472', (37, 41))	('misincorporation of fluoronucleotides', 'MPA', (73, 110))	('cytotoxicity', 'Disease', (21, 33))	('thymidylate synthase', 'Gene', (182, 202))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('suppression', 'NegReg', (135, 146))	('thymidylate synthase', 'Gene', '7298', (182, 202))	('5-FU', 'Var', (37, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('fluoronucleotides', 'Chemical', '-', (93, 110))
43999	32560530	In support of this idea, there has been a recent report that ANLN knockdown lowers the incidence of liver cancer but does not affect liver regeneration.	('reg', 'Gene', (139, 142))	('ANLN knockdown', 'Var', (61, 75))	('liver cancer', 'Phenotype', 'HP:0002896', (100, 112))	('liver cancer', 'Disease', 'MESH:D006528', (100, 112))	('lowers', 'NegReg', (76, 82))	('liver regeneration', 'biological_process', 'GO:0097421', ('133', '151'))	('liver cancer', 'Disease', (100, 112))	('knockdown', 'Var', (66, 75))	('reg', 'Gene', '5967', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
44012	32483414	Skipping of exon 10 in Axl pre-mRNA regulated by PTBP1 mediates invasion and metastasis process of liver cancer cells The Axl gene is known to encode for a receptor tyrosine kinase involved in the metastasis process of cancer.	('PTBP1', 'Gene', '5725', (49, 54))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('receptor tyrosine kinase', 'Gene', (156, 180))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('liver cancer', 'Phenotype', 'HP:0002896', (99, 111))	('Axl', 'Gene', '558', (23, 26))	('mediates', 'Reg', (55, 63))	('liver cancer', 'Disease', (99, 111))	('Axl', 'Gene', (23, 26))	('PTBP1', 'Gene', (49, 54))	('pre', 'molecular_function', 'GO:0003904', ('27', '30'))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Skipping', 'Var', (0, 8))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Axl', 'Gene', '558', (122, 125))	('Axl', 'Gene', (122, 125))	('receptor tyrosine kinase', 'Gene', '5979', (156, 180))	('liver cancer', 'Disease', 'MESH:D006528', (99, 111))
44016	32483414	Results: Knockdown of the PTBP1 and exon 10 skipping isoform of Axl (Axl-S), led to impaired invasion and metastasis in hepatoma cells.	('hepatoma', 'Disease', (120, 128))	('skipping', 'NegReg', (44, 52))	('impaired', 'NegReg', (84, 92))	('PTBP1', 'Gene', '5725', (26, 31))	('Knockdown', 'Var', (9, 18))	('hepatoma', 'Disease', 'MESH:D006528', (120, 128))	('PTBP1', 'Gene', (26, 31))
44025	32483414	More specifically, studies have shown that alternative splicing (AS) plays an important role in the development and metastasis of cancer.	('alternative splicing', 'Var', (43, 63))	('metastasis of cancer', 'Disease', (116, 136))	('metastasis of cancer', 'Disease', 'MESH:D009362', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('development', 'CPA', (100, 111))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))
44037	32483414	This important finding reinforces our hypothesis that the deletion of these 9 amino acids may lead to functional and structural differences between Axl-S and Axl-L in humans.	('functional', 'MPA', (102, 112))	('humans', 'Species', '9606', (167, 173))	('lead to', 'Reg', (94, 101))	('deletion', 'Var', (58, 66))	('structural differences', 'MPA', (117, 139))
44043	32483414	Isoform-specific knockdown of Axl-S inhibited cancer cell migration, invasion, and metastasis.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('inhibited', 'NegReg', (36, 45))	('cancer', 'Disease', (46, 52))	('rat', 'Species', '10116', (61, 64))	('cell migration', 'biological_process', 'GO:0016477', ('53', '67'))	('invasion', 'CPA', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('knockdown', 'Var', (17, 26))	('Axl-S', 'Gene', (30, 35))
44059	32483414	For construction of PTBP1 RRMs deletion mutant plasmids, the pMXs-Axl-L plasmid constructed above was used as a template with the upstream and downstream primers specifically designed to delete the RRMs fragment.	('RRMs', 'Gene', (198, 202))	('PTBP1', 'Gene', (20, 25))	('mutant', 'Var', (40, 46))	('PTBP1', 'Gene', '5725', (20, 25))	('deletion mutant', 'Var', (31, 46))
44071	32483414	U2AF2 (4ab044957) and Gas6 primary antibody (4ab081330) were purchased from 4A Biotechnology Company.	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('U2AF', 'cellular_component', 'GO:0089701', ('0', '4'))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('Gas6', 'Gene', '2621', (22, 26))	('U2AF2', 'Gene', '11338', (0, 5))	('4ab044957', 'Var', (7, 16))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('Gas6', 'Gene', (22, 26))	('U2AF2', 'Gene', (0, 5))
44074	32483414	Cell proliferation was measured at day 2 by adding 10 mul CCK8 (Beyotime) into each well and incubating for 4 h at 37  C. The OD450 values of each well were measured by microplate reader (Gen5, Ver2.1) and used to plot growth curves.	('CCK8', 'Var', (58, 62))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('rat', 'Species', '10116', (12, 15))	('Cell proliferation', 'CPA', (0, 18))
44111	32483414	We speculated that the ratio of the Axl-S isoform to total Axl variants may be related to the metastatic ability of liver cancer cells.	('liver cancer', 'Disease', 'MESH:D006528', (116, 128))	('liver cancer', 'Disease', (116, 128))	('metastatic ability', 'CPA', (94, 112))	('variants', 'Var', (63, 71))	('rat', 'Species', '10116', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('related', 'Reg', (79, 86))	('liver cancer', 'Phenotype', 'HP:0002896', (116, 128))
44114	32483414	Cell proliferation assays showed that knockdown of Axl and specific knockdown of Axl-S significantly inhibited the proliferation of HepG2 and HCCLM3 cells (Figure 1D-E).	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('HepG2', 'CellLine', 'CVCL:0027', (132, 137))	('rat', 'Species', '10116', (12, 15))	('proliferation', 'CPA', (115, 128))	('knockdown', 'Var', (68, 77))	('rat', 'Species', '10116', (122, 125))	('inhibited', 'NegReg', (101, 110))	('Axl-S', 'Gene', (81, 86))	('HCC', 'Phenotype', 'HP:0001402', (142, 145))
44115	32483414	However, there were no significant effects in HepG2 cells (Figure 1D), and only weak inhibition in HCCLM3 cells when knocking down the Axl-L isoform (Figure 1E).	('knocking down', 'Var', (117, 130))	('HCC', 'Phenotype', 'HP:0001402', (99, 102))	('Axl-L isoform', 'MPA', (135, 148))	('HepG2', 'CellLine', 'CVCL:0027', (46, 51))
44117	32483414	We posited that the two Axl isoforms caused by exon 10 inclusion or exclusion, might have different effects on cancer cell migration and invasion.	('inclusion', 'Var', (55, 64))	('effects', 'Reg', (100, 107))	('exon 10 inclusion', 'Var', (47, 64))	('invasion', 'CPA', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cell migration', 'biological_process', 'GO:0016477', ('118', '132'))	('rat', 'Species', '10116', (126, 129))	('exclusion', 'NegReg', (68, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
44119	32483414	Wound-healing (Figure 1F-I) and invasion assays (Figure 1J-L) showed that knockdown of Axl-S significantly inhibited the migration and invasion of liver cancer cells, while knockdown of Axl-L had no significant effects (or only weak inhibition) on the invasion and migration of liver cancer cells.	('rat', 'Species', '10116', (124, 127))	('liver cancer', 'Disease', 'MESH:D006528', (147, 159))	('liver cancer', 'Phenotype', 'HP:0002896', (147, 159))	('Axl-S', 'Gene', (87, 92))	('rat', 'Species', '10116', (268, 271))	('liver cancer', 'Disease', (147, 159))	('Wound-healing', 'biological_process', 'GO:0042060', ('0', '13'))	('liver cancer', 'Phenotype', 'HP:0002896', (278, 290))	('knockdown', 'Var', (74, 83))	('liver cancer', 'Disease', 'MESH:D006528', (278, 290))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('liver cancer', 'Disease', (278, 290))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('inhibited', 'NegReg', (107, 116))
44144	32483414	Earlier, we used RT-PCR to detect the expression levels of EIF4G2, PPP3CC, PRKDC, SPAG9, HTRA2, Axl after over-expression or knockdown of PTBP1 in HepG2 cells.	('over-expression', 'PosReg', (106, 121))	('knockdown', 'Var', (125, 134))	('PTBP1', 'Gene', (138, 143))	('expression', 'Species', '29278', (38, 48))	('PTBP1', 'Gene', '5725', (138, 143))	('expression', 'Species', '29278', (111, 121))	('Axl', 'MPA', (96, 99))	('EIF4G2', 'Gene', (59, 65))	('PPP3CC', 'Gene', (67, 73))	('EIF4', 'cellular_component', 'GO:0008304', ('59', '63'))	('HepG2', 'CellLine', 'CVCL:0027', (147, 152))
44153	32483414	We found that exon 10 of Axl pre-mRNA can generate Axl-L or Axl-S transcripts after different AS patterns, and that the AS pattern of Axl pre-mRNA at exon 10 is exon-skipping.	('pre', 'molecular_function', 'GO:0003904', ('138', '141'))	('rat', 'Species', '10116', (46, 49))	('exon', 'Var', (14, 18))	('exon-skipping', 'Var', (161, 174))	('Axl-S transcripts', 'MPA', (60, 77))	('Axl-L', 'MPA', (51, 56))	('pre', 'molecular_function', 'GO:0003904', ('29', '32'))
44156	32483414	The opposite result can be obtained by knocking down PTBP1 (Figure 3E).	('knocking down', 'Var', (39, 52))	('PTBP1', 'Gene', '5725', (53, 58))	('PTBP1', 'Gene', (53, 58))
44157	32483414	Over-expression or knockdown of PTBP1 in HepG2 cells did not affect the overall expression level of Axl (Figure 3D-E).	('HepG2', 'CellLine', 'CVCL:0027', (41, 46))	('expression level', 'MPA', (80, 96))	('knockdown', 'Var', (19, 28))	('PTBP1', 'Gene', '5725', (32, 37))	('expression', 'Species', '29278', (80, 90))	('PTBP1', 'Gene', (32, 37))	('expression', 'Species', '29278', (5, 15))
44158	32483414	The results in (Figure 3F) demonstrate that the percentage of exon 10 skipping was significantly increased in the PTBP1-over-expressed HepG2 cells, compared with non-treated HepG2 cells.	('skipping', 'NegReg', (70, 78))	('increased', 'PosReg', (97, 106))	('PTBP1', 'Gene', '5725', (114, 119))	('PTBP1', 'Gene', (114, 119))	('exon 10', 'Var', (62, 69))	('rat', 'Species', '10116', (34, 37))	('HepG2', 'CellLine', 'CVCL:0027', (174, 179))	('HepG2', 'CellLine', 'CVCL:0027', (135, 140))
44159	32483414	In addition, to test whether the absence of PTBP1 attenuated the percentage of Axl-S, we performed a knockdown of PTBP1 in liver cancer cells using shRNA.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('liver cancer', 'Disease', 'MESH:D006528', (123, 135))	('absence', 'Var', (33, 40))	('liver cancer', 'Disease', (123, 135))	('PTBP1', 'Gene', '5725', (114, 119))	('PTBP1', 'Gene', (114, 119))	('percentage of Axl-S', 'MPA', (65, 84))	('attenuated', 'NegReg', (50, 60))	('PTBP1', 'Gene', '5725', (44, 49))	('PTBP1', 'Gene', (44, 49))	('liver cancer', 'Phenotype', 'HP:0002896', (123, 135))
44164	32483414	The results of RT-PCR in (Figure 3I) showed that exon 10 skipping in minigene was significantly increased in liver cancer cells over-expressing PTBP1 compared with non-treated cells.	('increased', 'PosReg', (96, 105))	('exon 10 skipping', 'Var', (49, 65))	('minigene', 'Gene', (69, 77))	('liver cancer', 'Disease', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('liver cancer', 'Phenotype', 'HP:0002896', (109, 121))	('skipping', 'Var', (57, 65))	('over-expressing', 'PosReg', (128, 143))	('liver cancer', 'Disease', 'MESH:D006528', (109, 121))	('PTBP1', 'Gene', '5725', (144, 149))	('PTBP1', 'Gene', (144, 149))
44165	32483414	Consistent with expectations, we observed the opposite result in liver cancer cells knocked down by PTBP1 (Figure 3J).	('liver cancer', 'Phenotype', 'HP:0002896', (65, 77))	('PTBP1', 'Gene', '5725', (100, 105))	('PTBP1', 'Gene', (100, 105))	('knocked', 'Var', (84, 91))	('liver cancer', 'Disease', 'MESH:D006528', (65, 77))	('liver cancer', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
44167	32483414	Results indicated that over-expression of PTBP1 increased the mRNA levels of Axl-S (Figure S5A), while knockdown of PTBP1 inhibited the expression of Axl-S (Figure S5B).	('mRNA levels of Axl-S', 'MPA', (62, 82))	('increased', 'PosReg', (48, 57))	('PTBP1', 'Gene', (42, 47))	('expression', 'MPA', (136, 146))	('knockdown', 'Var', (103, 112))	('PTBP1', 'Gene', '5725', (42, 47))	('expression', 'Species', '29278', (28, 38))	('inhibited', 'NegReg', (122, 131))	('expression', 'Species', '29278', (136, 146))	('PTBP1', 'Gene', '5725', (116, 121))	('over-expression', 'PosReg', (23, 38))	('PTBP1', 'Gene', (116, 121))
44168	32483414	Combined with the above results, we concluded that expression of PTBP1 promoted the splicing of the Axl-S isoform in Axl pre-mRNA.	('PTBP1', 'Gene', (65, 70))	('promoted', 'PosReg', (71, 79))	('expression', 'Species', '29278', (51, 61))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('splicing of the Axl-S isoform in', 'MPA', (84, 116))	('PTBP1', 'Gene', '5725', (65, 70))	('expression', 'Var', (51, 61))	('pre', 'molecular_function', 'GO:0003904', ('121', '124'))
44169	32483414	Previous studies have reported that the consensus sequences for PTBP1 binding contain poly-pyrimidines, such as UCUU or CUCUCU.	('PTBP1', 'Gene', (64, 69))	('binding', 'Interaction', (70, 77))	('poly-pyrimidines', 'Chemical', '-', (86, 102))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('poly-pyrimidines', 'Var', (86, 102))	('PTBP1', 'Gene', '5725', (64, 69))
44188	32483414	However, PTBP1 significantly reduced the selective splicing regulation of Axl-minigene after single-segment mutation and double-segment mutation (Figure 4 G and Figure S6, "PTBP1+M1", "PTBP1+M2" and "PTBP1+M1+M2" group).	('PTBP1', 'Gene', (185, 190))	('Axl-minigene', 'Gene', (74, 86))	('double-segment mutation', 'Var', (121, 144))	('PTBP1', 'Gene', '5725', (9, 14))	('selective splicing regulation', 'MPA', (41, 70))	('PTBP1', 'Gene', (200, 205))	('PTBP1', 'Gene', '5725', (173, 178))	('PTBP1', 'Gene', '5725', (200, 205))	('PTBP1', 'Gene', (9, 14))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('reduced', 'NegReg', (29, 36))	('PTBP1', 'Gene', (173, 178))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('PTBP1', 'Gene', '5725', (185, 190))
44189	32483414	Interestingly, the inhibition of PTBP1's ability to regulate Axl AS was more pronounced after mutation of the "intron 9-2" sequence than the mutant "intron 9-1" sequence.	('PTBP1', 'Gene', '5725', (33, 38))	('inhibition', 'NegReg', (19, 29))	('PTBP1', 'Gene', (33, 38))	('ability', 'MPA', (41, 48))	('regulate Axl AS', 'MPA', (52, 67))	('mutation', 'Var', (94, 102))
44190	32483414	The results of RNA pulldown and site-directed mutagenesis experiments indicated that the polypyrimidine sequence in the "intron 9-2" sequence is more important for PTBP1-mediated AS of Axl.	('PTBP1', 'Gene', (164, 169))	('PTBP1', 'Gene', '5725', (164, 169))	('polypyrimidine', 'Chemical', '-', (89, 103))	('mutagenesis', 'biological_process', 'GO:0006280', ('46', '57'))	('polypyrimidine sequence', 'Var', (89, 112))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))
44211	32483414	In vivo imaging results showed that exogenous GFP-tagged HCCLM3 cells were specifically detected in the lung tissue of mice 60 days after injection of the HCCLM3 cells into the tail vein.	('mice', 'Species', '10090', (119, 123))	('GFP-tagged', 'Var', (46, 56))	('HCC', 'Phenotype', 'HP:0001402', (57, 60))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))	('HCCLM3', 'Gene', (57, 63))
44215	32483414	For example, alterations in AS of the GCH1, STK39, and TAFI genes have been implicated in the context of multiple liver carcinogenesis mechanisms.	('liver carcinogenesis', 'Disease', (114, 134))	('GCH1', 'Gene', (38, 42))	('STK39', 'Gene', (44, 49))	('rat', 'Species', '10116', (17, 20))	('STK39', 'Gene', '27347', (44, 49))	('TAFI', 'cellular_component', 'GO:0098774', ('55', '59'))	('STK', 'molecular_function', 'GO:0050359', ('44', '47'))	('TAFI', 'Gene', (55, 59))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (114, 134))	('alterations', 'Var', (13, 24))	('GCH1', 'Gene', '2643', (38, 42))	('implicated', 'Reg', (76, 86))	('TAFI', 'Gene', '1361', (55, 59))
44233	32483414	Their research showed that disruption of the binding site by replacement of two pyrimidines with two purines (CCUUUCU mutated to CCGGUCU) strongly affected PTBP1 binding to BCL-X RNA and impaired its ability to modulate BCL-X AS.	('ability', 'MPA', (200, 207))	('BCL-X', 'Gene', '598', (220, 225))	('purines', 'Chemical', 'MESH:D011687', (101, 108))	('pyrimidines', 'Chemical', 'MESH:D011743', (80, 91))	('binding', 'Interaction', (45, 52))	('replacement', 'Var', (61, 72))	('BCL-X', 'Gene', '598', (173, 178))	('affected', 'Reg', (147, 155))	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('BCL-X', 'Gene', (220, 225))	('RNA', 'cellular_component', 'GO:0005562', ('179', '182'))	('PTBP1', 'Gene', '5725', (156, 161))	('binding', 'Interaction', (162, 169))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('CCUUUCU', 'Chemical', '-', (110, 117))	('PTBP1', 'Gene', (156, 161))	('BCL-X', 'Gene', (173, 178))	('impaired', 'NegReg', (187, 195))
44238	32483414	Studies have shown that PTBP1 binds to the polypyrimidine sequence adjacent to the variable exon and forms a circular structure in the corresponding region of the pre-mRNA, which can inhibit the binding of the splicing factor and the assembly of splicing complexes.	('splicing', 'Protein', (210, 218))	('forms', 'Reg', (101, 106))	('inhibit', 'NegReg', (183, 190))	('polypyrimidine', 'Chemical', '-', (43, 57))	('PTBP1', 'Gene', (24, 29))	('assembly', 'MPA', (234, 242))	('binding', 'Interaction', (195, 202))	('splicing', 'biological_process', 'GO:0045292', ('210', '218'))	('pre', 'molecular_function', 'GO:0003904', ('163', '166'))	('splicing', 'biological_process', 'GO:0045292', ('246', '254'))	('binding', 'molecular_function', 'GO:0005488', ('195', '202'))	('PTBP1', 'Gene', '5725', (24, 29))	('polypyrimidine sequence', 'Var', (43, 66))
44242	32483414	have reported that knockout of U2AF2 can promote the expression of short isoform of the KIAA0515 (NM 013318, exon 30); TCERG1 (BI091338, exon 3); BAT2D1 (AV650960, exon 6); HNRNPH3 (NM 012207, exon 3); UTRN (NM 007124, exon 66) and so on.	('U2AF2', 'Gene', '11338', (31, 36))	('NM 007124', 'Var', (208, 217))	('knockout', 'Var', (19, 27))	('U2AF2', 'Gene', (31, 36))	('promote', 'PosReg', (41, 48))	('expression', 'Species', '29278', (53, 63))	('NM 013318', 'Var', (98, 107))	('expression', 'MPA', (53, 63))	('AV650960', 'Var', (154, 162))	('NM 012207', 'Var', (182, 191))	('U2AF', 'cellular_component', 'GO:0089701', ('31', '35'))	('BI091338', 'Var', (127, 135))
44245	32483414	We also showed that skipping Axl exon 10 generates the Axl-S isoform, which ultimately promotes the metastasis process of liver cancer (Figure 7).	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('skipping', 'Var', (20, 28))	('liver cancer', 'Disease', (122, 134))	('metastasis process', 'CPA', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('promotes', 'PosReg', (87, 95))	('rat', 'Species', '10116', (45, 48))	('Axl-S', 'MPA', (55, 60))
44306	32375670	The histological diagnosis of this patient was papillary thyroid carcinoma pT1aN0M0, Stage I, and multiple metastatic rectal adenocarcinoma rT4bN1M1b, stage IVB.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('pT1aN0M0', 'Var', (75, 83))	('papillary thyroid carcinoma', 'Disease', (47, 74))	('patient', 'Species', '9606', (35, 42))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (57, 74))	('adenocarcinoma', 'Disease', (125, 139))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (47, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (47, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))
44307	32375670	Due to metastatic rectal adenocarcinoma, RAS, BRAF V600E and PI3K molecular assay was performed and revealed that NRAS, BRAF V600E and PI3K was wild type but KRAS exons 2 had a mutation.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('KRAS', 'Gene', '3845', (158, 162))	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('NRAS', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (120, 124))	('NRAS', 'Gene', '4893', (114, 118))	('BRAF', 'Gene', (120, 124))	('adenocarcinoma', 'Disease', (25, 39))	('PI3K', 'Var', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))	('KRAS', 'Gene', (158, 162))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('V600E', 'Mutation', 'rs113488022', (125, 130))
44373	32375670	This hereditary syndrome results from a germline mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2).	('PMS2', 'Gene', (127, 131))	('MLH1', 'Gene', (105, 109))	('MMR', 'Gene', (93, 96))	('PMS2', 'Gene', '5395', (127, 131))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('mismatch repair', 'biological_process', 'GO:0006298', ('76', '91'))	('MSH6', 'Gene', (117, 121))	('germline mutation', 'Var', (40, 57))	('MSH6', 'Gene', '2956', (117, 121))	('results from', 'Reg', (25, 37))	('MSH2', 'Gene', (111, 115))	('hereditary syndrome', 'Disease', (5, 24))	('hereditary syndrome', 'Disease', 'MESH:D061325', (5, 24))	('MSH2', 'Gene', '4436', (111, 115))	('MMR', 'biological_process', 'GO:0006298', ('93', '96'))	('MLH1', 'Gene', '4292', (105, 109))
44374	32375670	Pelizzo et al., revealed that both colonic and thyroid cancers were more likely to occur in association with MLH1 or MSH2 germ-line mutations in HNPCC patients.	('MLH1', 'Gene', '4292', (109, 113))	('HNPCC', 'Gene', '4436', (145, 150))	('MLH1', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (132, 141))	('patients', 'Species', '9606', (151, 159))	('thyroid cancer', 'Phenotype', 'HP:0002890', (47, 61))	('MSH2', 'Gene', (117, 121))	('HNPCC', 'Gene', (145, 150))	('colonic and thyroid cancers', 'Disease', 'MESH:D015179', (35, 62))	('MSH2', 'Gene', '4436', (117, 121))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('association', 'Interaction', (92, 103))
44398	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))	('immune response', 'biological_process', 'GO:0006955', ('184', '199'))	('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))
44426	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))
44473	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-L2', 'Gene', (300, 305))	('PD-L1', 'Gene', (293, 298))	('BRCA2', 'Gene', '675', (203, 208))	('CYT', 'MPA', (233, 236))	('CTLA-4', 'Gene', (285, 291))	('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))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('PBRM1', 'Gene', '55193', (196, 201))	('mutations', 'Var', (185, 194))	('BRCA2', 'Gene', (203, 208))	('TMB', 'Gene', (164, 167))	('alter', 'Reg', (118, 123))
44482	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).	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('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))
44578	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))
44593	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))
44601	32206275	Persistent DNA damage may severely induce base substitutions, insertions, deletions and chromosomal rearrangements, causing genomic instability, premature ageing, developmental disorders and carcinogenesis progression.	('ageing', 'biological_process', 'GO:0007568', ('155', '161'))	('premature', 'Disease', (145, 154))	('deletions', 'Var', (74, 83))	('causing', 'Reg', (116, 123))	('carcinogenesis', 'Disease', (191, 205))	('developmental disorders', 'Disease', (163, 186))	('premature ageing', 'Phenotype', 'HP:0007495', (145, 161))	('induce', 'Reg', (35, 41))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('insertions', 'Var', (62, 72))	('base substitutions', 'MPA', (42, 60))	('developmental disorders', 'Disease', 'MESH:D002658', (163, 186))	('chromosomal rearrangements', 'CPA', (88, 114))	('genomic instability', 'MPA', (124, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))
44602	32206275	The dysregulation of DNA glycosylases is closely linked to multiple human diseases including neurodegeneration, immunodeficiency, hypoalbuminemia, lymphomas, leukaemias, xeroderma pigmentosum, cockayne syndrome, trichothiodystrophy, and cancers (e.g., lung, breast, gastric, gallbladder, bladder, orolaryngeal, and colorectal cancers).	('lymphomas', 'Disease', (147, 156))	('human', 'Species', '9606', (68, 73))	('gallbladder', 'Disease', (275, 286))	('dysregulation', 'Var', (4, 17))	('leukaemias', 'Disease', 'MESH:D007938', (158, 168))	('orolaryngeal', 'Disease', (297, 309))	('trichothiodystrophy', 'Disease', (212, 231))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (130, 145))	('trichothiodystrophy', 'Disease', 'MESH:D054463', (212, 231))	('neurodegeneration', 'Disease', (93, 110))	('breast', 'Disease', (258, 264))	('linked', 'Reg', (49, 55))	('colorectal cancers', 'Disease', (315, 333))	('cancers', 'Phenotype', 'HP:0002664', (326, 333))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (326, 333))	('cancers', 'Disease', (237, 244))	('immunodeficiency', 'Disease', (112, 128))	('cockayne syndrome', 'Disease', 'MESH:D003057', (193, 210))	('hypoalbuminemia', 'Disease', (130, 145))	('lymphomas', 'Disease', 'MESH:D008223', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (170, 191))	('bladder', 'Disease', (288, 295))	('lymphomas', 'Phenotype', 'HP:0002665', (147, 156))	('lung', 'Disease', (252, 256))	('neurodegeneration', 'Phenotype', 'HP:0002180', (93, 110))	('immunodeficiency', 'Disease', 'MESH:D007153', (112, 128))	('colorectal cancers', 'Disease', 'MESH:D015179', (315, 333))	('leukaemias', 'Disease', (158, 168))	('xeroderma pigmentosum', 'Disease', (170, 191))	('cockayne syndrome', 'Disease', (193, 210))	('neurodegeneration', 'Disease', 'MESH:D019636', (93, 110))	('cancers', 'Disease', 'MESH:D009369', (326, 333))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('gastric', 'Disease', (266, 273))	('immunodeficiency', 'Phenotype', 'HP:0002721', (112, 128))
44605	32206275	Bifunctional DNA glycosylases have both glycosylase and AP lyase activities, and they not only excise the glycosidic bond to generate an AP site, but also hydrolytically cleave the 5' phosphodiester bond at the AP site to create a single nucleotide incision.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('glycosylase', 'molecular_function', 'GO:0016798', ('40', '51'))	('glycosidic bond', 'MPA', (106, 121))	('AP lyase', 'Gene', (56, 64))	('excise', 'NegReg', (95, 101))	('AP lyase', 'Gene', '4968', (56, 64))	('cleave', 'Var', (170, 176))	('AP site', 'MPA', (137, 144))
44644	32066756	These metastatic diseases involve uncontrolled or neoplastic growth of cancer cells that arise after the accumulation of genomic mutations, but other factors with powerful effects on cancer behaviour and growth include genetic factors and environmental factors the suffer is exposed to.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', (71, 77))	('mutations', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('iron', 'Chemical', 'MESH:D007501', (242, 246))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('metastatic diseases', 'Disease', (6, 25))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('behaviour', 'biological_process', 'GO:0007610', ('190', '199'))
44663	32066756	We examined five different microarray datasets with accession numbers GSE62384, GSE25071, GSE55945, GSE10072 and GSE2685.	('GSE55945', 'Var', (90, 98))	('GSE2685', 'Chemical', '-', (113, 120))	('GSE62384', 'Var', (70, 78))
44719	32066756	Unlike in other morbidities, some altered gene expression may arise in individual cancer cells due to mutations which will affect survival of those cells; if such altered expression the is detected in whole cancer tissue across many individuals (as in our studies) then the alteration may be affecting pathways that encourage survival and growth.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('survival', 'CPA', (326, 334))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('encourage', 'PosReg', (316, 325))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (82, 88))	('affecting', 'Reg', (292, 301))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (102, 111))	('pathways', 'Pathway', (302, 310))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('growth', 'CPA', (339, 345))
44720	32066756	Thus we have applied a systematic approach to identify pathways that WFs may affect the cancer behaviours.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('affect', 'Reg', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('WFs', 'Var', (69, 72))
44773	32038612	Depletion of NK cell populations prior to tumor transplantation has been shown to cause a more aggressive phenotype with metastatic tumors.	('cause', 'Reg', (82, 87))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Depletion of NK cell populations', 'Phenotype', 'HP:0040218', (0, 32))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Depletion', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
44780	32038612	The lack of TLR3 signaling downregulates NK cell function following cytokine stimulation, leading to defective immune responses unable to constrain metastatic diseases.	('NK cell function', 'CPA', (41, 57))	('TLR3', 'Gene', '142980', (12, 16))	('downregulates', 'NegReg', (27, 40))	('lack', 'Var', (4, 8))	('immune responses', 'MPA', (111, 127))	('defective immune responses', 'Phenotype', 'HP:0002721', (101, 127))	('TLR3', 'Gene', (12, 16))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))
44815	32038612	Melanoma cells isolated from metastatic lymph nodes were efficiently lysed by circulating NK cells expressing high levels of NKG2D, NKp30, DNAM-1, and CD62L.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('NKG2D', 'Var', (125, 130))	('Melanoma', 'Disease', (0, 8))	('NKp30', 'Gene', '259197', (132, 137))	('CD62L', 'Gene', (151, 156))	('CD62L', 'Gene', '6402', (151, 156))	('NKp30', 'Gene', (132, 137))
44826	32038612	An early study reported that low NK cell cytotoxicity was predictive of colon cancer recurrence, independently of other prognostic factors.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colon cancer', 'Disease', (72, 84))	('low', 'Var', (29, 32))	('low NK cell', 'Phenotype', 'HP:0040218', (29, 40))	('cytotoxicity', 'Disease', (41, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('colon cancer', 'Disease', 'MESH:D015179', (72, 84))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
44842	32038612	These evidence indicate that infiltration of functional NK cells in hepatocellular carcinoma tissues may represent the host reaction to cancer and that TME impairs NK cell function during disease progression.	('impairs', 'NegReg', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (68, 92))	('cancer', 'Disease', (136, 142))	('TME', 'Var', (152, 155))	('NK cell function', 'CPA', (164, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('hepatocellular carcinoma', 'Disease', (68, 92))
44878	32038612	The authors showed that pharmacological inhibition of FBP1 can revert the dysfunctional phenotype of NK cells during tumor promotion, but not during tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FBP1', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('dysfunctional phenotype', 'MPA', (74, 97))	('tumor', 'Disease', (149, 154))	('pharmacological inhibition', 'Var', (24, 50))	('FBP1', 'Gene', '14121', (54, 58))	('revert', 'NegReg', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
44891	32038612	Preclinical studies show that the blocking of PGE2 in a murine model of metastatic breast cancer and in human gastric cancer cells restores NK cell function against tumor.	('gastric cancer', 'Disease', (110, 124))	('tumor', 'Disease', (165, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('restores', 'PosReg', (131, 139))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('blocking', 'Var', (34, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('human', 'Species', '9606', (104, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('PGE2', 'Chemical', 'MESH:D015232', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('murine', 'Species', '10090', (56, 62))	('PGE2', 'Gene', (46, 50))
44895	32038612	L-Kynurenine is known to affect NK cell activity by interfering with the IL-2-driven upregulation of NKp46 and NKG2D.	('L-Kynurenine', 'Var', (0, 12))	('IL-2', 'Gene', '3558', (73, 77))	('IL-2', 'molecular_function', 'GO:0005134', ('73', '77'))	('IL-2', 'Gene', (73, 77))	('L-Kynurenine', 'Chemical', 'MESH:C029366', (0, 12))	('interfering', 'NegReg', (52, 63))	('NKp46', 'Protein', (101, 106))	('upregulation', 'PosReg', (85, 97))	('affect', 'Reg', (25, 31))
44906	32038612	The acidification of the TME has been shown to induce apoptosis of liver-resident NK cells in colorectal cancer liver metastases.	('apoptosis', 'CPA', (54, 63))	('apoptosis of liver', 'Phenotype', 'HP:0001404', (54, 72))	('colorectal cancer liver metastases', 'Disease', 'MESH:D015179', (94, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('colorectal cancer liver metastases', 'Disease', (94, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('acidification', 'biological_process', 'GO:0045851', ('4', '17'))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('acidification', 'Var', (4, 17))
44912	32038612	In a murine model, the neutralization of soluble NKG2D ligands such as MICA and MICB with mAb B10G5 was effective against prostate carcinoma and metastasis, leading to the enhanced NK cell infiltration in the tumor parenchyma, and improving CTLA-4 blockade therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('improving', 'PosReg', (231, 240))	('metastasis', 'CPA', (145, 155))	('neutralization', 'Var', (23, 37))	('CTLA-4 blockade therapy', 'MPA', (241, 264))	('enhanced', 'PosReg', (172, 180))	('murine', 'Species', '10090', (5, 11))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (122, 140))	('tumor parenchyma', 'Disease', (209, 225))	('prostate carcinoma', 'Disease', (122, 140))	('tumor parenchyma', 'Disease', 'MESH:D009369', (209, 225))	('prostate carcinoma', 'Disease', 'MESH:D011471', (122, 140))	('soluble', 'cellular_component', 'GO:0005625', ('41', '48'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
44915	32038612	This therapeutic approach is very promising even in challenging pediatric tumors, such as neuroblastoma, in which amplification of the MYCN oncogene, clinically associated with poor prognosis, has been correlated with the reduced tumor susceptibility to NK cell-mediated killing.	('tumor', 'Disease', (230, 235))	('amplification', 'Var', (114, 127))	('neuroblastoma', 'Disease', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('challenging pediatric tumors', 'Disease', 'MESH:D063766', (52, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('MYCN', 'Gene', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', (74, 79))	('challenging pediatric tumors', 'Disease', (52, 80))	('MYCN', 'Gene', '4613', (135, 139))	('reduced', 'NegReg', (222, 229))	('neuroblastoma', 'Disease', 'MESH:D009447', (90, 103))
44918	32038612	In a xenograft model, anti-PD1 suppressed the tumor growth of digestive cancers in an NK cell-dependent manner, suggesting a crucial role of PD1 in NK cell function.	('anti-PD1', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('suppressed', 'NegReg', (31, 41))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
44919	32038612	Moreover, anti-CTLA-4 combined with IL-15/IL-15Ralpha enhances the NK cell tumor infiltration, improving the tumor growth control in xenograft murine models of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('anti-CTLA-4', 'Var', (10, 21))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('murine', 'Species', '10090', (143, 149))	('IL-15', 'molecular_function', 'GO:0016170', ('42', '47'))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('enhances', 'PosReg', (54, 62))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('solid tumors', 'Disease', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('IL-15Ralpha', 'Gene', '16169', (42, 53))	('IL-15', 'molecular_function', 'GO:0016170', ('36', '41'))	('improving', 'PosReg', (95, 104))	('IL-15Ralpha', 'Gene', (42, 53))	('tumor', 'Disease', (109, 114))
44920	32038612	Melanoma patients treated with anti-CTLA-4 (ipilimumab) had higher intratumoral CD56 expression.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('higher', 'PosReg', (60, 66))	('tumor', 'Disease', (72, 77))	('Melanoma', 'Disease', (0, 8))	('anti-CTLA-4', 'Var', (31, 42))	('CD56', 'Gene', '4684', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('CD56', 'Gene', (80, 84))
44924	32038612	In preclinical studies, the murine model anti-TIGIT is able to improve the antitumor effect of anti-HER2 mAb alone, and in combination with PD1/PD-L1 inhibitors.	('tumor', 'Disease', (79, 84))	('improve', 'PosReg', (63, 70))	('murine', 'Species', '10090', (28, 34))	('anti-TIGIT', 'Var', (41, 51))	('anti-HER2 mAb', 'Protein', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
44925	32038612	Preclinical studies showed that CD96 blocking combined with anti-PD1 or anti-CTLA-4 enhances NK cell infiltration and IFN-gamma production, thus reducing tumor lung metastases.	('tumor lung metastases', 'Disease', 'MESH:D009362', (154, 175))	('tumor lung', 'Phenotype', 'HP:0100526', (154, 164))	('enhances', 'PosReg', (84, 92))	('NK cell infiltration', 'CPA', (93, 113))	('tumor lung metastases', 'Disease', (154, 175))	('anti-CTLA-4', 'Var', (72, 83))	('IFN-gamma', 'Gene', (118, 127))	('IFN-gamma', 'Gene', '3458', (118, 127))	('reducing', 'NegReg', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CD96', 'Gene', (32, 36))	('CD96', 'Gene', '10225', (32, 36))
44926	32038612	The blockade of TIM-3 was also found to enhance NK cell function against melanoma cells.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('blockade', 'Var', (4, 12))	('TIM-3', 'Gene', (16, 21))	('enhance', 'PosReg', (40, 47))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
44927	32038612	The therapeutic efficacy of the combined use of different immune checkpoint inhibitors, such as anti-TIM-3 and anti-TIGIT, is currently tested in ongoing phase I and II clinical trials in solid tumor patients (Table 1).	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('anti-TIM-3', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))
44934	32038612	Thus, haploidentical allogenic NK cells represent an optimal cellular immunotherapy product, mainly for immunocompromising diseases, including solid tumors, whose patients can scantly count on their own cells and often need donor NK cells.	('solid tumors', 'Disease', (143, 155))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('solid tumors', 'Disease', 'MESH:D009369', (143, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('haploidentical', 'Var', (6, 20))	('donor', 'Species', '9606', (224, 229))
44957	31731655	Cigarette smoke regulates the expression of various miRNAs (e.g., epigenetic repression of miR-487b, reduced expression of mir-218), promoting smoking-induced carcinogenesis either through the silencing of anticancer molecules or upregulation of genes involved in lung cancer.	('smoking-induced', 'Disease', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('upregulation', 'PosReg', (230, 242))	('epigenetic repression', 'Var', (66, 87))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (269, 275))	('miR-487b', 'Gene', '664616', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('carcinogenesis', 'Disease', (159, 173))	('expression', 'MPA', (30, 40))	('expression', 'MPA', (109, 119))	('regulates', 'Reg', (16, 25))	('silencing', 'Var', (193, 202))	('miR-487b', 'Gene', (91, 99))	('lung cancer', 'Disease', (264, 275))	('reduced', 'NegReg', (101, 108))	('promoting', 'PosReg', (133, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
44959	31731655	Of note, tobacco cigarette smoking is the primary cause of chronic obstructive pulmonary disease (COPD) and is expected to be the third leading cause of global mortality by 2030, with COPD closely associated with the development of lung cancer.	('cause', 'Reg', (50, 55))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (67, 96))	('associated', 'Reg', (197, 207))	('COPD', 'Phenotype', 'HP:0006510', (98, 102))	('COPD', 'Disease', 'MESH:D029424', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (59, 96))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (59, 96))	('COPD', 'Disease', (98, 102))	('mortality', 'Disease', (160, 169))	('tobacco cigarette smoking', 'Var', (9, 34))	('COPD', 'Phenotype', 'HP:0006510', (184, 188))	('COPD', 'Disease', 'MESH:D029424', (184, 188))	('COPD', 'Disease', (184, 188))	('lung cancer', 'Disease', (232, 243))	('tobacco', 'Species', '4097', (9, 16))	('chronic obstructive pulmonary disease', 'Disease', (59, 96))	('mortality', 'Disease', 'MESH:D003643', (160, 169))
44963	31731655	showed the promotion of EMT via miR-331-3p, contributing to the progression of prostate cancer.	('promotion', 'PosReg', (11, 20))	('EMT', 'CPA', (24, 27))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('EMT', 'biological_process', 'GO:0001837', ('24', '27'))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('miR-331-3p', 'Chemical', '-', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-331-3p', 'Var', (32, 42))	('prostate cancer', 'Disease', (79, 94))
44964	31731655	miR-331-3p is over-expressed in asbestos-related lung cancer samples.	('miR-331-3p', 'Chemical', '-', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('miR-331-3p', 'Var', (0, 10))	('over-expressed', 'PosReg', (14, 28))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
44974	31731655	Several factors define the progression of ageing including increased genomic instability/mutation, increase in telomerase activity vis-a-vis a decrease in telomere size, epigenetics, dysregulation of autophagy, increase urea cycle activity, increased cellular senescence and associated inflammation, apoptosis, and functional alteration in cell communication.	('inflammation', 'biological_process', 'GO:0006954', ('286', '298'))	('inflammation', 'Disease', (286, 298))	('cellular senescence', 'CPA', (251, 270))	('cellular senescence', 'biological_process', 'GO:0090398', ('251', '270'))	('urea cycle', 'biological_process', 'GO:0000050', ('220', '230'))	('increased', 'PosReg', (59, 68))	('apoptosis', 'CPA', (300, 309))	('epigenetics', 'MPA', (170, 181))	('increase', 'PosReg', (211, 219))	('autophagy', 'biological_process', 'GO:0016236', ('200', '209'))	('ageing', 'biological_process', 'GO:0007568', ('42', '48'))	('genomic', 'MPA', (69, 76))	('telomerase', 'Protein', (111, 121))	('apoptosis', 'biological_process', 'GO:0006915', ('300', '309'))	('apoptosis', 'biological_process', 'GO:0097194', ('300', '309'))	('cell communication', 'CPA', (340, 358))	('telomerase activity', 'molecular_function', 'GO:0003720', ('111', '130'))	('cell communication', 'biological_process', 'GO:0007154', ('340', '358'))	('increased', 'PosReg', (241, 250))	('urea cycle activity', 'CPA', (220, 239))	('telomere', 'cellular_component', 'GO:0000781', ('155', '163'))	('telomere', 'cellular_component', 'GO:0005696', ('155', '163'))	('autophagy', 'biological_process', 'GO:0006914', ('200', '209'))	('increase', 'PosReg', (99, 107))	('telomere', 'MPA', (155, 163))	('inflammation', 'Disease', 'MESH:D007249', (286, 298))	('dysregulation', 'Var', (183, 196))	('decrease', 'NegReg', (143, 151))	('autophagy', 'CPA', (200, 209))	('urea', 'Chemical', 'MESH:D014508', (220, 224))	('instability/mutation', 'Var', (77, 97))	('activity', 'MPA', (122, 130))
44975	31731655	For example, downregulation of cancer-associated miRNAs, such as miR-103, -107, -128, and -221, was observed in an aged compared to a younger population, and repression of these miRNA was associated with increased cancer risk.	('miR-103', 'Var', (65, 72))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('downregulation', 'NegReg', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('repression', 'NegReg', (158, 168))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
44976	31731655	In the younger smoking population and COPD patients, lung ageing could play a crucial role in the overall dynamics associated with disease progression and hence dysregulation in miRNA is likely to be symptomatic in these patient populations.	('COPD', 'Phenotype', 'HP:0006510', (38, 42))	('dysregulation', 'Var', (161, 174))	('patient', 'Species', '9606', (43, 50))	('patients', 'Species', '9606', (43, 51))	('play', 'Reg', (71, 75))	('COPD', 'Disease', 'MESH:D029424', (38, 42))	('ageing', 'biological_process', 'GO:0007568', ('58', '64'))	('COPD', 'Disease', (38, 42))	('patient', 'Species', '9606', (221, 228))
44980	31731655	A more recent genome-wide study in the whole blood of COPD patients identified two blood-born microRNAs (miR-150-5p and miR-320b) that could efficiently predict patient survival.	('COPD', 'Disease', (54, 58))	('miR-150', 'Gene', (105, 112))	('predict', 'Reg', (153, 160))	('patient', 'Species', '9606', (161, 168))	('patient', 'Species', '9606', (59, 66))	('miR-150', 'Gene', '406942', (105, 112))	('miR-320b', 'Var', (120, 128))	('patients', 'Species', '9606', (59, 67))	('COPD', 'Phenotype', 'HP:0006510', (54, 58))	('COPD', 'Disease', 'MESH:D029424', (54, 58))
44984	31731655	Cigarette smoke extract induced HBEC-cells-derived exosomes carrying miRNA-210 was found to promote the transformation of the lung fibroblast into its more active and aggressive form, myofibroblast.	('HBEC-cells', 'CellLine', 'CVCL:X489', (32, 42))	('promote', 'PosReg', (92, 99))	('transformation', 'CPA', (104, 118))	('miRNA-210', 'Chemical', '-', (69, 78))	('miRNA-210', 'Var', (69, 78))
44985	31731655	miRNA210 significantly decreased autophagy induction in COPD patients by silencing ATG7, an autophagy regulator.	('miRNA210', 'Chemical', '-', (0, 8))	('autophagy', 'biological_process', 'GO:0016236', ('92', '101'))	('patients', 'Species', '9606', (61, 69))	('COPD', 'Phenotype', 'HP:0006510', (56, 60))	('ATG7', 'Gene', '10533', (83, 87))	('miRNA210', 'Var', (0, 8))	('COPD', 'Disease', 'MESH:D029424', (56, 60))	('autophagy', 'biological_process', 'GO:0006914', ('92', '101'))	('autophagy', 'biological_process', 'GO:0016236', ('33', '42'))	('autophagy induction', 'CPA', (33, 52))	('autophagy', 'biological_process', 'GO:0006914', ('33', '42'))	('decreased', 'NegReg', (23, 32))	('COPD', 'Disease', (56, 60))	('ATG7', 'Gene', (83, 87))	('silencing', 'NegReg', (73, 82))
44986	31731655	Inhibition of ATG7 was also observed to transform lung fibroblast to myofibroblast.	('lung fibroblast to myofibroblast', 'CPA', (50, 82))	('transform', 'Reg', (40, 49))	('ATG7', 'Gene', '10533', (14, 18))	('Inhibition', 'Var', (0, 10))	('ATG7', 'Gene', (14, 18))
44992	31731655	However, one study showed that two miRNAs, mir-138 and let-7c, were significantly downregulated in non-smokers with lung cancer.	('downregulated', 'NegReg', (82, 95))	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('let-7c', 'Gene', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('let-7c', 'Gene', '406885', (55, 61))	('mir-138', 'Var', (43, 50))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))
44995	31731655	For instance, studies reported that miRNA-486-5p is downregulated and correlated with ankyrin1 (ANK1) expression in non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', (144, 149))	('ANK1', 'Gene', '286', (96, 100))	('ankyrin1', 'Gene', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('ankyrin1', 'Gene', '286', (86, 94))	('downregulated', 'NegReg', (52, 65))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (116, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('lung cancer', 'Disease', (131, 142))	('miRNA-486-5p', 'Var', (36, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('ANK1', 'Gene', (96, 100))
44996	31731655	The study also found that ANK1 methylation is more prevalent in adenocarcinoma compared with squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('prevalent', 'Reg', (51, 60))	('adenocarcinoma', 'Disease', (64, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('squamous cell carcinoma', 'Disease', (93, 116))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('methylation', 'Var', (31, 42))	('ANK1', 'Gene', '286', (26, 30))	('ANK1', 'Gene', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
44998	31731655	miRNAs have also been shown to play a crucial role in lung cancer chemoresistance by affecting autophagic flux and expression of both programmed cell death-1 (PD-1) and ligand PD-L1 (PD-L1) through post-transcriptional regulation.	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('affecting', 'Reg', (85, 94))	('regulation', 'biological_process', 'GO:0065007', ('219', '229'))	('autophagic flux', 'CPA', (95, 110))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ligand', 'molecular_function', 'GO:0005488', ('169', '175'))	('programmed cell death', 'biological_process', 'GO:0012501', ('134', '155'))	('expression', 'MPA', (115, 125))	('PD-1', 'Gene', (159, 163))	('PD-1', 'Gene', '5133', (159, 163))	('miRNAs', 'Var', (0, 6))
45001	31731655	Accumulating evidence suggests that miRNAs can modulate several molecular mechanisms involved in tumour progression, autophagy activation, and metastasis.	('tumour', 'Disease', (97, 103))	('autophagy', 'biological_process', 'GO:0006914', ('117', '126'))	('autophagy', 'CPA', (117, 126))	('miRNAs', 'Var', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('modulate', 'Reg', (47, 55))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('metastasis', 'CPA', (143, 153))	('autophagy', 'biological_process', 'GO:0016236', ('117', '126'))
45007	31745090	Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing inflammation and the display of potentially immunogenic neoantigens.	('inducing', 'PosReg', (83, 91))	('tumor', 'Disease', (28, 33))	('reactivation', 'Var', (12, 24))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('inflammation', 'biological_process', 'GO:0006954', ('92', '104'))	('inflammation', 'Disease', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('TEs', 'Gene', (43, 46))
45011	31745090	Neoantigens stemming from point mutations in the coding exons alone, however, likely underestimate the true mutational burden in the tumor; other cancer-specific antigens might also exist and contribute to immune response against the tumor.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', (234, 239))	('point mutations', 'Var', (26, 41))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('underestimate', 'NegReg', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('contribute', 'Reg', (192, 202))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('immune response', 'biological_process', 'GO:0006955', ('206', '221'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
45014	31745090	Although in normal tissue, much of TE activity is under tight epigenetic control, in cancer, we hypothesized that wide-spread TE expression occurs, particularly in those with extensive epigenetic dysregulation.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('epigenetic dysregulation', 'Var', (185, 209))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
45019	31745090	We show that tumor cells present potentially immunogenic peptides derived not only from HERVs, but also other classes of TE: long interspersed nuclear elements (LINE), short interspersed nuclear elements (SINE), and SINE-VNTR-Alu (SVA).	('tumor', 'Disease', (13, 18))	('short interspersed nuclear', 'Var', (168, 194))	('long interspersed nuclear elements', 'Var', (125, 159))	('HERVs', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
45025	31745090	Although these data cannot address transposition, our results suggest active gene expression by DNA transposons in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gene expression', 'MPA', (77, 92))	('active', 'PosReg', (70, 76))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('transposition', 'biological_process', 'GO:0032196', ('35', '48'))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('DNA transposons', 'Var', (96, 111))
45043	31745090	At the global level, we observed strong CpG demethylation of tumor tissue compared with normal in liver, head and neck, bladder and lung squamous and colon cancers (Supplementary Fig.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('CpG', 'Var', (40, 43))	('neck', 'cellular_component', 'GO:0044326', ('114', '118'))	('liver', 'Disease', (98, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (150, 162))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('bladder and lung squamous and colon cancers', 'Disease', 'MESH:D001749', (120, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('demethylation', 'biological_process', 'GO:0070988', ('44', '57'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('colon cancers', 'Phenotype', 'HP:0003003', (150, 163))	('tumor', 'Disease', (61, 66))
45044	31745090	3b), where the majority of differentially methylated CpGs (DMCs) in these cancer types were demethylated (Deltabeta < -0.1, FDR < 0.05, Fig.	('demethylated', 'MPA', (92, 104))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('CpGs', 'Chemical', 'MESH:C024660', (53, 57))	('differentially', 'Var', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
45045	31745090	However, in all 10 cancer types considered, we discovered a striking enrichment of demethylated DMCs located within TEs as compared with background level of DNA demethylation on the 450 K array (Fig.	('DNA demethylation', 'biological_process', 'GO:0080111', ('157', '174'))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('demethylated', 'Var', (83, 95))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('DMCs', 'Gene', (96, 100))
45063	31745090	MER75 (piggyBac DNA transposon), MER4A (ERV1 family), MER54A (ERV3), and MER67A (ERV1) were identified by the true TE model as top predictors for DDR activities (Fig.	('ERV1', 'Gene', (40, 44))	('MER4A', 'Var', (33, 38))	('ERV1', 'Gene', '2671', (40, 44))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('ERV3', 'Gene', '2086', (62, 66))	('ERV1', 'Gene', (81, 85))	('DDR', 'MPA', (146, 149))	('MER54A', 'Var', (54, 60))	('ERV1', 'Gene', '2671', (81, 85))	('ERV3', 'Gene', (62, 66))	('MER67A', 'Var', (73, 79))
45065	31745090	MamGypLTR2b (Gypsy), THE1C-int (ERVL), LTR21B (ERV1), and MER57F (ERV1) were identified as TEs with the strongest positive association to type I IFN response (Fig.	('MamGypLTR2b', 'Var', (0, 11))	('ERV1', 'Gene', (47, 51))	('type I IFN response', 'MPA', (138, 157))	('ERV1', 'Gene', (66, 70))	('LTR21B', 'Var', (39, 45))	('ERV1', 'Gene', '2671', (47, 51))	('positive', 'PosReg', (114, 122))	('ERV1', 'Gene', '2671', (66, 70))	('MER57F', 'Var', (58, 64))
45071	31745090	KIRC, a highly immunogenic type of tumor, was recently found to harbor the highest proportion of insertion-and-deletion tumor mutations compared with other TCGA cancer types.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', (120, 125))
45073	31745090	Somatic TE transposition events have been previously described in TCGA samples to lead to insertional mutations private to tumors and retrotransposition is known to create DNA double-strand breaks.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (123, 129))	('lead', 'Reg', (82, 86))	('transposition', 'biological_process', 'GO:0032196', ('11', '24'))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('retrotransposition', 'biological_process', 'GO:0032197', ('134', '152'))	('insertional', 'Var', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TE transposition', 'Phenotype', 'HP:0011540', (8, 24))
45074	31745090	Although DDR is known to activate immune signaling and inflammation, more research is needed to elucidate the connection between TE expression, DDR and immunogenicity in cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('activate', 'PosReg', (25, 33))	('cancer', 'Disease', (170, 176))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('DDR', 'Var', (9, 12))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('inflammation', 'biological_process', 'GO:0006954', ('55', '67'))	('immune', 'CPA', (34, 40))	('inflammation', 'Disease', (55, 67))
45079	31745090	Epigenetic de-repression by decitabine resulted in strong overexpression of TEs originating from intergenic and intronic regions in these GBM cell lines, particularly TEs from SVA (SVA_B, C, D, E, F), ERV1 (n = 27), L1 (n = 2), and Alu (n = 9) families (FDR < 0.05 and FC > 2, Fig.	('ERV1', 'Gene', '2671', (201, 205))	('decitabine', 'Chemical', 'MESH:C014347', (28, 38))	('Epigenetic', 'Var', (0, 10))	('overexpression', 'PosReg', (58, 72))	('decitabine', 'Gene', (28, 38))	('ERV1', 'Gene', (201, 205))
45081	31745090	Among the 39 MHC-I TE peptides, 16 (41%) were detected only in the decitabine-treated condition, suggesting increased presentation of possibly novel peptides induced by a 5-aza-2'.	('decitabine', 'Chemical', 'MESH:C014347', (67, 77))	("5-aza-2'", 'Chemical', 'MESH:D001372', (171, 179))	("5-aza-2'", 'Var', (171, 179))	('increased', 'PosReg', (108, 117))	('presentation', 'MPA', (118, 130))
45093	31745090	Synergistic effect between epigenetic therapy and immunotherapy have been observed in preclinical models, where induction of antiviral immunity to retroviral expression is proposed to be a mechanism of tumor regression.	('epigenetic therapy', 'Var', (27, 45))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('antiviral', 'MPA', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
45164	31745090	CGP RNA sequencing data have been deposited in the European genome-phenome archive under the following accession codes: small cell lung cancer screen, EGAS00001000334; colon cancer screen, EGAS00001000288; Exome sequencing, RNA Sequencing, SNP array profiling of gastric tumor samples and cell lines, EGAS00001000736 and non-clear cell renal cell carcinoma, EGAS00001000926.	('colon cancer', 'Disease', (168, 180))	('gastric tumor', 'Disease', (263, 276))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('small cell lung cancer', 'Disease', (120, 142))	('gastric tumor', 'Disease', 'MESH:D013274', (263, 276))	('gastric tumor', 'Phenotype', 'HP:0006753', (263, 276))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('non-clear', 'Disease', (321, 330))	('colon cancer', 'Phenotype', 'HP:0003003', (168, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (336, 356))	('RNA', 'cellular_component', 'GO:0005562', ('224', '227'))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('EGAS00001000736', 'Var', (301, 316))	('CGP', 'Chemical', 'MESH:C428863', (0, 3))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('colon cancer', 'Disease', 'MESH:D015179', (168, 180))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (325, 356))	('cell renal cell carcinoma', 'Disease', 'MESH:D002292', (331, 356))	('small cell lung cancer', 'Disease', 'MESH:D055752', (120, 142))	('cell renal cell carcinoma', 'Disease', (331, 356))
45174	31737785	According to the information mined from the tumor gene database, CD276 mRNA was found highly expressed in NSCLC tissue and the expression of CD276 has a significant impact on survival of NSCLC patients, which provides an important theoretical basis for further study of the role of CD276 in the occurrence and development of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (325, 330))	('survival', 'CPA', (175, 183))	('CD276', 'Gene', '80381', (282, 287))	('CD276', 'Gene', (65, 70))	('CD276', 'Gene', '80381', (65, 70))	('NSCLC', 'Disease', (325, 330))	('tumor', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (325, 330))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('patients', 'Species', '9606', (193, 201))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CD276', 'Gene', '80381', (141, 146))	('CD276', 'Gene', (141, 146))	('NSCLC', 'Disease', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('impact', 'Reg', (165, 171))	('expression', 'Var', (127, 137))	('CD276', 'Gene', (282, 287))
45183	31737785	However, with the deepening of research, experiments have shown that the co-inhibition of CD276 in humans and mice can inhibit Treg cells, thereby allowing tumors to escape immune responses, and the mechanism may be related to NFAT, NF-kB and AP-1 factors.	('CD276', 'Gene', (90, 95))	('CD276', 'Gene', '80381', (90, 95))	('AP-1', 'cellular_component', 'GO:0005907', ('243', '247'))	('mice', 'Species', '10090', (110, 114))	('inhibit', 'NegReg', (119, 126))	('humans', 'Species', '9606', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('allowing', 'Reg', (147, 155))	('Treg cells', 'CPA', (127, 137))	('tumors', 'Disease', (156, 162))	('escape immune responses', 'CPA', (166, 189))	('co-inhibition', 'Var', (73, 86))
45206	31737785	Further subgroup analysis showed that in 673 patients with lung adenocarcinoma, high RPA3 expression levels had a significant effect on OS (HR=2.38, logrankP=3.3e-12, Figure 5B), whereas in 271 patients with lung squamous cell carcinoma, Its high expression level had no significant effect on OS (HR=0.73, logrankP=0.052, Figure 5C).	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('RPA', 'cellular_component', 'GO:0005662', ('85', '88'))	('patients', 'Species', '9606', (194, 202))	('expression levels', 'MPA', (90, 107))	('RPA3', 'Gene', '6119', (85, 89))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (59, 78))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (208, 236))	('patients', 'Species', '9606', (45, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('RPA3', 'Gene', (85, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (208, 236))	('high', 'Var', (80, 84))	('lung adenocarcinoma', 'Disease', (59, 78))	('lung squamous cell carcinoma', 'Disease', (208, 236))
45216	31737785	In another study, high CD276 expression was observed to be associated with high tumor grade and short overall survival, possibly in synergy with Treg cells, allowing tumors to evade immune responses.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('CD276', 'Gene', (23, 28))	('CD276', 'Gene', '80381', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('short', 'NegReg', (96, 101))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (80, 85))	('high', 'Var', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (166, 172))	('expression', 'MPA', (29, 39))	('overall survival', 'CPA', (102, 118))
45217	31737785	However, there are also statistics showing that abnormal expression of CD276 is associated with lymph node metastasis and late stage of NSCLC in TNM stage.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('CD276', 'Gene', (71, 76))	('CD276', 'Gene', '80381', (71, 76))	('TNM', 'Gene', '10178', (145, 148))	('abnormal', 'Var', (48, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('associated', 'Reg', (80, 90))	('lymph node metastasis', 'CPA', (96, 117))	('TNM', 'Gene', (145, 148))	('NSCLC', 'Disease', (136, 141))
45225	31737785	The results showed that the expression level of CD276 was correlated with the OS of NSCLC, and the OS of patients with high CD276 expression was significantly decreased, indicating that high expression of CD276 is an independent risk factor for poor prognosis in patients with NSCLC.	('high expression', 'Var', (186, 201))	('CD276', 'Gene', '80381', (124, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('patients', 'Species', '9606', (105, 113))	('CD276', 'Gene', (205, 210))	('CD276', 'Gene', '80381', (205, 210))	('patients', 'Species', '9606', (263, 271))	('NSCLC', 'Phenotype', 'HP:0030358', (277, 282))	('NSCLC', 'Disease', (84, 89))	('decreased', 'NegReg', (159, 168))	('CD276', 'Gene', (48, 53))	('CD276', 'Gene', '80381', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('NSCLC', 'Disease', (277, 282))	('CD276', 'Gene', (124, 129))	('correlated', 'Reg', (58, 68))	('expression level', 'MPA', (28, 44))	('NSCLC', 'Disease', 'MESH:D002289', (277, 282))
45233	31476386	However, according to NGS, five mutually exclusive gene mutations were identified (E1A binding protein P300 [EP300] p.N217S; p.E152K; human epidermal growth factor receptor 4 [ERBB4] p.E317K; BRCA1, DNA repair associated [BRCA1] p.E1661N, and epidermal growth factor receptor [EGFR] p.V742A).	('p.E152K', 'Var', (125, 132))	('EP300', 'Gene', '2033', (109, 114))	('p.E1661N', 'Var', (229, 237))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('EGFR', 'Gene', '1956', (277, 281))	('E1A binding protein P300', 'Gene', (83, 107))	('DNA repair', 'biological_process', 'GO:0006281', ('199', '209'))	('E1A binding protein P300', 'Gene', '2033', (83, 107))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('140', '163'))	('EP300', 'Gene', (109, 114))	('p.V742A', 'Mutation', 'rs121913466', (283, 290))	('epidermal growth factor receptor 4', 'Gene', '2066', (140, 174))	('epidermal growth factor receptor', 'Gene', '1956', (140, 172))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('DNA', 'Disease', (199, 202))	('p.E317K', 'Mutation', 'rs267599193', (183, 190))	('p.V742A', 'Var', (283, 290))	('BRCA1', 'Gene', '672', (192, 197))	('epidermal growth factor receptor', 'Gene', (243, 275))	('human', 'Species', '9606', (134, 139))	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('epidermal growth factor receptor', 'Gene', '1956', (243, 275))	('BRCA1', 'Gene', (192, 197))	('p.N217S', 'Mutation', 'rs139130083', (116, 123))	('epidermal growth factor receptor 4', 'Gene', (140, 174))	('BRCA1', 'Gene', '672', (222, 227))	('EGFR', 'Gene', (277, 281))	('p.E152K', 'Mutation', 'p.E152K', (125, 132))	('BRCA1', 'Gene', (222, 227))	('EGFR', 'molecular_function', 'GO:0005006', ('277', '281'))	('p.E1661N', 'Mutation', 'p.E1661N', (229, 237))	('ERBB4', 'Gene', '2066', (176, 181))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('243', '266'))	('ERBB4', 'Gene', (176, 181))	('p.E317K', 'Var', (183, 190))
45247	31476386	Another exceptional responder was a patient with TSC2 mutant anaplastic thyroid cancer with an 18-month response to everolimus.	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (61, 86))	('thyroid cancer', 'Phenotype', 'HP:0002890', (72, 86))	('TSC2', 'Gene', '7249', (49, 53))	('TSC2', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('thyroid cancer', 'Disease', 'MESH:D013964', (72, 86))	('everolimus', 'Chemical', 'MESH:D000068338', (116, 126))	('mutant', 'Var', (54, 60))	('thyroid cancer', 'Disease', (72, 86))	('patient', 'Species', '9606', (36, 43))
45248	31476386	In other examples, antiangiogenic receptor tyrosine kinase inhibitors such as sunitinib or pazopanib were associated with favorable or poor response in patients with PBRM1 and TP53 mutated metastatic renal cell carcinoma, respectively.	('pazopanib', 'Chemical', 'MESH:C516667', (91, 100))	('renal cell carcinoma', 'Disease', (200, 220))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (200, 220))	('TP53', 'Gene', '7157', (176, 180))	('mutated', 'Var', (181, 188))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (200, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('TP53', 'Gene', (176, 180))	('sunitinib', 'Chemical', 'MESH:D000077210', (78, 87))	('PBRM1', 'Gene', (166, 171))	('PBRM1', 'Gene', '55193', (166, 171))	('patients', 'Species', '9606', (152, 160))
45249	31476386	For example, an unusual curative response to irinotecan and a checkpoint kinase 1 inhibitor in a urothelial small cell cancer patient with a somatic mutation in the RAD50 gene was reported by Al-Ahmadie et al.	('urothelial small cell cancer', 'Disease', (97, 125))	('RAD50', 'Gene', (165, 170))	('RAD50', 'Gene', '10111', (165, 170))	('small cell cancer', 'Phenotype', 'HP:0030357', (108, 125))	('response to irinotecan', 'biological_process', 'GO:0061482', ('33', '55'))	('patient', 'Species', '9606', (126, 133))	('RAD', 'biological_process', 'GO:1990116', ('165', '168'))	('checkpoint kinase 1', 'Gene', '1111', (62, 81))	('urothelial small cell cancer', 'Disease', 'MESH:D055752', (97, 125))	('checkpoint kinase 1', 'Gene', (62, 81))	('irinotecan', 'Chemical', 'MESH:D000077146', (45, 55))	('mutation', 'Var', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
45270	31476386	A comprehensive NGS test was performed to analyze actionable gene mutations, copy number variations (CNVs), and mRNA expression by using the Paradigm Cancer Diagnostic's (PCDx) NGS platform according to the previously described methodology.	('mutations', 'Var', (66, 75))	('PCDx', 'Gene', '6103', (171, 175))	('Cancer', 'Disease', 'MESH:D009369', (150, 156))	('Cancer', 'Disease', (150, 156))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('PCDx', 'Gene', (171, 175))
45290	31476386	Supplementary Figure 1 shows CNVs, MMR abnormalities, and DNA point mutations according to ST vs. LT. We identified in five patients four mutations in cancer that have not been previously reported (E1A binding protein P300 [EP300]: c.650A > G p.N217S and c.4561G > A p.E152K; human epidermal growth factor receptor 4 [ERBB4]: c.949G > A p.E317K; BRCA1, DNA repair associated [BRCA1]: c.4981G > A p.E1661N).	('ERBB4', 'Gene', (318, 323))	('BRCA1', 'Gene', (346, 351))	('BRCA1', 'Gene', '672', (376, 381))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('282', '305'))	('DNA repair', 'biological_process', 'GO:0006281', ('353', '363'))	('BRCA1', 'Gene', (376, 381))	('p.E317K', 'Mutation', 'rs267599193', (337, 344))	('binding', 'molecular_function', 'GO:0005488', ('202', '209'))	('patients', 'Species', '9606', (124, 132))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('MMR', 'biological_process', 'GO:0006298', ('35', '38'))	('c.4561G > A', 'Mutation', 'rs80357119', (255, 266))	('human', 'Species', '9606', (276, 281))	('c.4561G > A', 'Var', (255, 266))	('cancer', 'Disease', (151, 157))	('epidermal growth factor receptor 4', 'Gene', '2066', (282, 316))	('c.650A > G', 'Mutation', 'rs139130083', (232, 242))	('DNA', 'cellular_component', 'GO:0005574', ('353', '356'))	('c.650A', 'Var', (232, 238))	('c.949G > A', 'Mutation', 'rs267599193', (326, 336))	('p.N217S', 'Mutation', 'rs139130083', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('EP300', 'Gene', '2033', (224, 229))	('epidermal growth factor receptor 4', 'Gene', (282, 316))	('p.E317K', 'Var', (337, 344))	('men', 'Species', '9606', (6, 9))	('c.4981G > A', 'Mutation', 'rs80357401', (384, 395))	('E1A binding protein P300', 'Gene', (198, 222))	('p.E152K', 'Mutation', 'p.E152K', (267, 274))	('E1A binding protein P300', 'Gene', '2033', (198, 222))	('p.E1661N', 'Mutation', 'p.E1661N', (396, 404))	('EP300', 'Gene', (224, 229))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('ERBB4', 'Gene', '2066', (318, 323))	('MMR abnormalities', 'Disease', (35, 52))	('BRCA1', 'Gene', '672', (346, 351))	('MMR abnormalities', 'Disease', 'MESH:C536928', (35, 52))
45291	31476386	Additionally, we found the epidermal growth factor receptor [EGFR] mutation c.2225T > C p.V742A which was described in NSCLC (COSM13183) but not in SCLC.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('p.V742A', 'Mutation', 'rs121913466', (88, 95))	('SCLC', 'Gene', '7864', (148, 152))	('COSM13183', 'Chemical', '-', (126, 135))	('SCLC', 'Gene', (148, 152))	('epidermal growth factor receptor', 'Gene', (27, 59))	('epidermal growth factor receptor', 'Gene', '1956', (27, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('EGFR', 'Gene', '1956', (61, 65))	('c.2225T > C', 'Mutation', 'rs121913466', (76, 87))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('27', '50'))	('NSCLC', 'Disease', (119, 124))	('SCLC', 'Gene', '7864', (120, 124))	('c.2225T > C p.V742A', 'Var', (76, 95))	('SCLC', 'Gene', (120, 124))	('EGFR', 'Gene', (61, 65))
45318	31476386	We identified EGFR V742A mutation.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('V742A', 'Mutation', 'rs121913466', (19, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('V742A', 'Var', (19, 24))
45338	31476386	Interestingly, in our study, we found a baseline, pretreatment EGFR mutation in an LT patient.	('EGFR', 'Gene', '1956', (63, 67))	('mutation', 'Var', (68, 76))	('EGFR', 'Gene', (63, 67))	('patient', 'Species', '9606', (86, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('men', 'Species', '9606', (58, 61))
45341	31476386	We also identified four cancer mutations that have not been previously reported in SCLC.	('SCLC', 'Gene', (83, 87))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('SCLC', 'Gene', '7864', (83, 87))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))
45342	31476386	ERBB4, EGFR, and EP300 belong to the same HER2 signal transduction pathway, and although the exact clinical relevance of the aforementioned genes is still partly unknown, the activation of ERBB3 and PI3K signaling contributes to acquired resistance to tyrosine kinase inhibitors targeting EGFR and HER2 in lung and breast cancer.	('HER2', 'Gene', '2064', (42, 46))	('ERBB3', 'Gene', '2065', (189, 194))	('ERBB4', 'Gene', '2066', (0, 5))	('EGFR', 'Gene', (289, 293))	('ERBB4', 'Gene', (0, 5))	('HER2', 'Gene', (298, 302))	('men', 'Species', '9606', (130, 133))	('EGFR', 'Gene', '1956', (7, 11))	('PI3K signaling', 'biological_process', 'GO:0014065', ('199', '213'))	('breast cancer', 'Phenotype', 'HP:0003002', (315, 328))	('acquired resistance', 'MPA', (229, 248))	('activation', 'PosReg', (175, 185))	('PI3K', 'molecular_function', 'GO:0016303', ('199', '203'))	('HER2', 'Gene', (42, 46))	('breast cancer', 'Disease', 'MESH:D001943', (315, 328))	('EGFR', 'Gene', '1956', (289, 293))	('breast cancer', 'Disease', (315, 328))	('PI3K', 'Var', (199, 203))	('EGFR', 'molecular_function', 'GO:0005006', ('7', '11'))	('EP300', 'Gene', '2033', (17, 22))	('ERBB3', 'Gene', (189, 194))	('HER2', 'Gene', '2064', (298, 302))	('signal transduction', 'biological_process', 'GO:0007165', ('47', '66'))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('EGFR', 'molecular_function', 'GO:0005006', ('289', '293'))	('EGFR', 'Gene', (7, 11))	('EP300', 'Gene', (17, 22))	('lung', 'Disease', (306, 310))
45343	31476386	According to a recent study on lung adenocarcinoma patients, a positive correlation might exist between EGFR and BRCA1 methylation but not EGFR mutation, and epigenetic modifications of BRCA1 are independent events against EGFR mutation.	('epigenetic modifications', 'Var', (158, 182))	('EGFR', 'Gene', '1956', (223, 227))	('mutation', 'Var', (228, 236))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('methylation', 'Var', (119, 130))	('BRCA1', 'Gene', '672', (186, 191))	('BRCA1', 'Gene', (186, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('EGFR', 'Gene', (139, 143))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('EGFR', 'Gene', (104, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('223', '227'))	('patients', 'Species', '9606', (51, 59))	('BRCA1', 'Gene', '672', (113, 118))	('BRCA1', 'Gene', (113, 118))	('EGFR', 'Gene', (223, 227))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', '1956', (104, 108))	('lung adenocarcinoma', 'Disease', (31, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))
45367	31476386	High TOP1 protein expression was associated with irinotecan and topotecan sensitivity based on previous reports of CRC and ovarian carcinoma studies.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (123, 140))	('topotecan', 'Chemical', 'MESH:D019772', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('irinotecan', 'MPA', (49, 59))	('High', 'Var', (0, 4))	('CRC', 'Disease', (115, 118))	('protein', 'Protein', (10, 17))	('topotecan sensitivity', 'MPA', (64, 85))	('associated', 'Reg', (33, 43))	('expression', 'MPA', (18, 28))	('irinotecan', 'Chemical', 'MESH:D000077146', (49, 59))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (123, 140))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('CRC', 'Disease', 'MESH:D015179', (115, 118))	('ovarian carcinoma', 'Disease', (123, 140))
45368	31476386	In our study, in most of the cases, the presence of TOP1 supports the current guidelines that camptothecins can be effective drugs in SCLC.	('TOP1', 'Gene', (52, 56))	('presence', 'Var', (40, 48))	('camptothecins', 'Chemical', 'MESH:D002166', (94, 107))	('SCLC', 'Gene', '7864', (134, 138))	('SCLC', 'Gene', (134, 138))
45370	31476386	In contrast, two recent studies have reported PD-L1 positivity in 16.5%-28.6% of SCLCs.	('PD-L1', 'Gene', (46, 51))	('PD-L1', 'Gene', '29126', (46, 51))	('positivity', 'Var', (52, 62))	('SCLC', 'Gene', '7864', (81, 85))	('SCLC', 'Gene', (81, 85))
45381	31476386	Thoracic RT was coincidentally linked to improved OS in this cohort of patients.	('Thoracic RT', 'Var', (0, 11))	('OS', 'Chemical', '-', (50, 52))	('improved', 'PosReg', (41, 49))	('patients', 'Species', '9606', (71, 79))
45384	31476386	Finally, according to our findings regarding the therapeutic associations at the time of this analysis, there would have been potential clinical trials available for two patients: LT9 patient could have been a potential candidate for a trial with treatment including lapatinib, erlotinib, and sunitinib for primary tumor type based on EGFR mutation and also for trials conducted in cancer outside of primary tumor type based on BCL-2 and EGFR mutations, while ST2 patient could have been a potential candidate for other trials only outside of the primary tumor type based on high BRCA1 and mTOR mRNA expression.	('patient', 'Species', '9606', (170, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('335', '339'))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (555, 560))	('lapatinib', 'Chemical', 'MESH:D000077341', (267, 276))	('mTOR', 'Gene', (590, 594))	('patient', 'Species', '9606', (184, 191))	('tumor', 'Disease', (408, 413))	('cancer', 'Disease', (382, 388))	('EGFR', 'molecular_function', 'GO:0005006', ('438', '442'))	('tumor', 'Disease', 'MESH:D009369', (408, 413))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('sunitinib', 'Chemical', 'MESH:D000077210', (293, 302))	('BCL-2', 'Gene', '596', (428, 433))	('tumor', 'Disease', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('BCL-2', 'molecular_function', 'GO:0015283', ('428', '433'))	('EGFR', 'Gene', (438, 442))	('BRCA1', 'Gene', '672', (580, 585))	('mutations', 'Var', (443, 452))	('erlotinib', 'Chemical', 'MESH:D000069347', (278, 287))	('mTOR', 'Gene', '2475', (590, 594))	('BCL-2', 'Gene', (428, 433))	('patients', 'Species', '9606', (170, 178))	('BRCA1', 'Gene', (580, 585))	('EGFR', 'Gene', (335, 339))	('ST2', 'Gene', '6761', (460, 463))	('men', 'Species', '9606', (252, 255))	('tumor', 'Disease', (555, 560))	('tumor', 'Phenotype', 'HP:0002664', (408, 413))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('EGFR', 'Gene', '1956', (335, 339))	('patient', 'Species', '9606', (464, 471))	('EGFR', 'Gene', '1956', (438, 442))	('tumor', 'Disease', 'MESH:D009369', (555, 560))	('ST2', 'Gene', (460, 463))
45398	31400611	Genetic Interaction-Based Biomarkers Identification for Drug Resistance and Sensitivity in Cancer Cells Cancer cells generally harbor hundreds of alterations in the cancer genomes and act as crucial factors in the development and progression of cancer.	('Drug Resistance', 'Phenotype', 'HP:0020174', (56, 71))	('Cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('alterations', 'Var', (146, 157))	('factors', 'Reg', (199, 206))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (245, 251))	('Cancer', 'Disease', (104, 110))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('Drug Resistance', 'biological_process', 'GO:0009315', ('56', '71'))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('Drug Resistance', 'biological_process', 'GO:0042493', ('56', '71'))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
45399	31400611	Gene alterations in the cancer genome form genetic interactions, which affect the response of patients to drugs.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('patients', 'Species', '9606', (94, 102))	('Gene alterations', 'Var', (0, 16))	('interactions', 'Interaction', (51, 63))	('affect', 'Reg', (71, 77))	('response', 'MPA', (82, 90))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))
45403	31400611	Deletions of HDAC1 and DVL1, both of which participate in the Notch signaling pathway, had an SV effect in cancer cells, and deletion of DVL1 induced resistance to HDAC1 inhibitors in cancer cells.	('cancer', 'Disease', (184, 190))	('DVL1', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Deletions', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('SV', 'Chemical', '-', (94, 96))	('HDAC1', 'Gene', (13, 18))	('HDAC1', 'Gene', (164, 169))	('DVL1', 'Gene', '1855', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('induced', 'Reg', (142, 149))	('deletion', 'Var', (125, 133))	('DVL1', 'Gene', (137, 141))	('HDAC1', 'Gene', '3065', (13, 18))	('cancer', 'Disease', (107, 113))	('HDAC1', 'Gene', '3065', (164, 169))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('62', '85'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Notch', 'Gene', '4851', (62, 67))	('Notch', 'Gene', (62, 67))	('resistance', 'MPA', (150, 160))	('DVL1', 'Gene', '1855', (137, 141))	('SV effect', 'MPA', (94, 103))
45412	31400611	Tremendous efforts and progress have been made over the past few years to reveal the specific mechanism of drug resistance and sensitivity, including genetic interactions among gene alterations in the cancer genome.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('drug resistance', 'Phenotype', 'HP:0020174', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('drug resistance', 'biological_process', 'GO:0009315', ('107', '122'))	('alterations', 'Var', (182, 193))	('drug resistance', 'biological_process', 'GO:0042493', ('107', '122'))
45414	31400611	Synthetic lethality (SL) describes the scenario in which single-gene defects are compatible with cell viability, but the combination of alterations in both genes induces cell death, which is generally used to identify drug-sensitive biomarkers or drug targets.	('cell death', 'Disease', 'MESH:D003643', (170, 180))	('combination', 'Var', (121, 132))	('cell death', 'Disease', (170, 180))	('alterations', 'Var', (136, 147))	('induces', 'Reg', (162, 169))	('cell death', 'biological_process', 'GO:0008219', ('170', '180'))
45415	31400611	A well-known example of an SL effect is the selective impediment of PARP inhibitors on the growth of BRCA1/2-mutated cancer cells, and this SL effect has been successfully applied to clinical therapy.	('impediment', 'Reg', (54, 64))	('PARP', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('growth', 'MPA', (91, 97))	('BRCA1/2', 'Gene', (101, 108))	('PARP', 'Gene', '142', (68, 72))	('BRCA1/2', 'Gene', '672;675', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('inhibitors', 'Var', (73, 83))
45417	31400611	However, many ovarian cancer patients carrying mutations of BRCA1/2 have resistance to olaparib in clinical applications.	('ovarian cancer', 'Disease', (14, 28))	('patients', 'Species', '9606', (29, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('mutations', 'Var', (47, 56))	('olaparib', 'Chemical', 'MESH:C531550', (87, 95))	('BRCA1/2', 'Gene', (60, 67))	('resistance to olaparib', 'MPA', (73, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('BRCA1/2', 'Gene', '672;675', (60, 67))
45421	31400611	reported that an SL effect underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma.	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', (82, 86))	('lung adenocarcinoma', 'Disease', (100, 119))	('KRAS', 'Gene', (73, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('KRAS', 'Gene', '3845', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('EGFR', 'Gene', '1956', (82, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('mutations', 'Var', (87, 96))
45422	31400611	Co-occurring alterations, in which both gene alterations significantly and simultaneously occur in cancer patients, may have an SV effect on cancer cells, and these alterations have been validated in our previous work.	('alterations', 'Var', (45, 56))	('SV effect', 'MPA', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('SV', 'Chemical', '-', (128, 130))	('cancer', 'Disease', (99, 105))	('occur', 'Reg', (90, 95))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('alterations', 'Var', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
45426	31400611	Moreover, the present study further detected drug-resistance biomarkers using SV interactions based on the hypothesis that cancer cells with alterations in partner genes are resistant to specific drugs if drug targets and partner genes have SV effects.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SV', 'Chemical', '-', (241, 243))	('alterations', 'Var', (141, 152))	('drug-resistance', 'Phenotype', 'HP:0020174', (45, 60))	('drug-resistance', 'biological_process', 'GO:0042493', ('45', '60'))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('resistant to', 'MPA', (174, 186))	('drug-resistance', 'biological_process', 'GO:0009315', ('45', '60'))	('cancer', 'Disease', (123, 129))	('SV', 'Chemical', '-', (78, 80))
45428	31400611	The strategy was based on the notion that knockdown of one gene causes a selective enhancement (SV) or reduction (SL) in cell viability, with simultaneous alterations in another gene.	('SV', 'Chemical', '-', (96, 98))	('enhancement', 'PosReg', (83, 94))	('cell viability', 'CPA', (121, 135))	('reduction', 'NegReg', (103, 112))	('knockdown', 'Var', (42, 51))	('alterations', 'Reg', (155, 166))
45431	31400611	SV and SL interactions were validated by (1) showing the expected drug response detected by four pharmacogenomic datasets (Figure 1D) as well as (2) observing worse survival of patients with alterations in SV interactions and better survival of patients with alterations in SL interactions in the prognosis analysis (Figure 1E).	('patients', 'Species', '9606', (245, 253))	('worse', 'PosReg', (159, 164))	('better', 'PosReg', (226, 232))	('alterations', 'Var', (191, 202))	('patients', 'Species', '9606', (177, 185))	('SV interactions', 'MPA', (206, 221))	('alterations', 'Var', (259, 270))	('SV', 'Chemical', '-', (206, 208))	('SV', 'Chemical', '-', (0, 2))
45442	31400611	For SV interactions, if one gene was targeted by a particular drug, the drug response measures (IC50 or AUC) in cell lines with alterations of the partner gene were significantly higher than those in the cell lines with the wild-type (WT) partner gene.	('higher', 'PosReg', (179, 185))	('drug response measures', 'MPA', (72, 94))	('SV', 'Chemical', '-', (4, 6))	('alterations', 'Var', (128, 139))
45445	31400611	A well-known example of SL is that ovarian cancer patients with BRCA1/2 mutations are treated with PARP inhibitors.	('mutations', 'Var', (72, 81))	('PARP', 'Gene', (99, 103))	('patients', 'Species', '9606', (50, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('PARP', 'Gene', '142', (99, 103))	('BRCA1/2', 'Gene', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA1/2', 'Gene', '672;675', (64, 71))	('ovarian cancer', 'Disease', (35, 49))
45446	31400611	Figure S3 demonstrates that the BRCA2 mutation was associated with sensitivity to olaparib, a PARP inhibitor, in cancer cells.	('olaparib', 'Chemical', 'MESH:C531550', (82, 90))	('PARP', 'Gene', '142', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('BRCA2', 'Gene', (32, 37))	('sensitivity to olaparib', 'MPA', (67, 90))	('associated with', 'Reg', (51, 66))	('cancer', 'Disease', (113, 119))	('mutation', 'Var', (38, 46))	('BRCA2', 'Gene', '675', (32, 37))	('PARP', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
45452	31400611	According to the present results, the breast cancer cell lines with alterations of PSEN1 were related to paclitaxel resistance (Figure S4), which has been reported in esophageal cancer.	('PSEN1', 'Gene', (83, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('PSEN1', 'Gene', '5663', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('paclitaxel resistance', 'MPA', (105, 126))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('alterations', 'Var', (68, 79))	('esophageal cancer', 'Disease', (167, 184))	('related', 'Reg', (94, 101))
45455	31400611	Cell lines with alterations of EGFR were more sensitive to erlotinib in the CCLE (Figure 3D), CTRP (Figure 3E), and GDSC (Figures 3F and 3G) datasets, which demonstrated the reliability of the present results.	('EGFR', 'Gene', '1956', (31, 35))	('alterations', 'Var', (16, 27))	('EGFR', 'Gene', (31, 35))	('more', 'PosReg', (41, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('CCLE', 'Chemical', '-', (76, 80))	('erlotinib', 'Chemical', 'MESH:D000069347', (59, 68))	('sensitive to erlotinib', 'MPA', (46, 68))
45465	31400611	The present study predicted that alterations of RHOA may induce resistance to drugs, such as fluorouracil, in cancer cells.	('RHOA', 'Gene', (48, 52))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (33, 44))	('induce', 'Reg', (57, 63))	('fluorouracil', 'MPA', (93, 105))	('RHOA', 'Gene', '387', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('resistance to drugs', 'MPA', (64, 83))	('fluorouracil', 'Chemical', 'MESH:D005472', (93, 105))
45466	31400611	Several studies have reported that alterations of RHOA mediate tumor invasion and drug resistance in cancer.	('drug resistance', 'CPA', (82, 97))	('tumor', 'Disease', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('alterations', 'Var', (35, 46))	('RHOA', 'Gene', '387', (50, 54))	('drug resistance', 'Phenotype', 'HP:0020174', (82, 97))	('cancer', 'Disease', (101, 107))	('RHOA', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('drug resistance', 'biological_process', 'GO:0009315', ('82', '97'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('drug resistance', 'biological_process', 'GO:0042493', ('82', '97'))
45469	31400611	The present work predicted that alterations of TP53 were related to drug sensitivity, which has been validated in other studies.	('related', 'Reg', (57, 64))	('drug sensitivity', 'Phenotype', 'HP:0020174', (68, 84))	('alterations', 'Var', (32, 43))	('drug sensitivity', 'Disease', (68, 84))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
45472	31400611	In the SV network, many genes interacted with HDAC1, whose alterations may induce resistance to a HDAC1 inhibitor in cancer cells.	('alterations', 'Var', (59, 70))	('HDAC1', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('HDAC1', 'Gene', '3065', (46, 51))	('HDAC1', 'Gene', '3065', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('resistance to a', 'MPA', (82, 97))	('induce', 'Reg', (75, 81))	('HDAC1', 'Gene', (46, 51))	('SV', 'Chemical', '-', (7, 9))
45475	31400611	In the pharmacogenomic dataset of CTRP, the deletions of DVL1 were related to HDAC1 inhibitor (pandacostat) resistance in the cell lines of CNS tissues (p = 0.01, Wilcoxon rank-sum test; Figure 5C).	('HDAC1', 'Gene', (78, 83))	('related', 'Reg', (67, 74))	('DVL1', 'Gene', (57, 61))	('deletions', 'Var', (44, 53))	('HDAC1', 'Gene', '3065', (78, 83))	('DVL1', 'Gene', '1855', (57, 61))
45476	31400611	Knockout of HDAC1 by CRISPR demonstrated that cell lines with DVL1 deletion survived better than those with WT DVL1 (p = 0.003, Wilcoxon rank-sum test; Figure 5D).	('better', 'PosReg', (85, 91))	('survived', 'CPA', (76, 84))	('DVL1', 'Gene', '1855', (62, 66))	('deletion', 'Var', (67, 75))	('DVL1', 'Gene', '1855', (111, 115))	('HDAC1', 'Gene', '3065', (12, 17))	('DVL1', 'Gene', (62, 66))	('DVL1', 'Gene', (111, 115))	('HDAC1', 'Gene', (12, 17))
45480	31400611	However, deletion of DVL1 may compensate for transcriptional inhibition.	('DVL1', 'Gene', (21, 25))	('DVL1', 'Gene', '1855', (21, 25))	('transcriptional', 'MPA', (45, 60))	('deletion', 'Var', (9, 17))
45481	31400611	DVL1 inhibits the Notch1 receptor, and deletion of DVL1 may upregulate Notch1, which produces anti-apoptotic signals by regulating the phosphatidylinositol 3-kinase (PI3K)-PKB/Akt pathway.	('DVL1', 'Gene', '1855', (0, 4))	('DVL1', 'Gene', '1855', (51, 55))	('PKB', 'Gene', '207', (172, 175))	('phosphatidylinositol 3-kinase', 'Gene', (135, 164))	('regulating', 'Reg', (120, 130))	('PI3K', 'molecular_function', 'GO:0016303', ('166', '170'))	('Notch1', 'Gene', (18, 24))	('PKB', 'Gene', (172, 175))	('upregulate', 'PosReg', (60, 70))	('deletion', 'Var', (39, 47))	('Notch1', 'Gene', (71, 77))	('DVL1', 'Gene', (0, 4))	('DVL1', 'Gene', (51, 55))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (135, 164))	('Notch1', 'Gene', '4851', (18, 24))	('inhibits', 'NegReg', (5, 13))	('Notch1', 'Gene', '4851', (71, 77))	('anti-apoptotic signals', 'MPA', (94, 116))
45482	31400611	To confirm this conjecture, differentially expressed genes were examined in liver hepatocellular carcinoma (LIHC) samples containing both deletions of HDAC1 and DVL1 versus LIHC samples with WT HDAC1 and DVL1.	('LIHC', 'Disease', (108, 112))	('LIHC', 'Disease', 'None', (108, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('HDAC1', 'Gene', '3065', (194, 199))	('HDAC1', 'Gene', '3065', (151, 156))	('LIHC', 'Disease', (173, 177))	('liver hepatocellular carcinoma', 'Disease', (76, 106))	('DVL1', 'Gene', (161, 165))	('LIHC', 'Disease', 'None', (173, 177))	('HDAC1', 'Gene', (151, 156))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 106))	('deletions', 'Var', (138, 147))	('DVL1', 'Gene', '1855', (204, 208))	('DVL1', 'Gene', '1855', (161, 165))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('HDAC1', 'Gene', (194, 199))	('DVL1', 'Gene', (204, 208))
45483	31400611	Notch1 was significantly upregulated in samples containing deletions of both HDAC1 and DVL1 (p = 0.001, t test; Figure S6).	('Notch1', 'Gene', (0, 6))	('HDAC1', 'Gene', (77, 82))	('DVL1', 'Gene', '1855', (87, 91))	('Notch1', 'Gene', '4851', (0, 6))	('deletions', 'Var', (59, 68))	('upregulated', 'PosReg', (25, 36))	('HDAC1', 'Gene', '3065', (77, 82))	('DVL1', 'Gene', (87, 91))
45484	31400611	Thus, when HDAC1 inhibitors promote transcriptional inhibition, the deletion of DVL1 may lead to an increase in the activity of the Notch receptor, which promotes cell proliferation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('234', '238'))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('234', '249'))	('regulating', 'Reg', (185, 195))	('promotes', 'PosReg', (154, 162))	('DVL1', 'Gene', '1855', (80, 84))	('signaling pathway', 'biological_process', 'GO:0007165', ('240', '257'))	('deletion', 'Var', (68, 76))	('HDAC1', 'Gene', (11, 16))	('Notch', 'Gene', '4851', (132, 137))	('HDAC1', 'Gene', '3065', (11, 16))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('cell proliferation', 'biological_process', 'GO:0008283', ('163', '181'))	('activity', 'MPA', (116, 124))	('cell proliferation', 'CPA', (163, 181))	('Notch', 'Gene', (132, 137))	('DVL1', 'Gene', (80, 84))	('increase', 'PosReg', (100, 108))
45486	31400611	In ovarian cancer, patients with deletions of both HDAC1 and DVL1 showed worse survival than patients with deletions of either HDAC1 or DVL1 (p = 0.0303, log-rank test).	('DVL1', 'Gene', '1855', (61, 65))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (19, 27))	('HDAC1', 'Gene', '3065', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('DVL1', 'Gene', (136, 140))	('DVL1', 'Gene', (61, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('HDAC1', 'Gene', (127, 132))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('worse', 'NegReg', (73, 78))	('ovarian cancer', 'Disease', (3, 17))	('DVL1', 'Gene', '1855', (136, 140))	('HDAC1', 'Gene', (51, 56))	('HDAC1', 'Gene', '3065', (127, 132))	('survival', 'MPA', (79, 87))	('deletions', 'Var', (33, 42))
45490	31400611	These results indicated that the alterations of the partner genes, which had an SL effect with deletion of AKT1, were related to gefitinib sensitivity in cancer cells.	('related', 'Reg', (118, 125))	('deletion', 'Var', (95, 103))	('AKT1', 'Gene', '207', (107, 111))	('cancer', 'Disease', (154, 160))	('gefitinib sensitivity', 'MPA', (129, 150))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('AKT1', 'Gene', (107, 111))	('gefitinib', 'Chemical', 'MESH:D000077156', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
45492	31400611	Knockout of AKT1 by CRISPR in cells with ARHGDIA deletion showed worse survival than cells with WT ARHGDIA (p = 0.02, Wilcoxon rank-sum test; Figure 6D).	('ARHGDIA', 'Gene', '396', (99, 106))	('worse', 'NegReg', (65, 70))	('survival', 'CPA', (71, 79))	('ARHGDIA', 'Gene', (99, 106))	('ARHGDIA', 'Gene', '396', (41, 48))	('Knockout', 'Var', (0, 8))	('deletion', 'Var', (49, 57))	('AKT1', 'Gene', '207', (12, 16))	('AKT1', 'Gene', (12, 16))	('ARHGDIA', 'Gene', (41, 48))
45497	31400611	Cancer patient prognostic data were used to test whether co-deletions of AKT1 and ARHGDIA are beneficial to patient survival.	('ARHGDIA', 'Gene', '396', (82, 89))	('co-deletions', 'Var', (57, 69))	('patient', 'Species', '9606', (7, 14))	('beneficial', 'PosReg', (94, 104))	('AKT1', 'Gene', '207', (73, 77))	('AKT1', 'Gene', (73, 77))	('ARHGDIA', 'Gene', (82, 89))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patient', 'Species', '9606', (108, 115))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
45498	31400611	As shown in Figure 6E, the prognosis of lung squamous cell carcinoma patients with AKT1 and ARHGDIA deletions was better than that for patients with single-gene deletions (p = 0.0582, log-rank test).	('patients', 'Species', '9606', (135, 143))	('ARHGDIA', 'Gene', '396', (92, 99))	('AKT1', 'Gene', '207', (83, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('AKT1', 'Gene', (83, 87))	('ARHGDIA', 'Gene', (92, 99))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (40, 68))	('better', 'PosReg', (114, 120))	('deletions', 'Var', (100, 109))	('patients', 'Species', '9606', (69, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 68))	('lung squamous cell carcinoma', 'Disease', (40, 68))
45499	31400611	Thus, alterations of ARHGDIA in cancer cells are beneficial for gefitinib treatment, and patients with co-alterations of AKT1 and ARHGDIA have better prognosis.	('alterations', 'Var', (6, 17))	('gefitinib', 'Chemical', 'MESH:D000077156', (64, 73))	('ARHGDIA', 'Gene', '396', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('beneficial', 'PosReg', (49, 59))	('ARHGDIA', 'Gene', '396', (21, 28))	('cancer', 'Disease', (32, 38))	('ARHGDIA', 'Gene', (130, 137))	('AKT1', 'Gene', '207', (121, 125))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('AKT1', 'Gene', (121, 125))	('ARHGDIA', 'Gene', (21, 28))
45503	31400611	As expected, breast cancer cell lines with LAMP1 amplifications were related to paclitaxel sensitivity compared to WT cell lines (p = 0.02, Wilcoxon rank-sum test; Figure 7B).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('paclitaxel sensitivity', 'MPA', (80, 102))	('LAMP1', 'Gene', (43, 48))	('amplifications', 'Var', (49, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('LAMP1', 'Gene', '3916', (43, 48))	('related', 'Reg', (69, 76))
45504	31400611	Knockout of TUBB3 by CRISPR in cells with LAMP1 amplifications showed worse survival than cells with WT LAMP1 (p = 0.006, Wilcoxon rank-sum test; Figure 7C).	('worse', 'NegReg', (70, 75))	('LAMP1', 'Gene', '3916', (104, 109))	('TUBB3', 'Gene', (12, 17))	('TUBB3', 'Gene', '10381', (12, 17))	('Knockout', 'Var', (0, 8))	('LAMP1', 'Gene', (42, 47))	('survival', 'CPA', (76, 84))	('LAMP1', 'Gene', (104, 109))	('LAMP1', 'Gene', '3916', (42, 47))
45505	31400611	These results indicated that breast cancer patients with amplifications of LAMP1 may benefit from paclitaxel chemotherapy.	('amplifications', 'Var', (57, 71))	('patients', 'Species', '9606', (43, 51))	('LAMP1', 'Gene', (75, 80))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('benefit', 'PosReg', (85, 92))	('LAMP1', 'Gene', '3916', (75, 80))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
45514	31400611	Cancer cells have frequent defects in specific genes that drive growth and metastasis, and alterations in different genes may induce a genetic interaction effect.	('induce', 'Reg', (126, 132))	('genetic', 'Interaction', (135, 142))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('alterations', 'Var', (91, 102))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('growth', 'CPA', (64, 70))	('defects', 'NegReg', (27, 34))
45516	31400611	The present study developed a new strategy for identifying genetic interactions in cancer cells based on CNAs, mutations, and expression profiles across 8,580 samples from 32 cancer types from the TCGA dataset, which were further filtered applying the shRNA, CRISPR, and yeast datasets.	('mutations', 'Var', (111, 120))	('CNAs', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('yeast', 'Species', '4932', (271, 276))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
45518	31400611	The results highlighted that DVL1 deletion induces resistance to HDAC1 inhibitors through disturbing the Notch signaling pathway, which was confirmed by gene expression profiles.	('DVL1', 'Gene', (29, 33))	('gene expression', 'biological_process', 'GO:0010467', ('153', '168'))	('disturbing', 'NegReg', (90, 100))	('resistance to', 'MPA', (51, 64))	('DVL1', 'Gene', '1855', (29, 33))	('deletion', 'Var', (34, 42))	('HDAC1', 'Gene', (65, 70))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('105', '128'))	('Notch', 'Gene', '4851', (105, 110))	('HDAC1', 'Gene', '3065', (65, 70))	('Notch', 'Gene', (105, 110))	('induces', 'PosReg', (43, 50))
45520	31400611	An expected application of genetic interaction screens is to optimize the therapeutic regimen of patients and to make an improvement in overall survival, which was verified in the clinical prognostic data.	('screens', 'Var', (47, 54))	('genetic', 'Var', (27, 34))	('improvement', 'PosReg', (121, 132))	('overall', 'MPA', (136, 143))	('patients', 'Species', '9606', (97, 105))
45523	31400611	However, the shRNA or CRISPR studies were limited as follows: (1) lack of mutation information of cell lines:for example, the CCLE collection of 1,000 cell lines contained no acute myeloid leukemia (AML) cell line with IDH1 mutation, even though the rate of mutation in the AML patients is up to 10%; and (2) the inevitable difference of tumor microenvironment between in vitro screening conditions and in vivo tumors.	('IDH1', 'Gene', '3417', (219, 223))	('myeloid leukemia', 'Disease', (181, 197))	('tumor', 'Disease', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (175, 197))	('tumors', 'Phenotype', 'HP:0002664', (411, 417))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('myeloid leukemia', 'Disease', 'MESH:D007951', (181, 197))	('mutation', 'Var', (224, 232))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (181, 197))	('AML', 'Disease', 'MESH:D015470', (199, 202))	('AML', 'Phenotype', 'HP:0004808', (199, 202))	('AML', 'Disease', (199, 202))	('CCLE', 'Chemical', '-', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumors', 'Disease', (411, 417))	('IDH1', 'Gene', (219, 223))	('tumor', 'Disease', (411, 416))	('AML', 'Disease', 'MESH:D015470', (274, 277))	('tumors', 'Disease', 'MESH:D009369', (411, 417))	('AML', 'Phenotype', 'HP:0004808', (274, 277))	('tumor', 'Disease', 'MESH:D009369', (411, 416))	('AML', 'Disease', (274, 277))	('patients', 'Species', '9606', (278, 286))
45536	31400611	When HDAC1 is inhibited by drugs to promote transcriptional inhibition in the Notch signaling pathway, DVL1 deletion activates the MAPK signaling pathway by the Notch receptor and further promotes cell proliferation.	('promotes', 'PosReg', (188, 196))	('cell proliferation', 'biological_process', 'GO:0008283', ('197', '215'))	('Notch', 'Gene', '4851', (161, 166))	('activates', 'PosReg', (117, 126))	('Notch', 'Gene', (161, 166))	('HDAC1', 'Gene', (5, 10))	('DVL1', 'Gene', '1855', (103, 107))	('MAPK signaling pathway', 'Pathway', (131, 153))	('deletion', 'Var', (108, 116))	('HDAC1', 'Gene', '3065', (5, 10))	('MAPK signaling', 'biological_process', 'GO:0000165', ('131', '145'))	('Notch', 'Gene', '4851', (78, 83))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('78', '101'))	('cell proliferation', 'CPA', (197, 215))	('Notch', 'Gene', (78, 83))	('transcriptional inhibition', 'MPA', (44, 70))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('DVL1', 'Gene', (103, 107))
45537	31400611	Thus, interactions between HDAC1 inhibition and DVL1 deletion may enhance cancer cell survival.	('HDAC1', 'Gene', '3065', (27, 32))	('enhance', 'PosReg', (66, 73))	('interactions', 'Interaction', (6, 18))	('DVL1', 'Gene', '1855', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('inhibition', 'NegReg', (33, 43))	('deletion', 'Var', (53, 61))	('cancer', 'Disease', (74, 80))	('HDAC1', 'Gene', (27, 32))	('DVL1', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
45538	31400611	Therefore, DVL1 deletion may induce resistance to HDAC1 inhibitors in cancer cells by disturbing the Notch signaling pathway, which was confirmed by the gene expression profile.	('gene expression', 'biological_process', 'GO:0010467', ('153', '168'))	('HDAC1', 'Gene', (50, 55))	('disturbing', 'Reg', (86, 96))	('DVL1', 'Gene', '1855', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Notch', 'Gene', '4851', (101, 106))	('deletion', 'Var', (16, 24))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('101', '124'))	('resistance', 'MPA', (36, 46))	('HDAC1', 'Gene', '3065', (50, 55))	('Notch', 'Gene', (101, 106))	('DVL1', 'Gene', (11, 15))	('induce', 'PosReg', (29, 35))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
45539	31400611	NOTCH1 was significantly upregulated in samples with deletions of both HDAC1 and DVL1 compared to samples with single-gene deletions.	('deletions', 'Var', (53, 62))	('HDAC1', 'Gene', (71, 76))	('DVL1', 'Gene', (81, 85))	('upregulated', 'PosReg', (25, 36))	('HDAC1', 'Gene', '3065', (71, 76))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('DVL1', 'Gene', '1855', (81, 85))
45540	31400611	Importantly, ovarian cancer patients with deletions of both HDAC1 and DVL1 had worse survival than patients with deletions of either HDAC1 or DVL1.	('HDAC1', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('worse', 'NegReg', (79, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('DVL1', 'Gene', '1855', (142, 146))	('HDAC1', 'Gene', (60, 65))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('DVL1', 'Gene', '1855', (70, 74))	('HDAC1', 'Gene', '3065', (133, 138))	('patients', 'Species', '9606', (99, 107))	('deletions', 'Var', (42, 51))	('HDAC1', 'Gene', '3065', (60, 65))	('DVL1', 'Gene', (142, 146))	('DVL1', 'Gene', (70, 74))	('ovarian cancer', 'Disease', (13, 27))	('patients', 'Species', '9606', (28, 36))
45544	31400611	The present analysis identified the well-known SL interaction between PARP inhibition and BRCA1 mutation.	('PARP', 'Gene', '142', (70, 74))	('BRCA1', 'Gene', '672', (90, 95))	('mutation', 'Var', (96, 104))	('BRCA1', 'Gene', (90, 95))	('PARP', 'Gene', (70, 74))
45545	31400611	In the present results, alterations of the partner genes of PARP in the SL network were significantly related to the sensitivity of PARP inhibitors in cancer cell lines.	('alterations', 'Var', (24, 35))	('PARP', 'Gene', '142', (132, 136))	('sensitivity', 'MPA', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('PARP', 'Gene', '142', (60, 64))	('related', 'Reg', (102, 109))	('PARP', 'Gene', (132, 136))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('PARP', 'Gene', (60, 64))
45546	31400611	For example, the mutation of POLE mediated sensitivity to the PARP inhibitor veliparib in lung cancer cell lines, which was previously characterized by Safiri et al.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('veliparib', 'Chemical', 'MESH:C521013', (77, 86))	('mutation', 'Var', (17, 25))	('POLE', 'Gene', (29, 33))	('PARP', 'Gene', (62, 66))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('mediated sensitivity', 'Reg', (34, 54))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PARP', 'Gene', '142', (62, 66))
45547	31400611	In addition, there were many newly discovered alterations of genes that enhanced cell-line sensitivity to PARP inhibitors, such as DOCK3, CLASP2, CMTM6, and MAP4.	('MAP', 'molecular_function', 'GO:0004239', ('157', '160'))	('genes', 'Gene', (61, 66))	('MAP4', 'Gene', (157, 161))	('PARP', 'Gene', (106, 110))	('CMTM6', 'Gene', (146, 151))	('MAP4', 'Gene', '4134', (157, 161))	('alterations', 'Var', (46, 57))	('enhanced', 'PosReg', (72, 80))	('DOCK3', 'Gene', '1795', (131, 136))	('CLASP2', 'Gene', (138, 144))	('CMTM6', 'Gene', '54918', (146, 151))	('PARP', 'Gene', '142', (106, 110))	('CLASP2', 'Gene', '23122', (138, 144))	('DOCK3', 'Gene', (131, 136))
45555	31400611	The genetic background of these cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE; https://www.broadinstitute.org/ccle/home), including mutation and copy number variation.	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (65, 94))	('CCLE', 'Chemical', '-', (96, 100))	('copy number variation', 'Var', (168, 189))	('Cancer Cell Line Encyclopedia', 'Disease', (65, 94))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))
45561	31400611	The present study used a cutoff of epsilon > 0.08 with p < 0.05 (yeast p value) to detect yeast SV interactions and epsilon < -0.08 with p < 0.05 to detect yeast SL interactions (epsilon is a measure of genetic interaction strength) (Figure 1C).	('SV', 'Chemical', '-', (96, 98))	('yeast', 'Species', '4932', (156, 161))	('yeast', 'Species', '4932', (90, 95))	('yeast', 'Species', '4932', (65, 70))	('yeast', 'MPA', (90, 95))	('yeast SL interactions', 'MPA', (156, 177))	('epsilon < -0.08', 'Var', (116, 131))
45633	31100816	p53 is the most commonly mutated tumor suppressor, which may explain in part the frequent overexpression of xCT in human cancers.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('human', 'Species', '9606', (115, 120))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('tumor', 'Disease', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('mutated', 'Var', (25, 32))
45637	31100816	Oncogenic phosphatidylinositol 3-kinase (PI3KCA) mutations activate protein kinase B (AKT), which phosphorylates xCT at serine 26 to suppress cystine/glutamate antiport.	('serine', 'Chemical', 'MESH:D012694', (120, 126))	('antiport', 'molecular_function', 'GO:0015297', ('160', '168'))	('AKT', 'Gene', (86, 89))	('mutations', 'Var', (49, 58))	('PI3KCA', 'Gene', (41, 47))	('cystine', 'Chemical', 'MESH:D003553', (142, 149))	('activate', 'PosReg', (59, 67))	('antiport', 'biological_process', 'GO:0015982', ('160', '168'))	('protein kinase B', 'Gene', (68, 84))	('suppress', 'NegReg', (133, 141))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('cystine/glutamate antiport', 'MPA', (142, 168))	('AKT', 'Gene', '207', (86, 89))	('protein kinase B', 'Gene', '2185', (68, 84))	('glutamate', 'Chemical', 'MESH:D018698', (150, 159))
45639	31100816	This modulation of xCT activity by aberrantly active AKT may be specific to breast cancer cell lines and/or only present in cancer cells with oncogenic PI3KCA mutations as many cancer cells are cystine dependent.	('cancer', 'Disease', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('mutations', 'Var', (159, 168))	('activity', 'MPA', (23, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('AKT', 'Gene', (53, 56))	('aberrantly', 'Var', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('breast cancer', 'Disease', (76, 89))	('PI3KCA', 'Gene', (152, 158))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('xCT', 'Enzyme', (19, 22))	('cystine', 'Chemical', 'MESH:D003553', (194, 201))	('cancer', 'Disease', (124, 130))	('AKT', 'Gene', '207', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (83, 89))
45641	31100816	Oncogenic activation of AKT by mutant PI3KCA and mTORC2 signaling are common in cancers, and consequently xCT activity may be influenced by multiple posttranslational and metabolic inputs.	('mutant', 'Var', (31, 37))	('AKT', 'Gene', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('PI3KCA', 'Gene', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('mTORC2', 'cellular_component', 'GO:0031932', ('49', '55'))	('mTORC2', 'Gene', (49, 55))	('AKT', 'Gene', '207', (24, 27))	('mTORC2', 'Gene', '74343', (49, 55))	('activation', 'PosReg', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
45646	31100816	Inhibition of xCT suppresses intracellular cysteine and stabilizes HIF1alpha.	('HIF1alpha', 'Gene', '3091', (67, 76))	('intracellular', 'cellular_component', 'GO:0005622', ('29', '42'))	('stabilizes', 'MPA', (56, 66))	('xCT', 'Gene', (14, 17))	('cysteine', 'Chemical', 'MESH:D003545', (43, 51))	('Inhibition', 'Var', (0, 10))	('suppresses', 'NegReg', (18, 28))	('HIF1alpha', 'Gene', (67, 76))	('intracellular cysteine', 'MPA', (29, 51))
45654	31100816	Tumors bearing a mutant form of KEAP1 unable to bind and degrade NRF2 are sensitive to glutaminase inhibition as a consequence of xCT activity.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('bind', 'Interaction', (48, 52))	('NRF2', 'Gene', (65, 69))	('degrade', 'NegReg', (57, 64))	('Tumors', 'Disease', (0, 6))	('KEAP1', 'Gene', '9817', (32, 37))	('glutaminase inhibition', 'MPA', (87, 109))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutant', 'Var', (17, 23))	('KEAP1', 'Gene', (32, 37))
45655	31100816	KEAP1 mutant cells are glutamate deficient due to a high demand for glutamate for both glutathione synthesis and glutamate/cystine exchange, leading to inadequate glutamine entry into the TCA cycle.	('cystine', 'Chemical', 'MESH:D003553', (123, 130))	('glutathione synthesis', 'biological_process', 'GO:0006750', ('87', '108'))	('glutamate', 'Chemical', 'MESH:D018698', (68, 77))	('mutant', 'Var', (6, 12))	('glutamine', 'Chemical', 'MESH:D005973', (163, 172))	('TCA', 'Chemical', '-', (188, 191))	('glutamate', 'Chemical', 'MESH:D018698', (113, 122))	('KEAP1', 'Gene', (0, 5))	('glutamate deficient', 'Phenotype', 'HP:0500150', (23, 42))	('inadequate', 'NegReg', (152, 162))	('inadequate glutamine', 'Phenotype', 'HP:0500147', (152, 172))	('TCA cycle', 'biological_process', 'GO:0006099', ('188', '197'))	('glutamate', 'Chemical', 'MESH:D018698', (23, 32))	('glutathione', 'Chemical', 'MESH:D005978', (87, 98))	('glutamine entry into', 'MPA', (163, 183))	('KEAP1', 'Gene', '9817', (0, 5))
45661	31100816	Inhibition, knockdown, or knockout of xCT remains a prime strategy to induce cancer cell death for therapeutic treatment.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('xCT', 'Gene', (38, 41))	('knockdown', 'Var', (12, 21))	('knockout', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cell death', 'biological_process', 'GO:0008219', ('84', '94'))
45664	31100816	Cell death induced by cystine starvation or blockade of xCT is mediated by the non-apoptotic cell death mechanism, ferroptosis.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('83', '103'))	('blockade', 'Var', (44, 52))	('Cell death', 'biological_process', 'GO:0008219', ('0', '10'))	('Cell death', 'CPA', (0, 10))	('ferroptosis', 'biological_process', 'GO:0097707', ('115', '126'))	('xCT', 'Gene', (56, 59))	('cystine', 'Chemical', 'MESH:D003553', (22, 29))
45667	31100816	Ferroptosis by these small molecules is attributed to inhibition of both xCT activity and glutathione synthesis.	('small molecules', 'Var', (21, 36))	('xCT', 'Enzyme', (73, 76))	('glutathione synthesis', 'biological_process', 'GO:0006750', ('90', '111'))	('inhibition', 'NegReg', (54, 64))	('glutathione', 'Chemical', 'MESH:D005978', (90, 101))	('glutathione synthesis', 'MPA', (90, 111))	('Ferroptosis', 'Disease', (0, 11))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))
45669	31100816	The rate of glutathione depletion may play a role in this discrepancy, as active mitochondria deplete glutathione and lead to ferroptosis but inhibition of mitochondrial respiration spares glutathione and promotes cell survival.	('lead to', 'Reg', (118, 125))	('mitochondria', 'cellular_component', 'GO:0005739', ('81', '93'))	('glutathione', 'Chemical', 'MESH:D005978', (102, 113))	('respiration', 'biological_process', 'GO:0045333', ('170', '181'))	('glutathione', 'Chemical', 'MESH:D005978', (189, 200))	('ferroptosis', 'Disease', (126, 137))	('promotes', 'PosReg', (205, 213))	('ferroptosis', 'biological_process', 'GO:0097707', ('126', '137'))	('cell survival', 'CPA', (214, 227))	('spares', 'NegReg', (182, 188))	('glutathione', 'Chemical', 'MESH:D005978', (12, 23))	('inhibition', 'Var', (142, 152))	('respiration', 'biological_process', 'GO:0007585', ('170', '181'))	('glutathione', 'MPA', (189, 200))
45684	31100816	While solute carrier family 3 member 1 (SLC3A1) is proposed to be a cysteine transporter, mutations in SLC3A1 lead to cystinuria, suggesting it instead transports cystine.	('SLC3A1', 'Gene', (40, 46))	('cystinuria', 'Disease', (118, 128))	('mutations', 'Var', (90, 99))	('cystine', 'Chemical', 'MESH:D003553', (163, 170))	('cystinuria', 'Phenotype', 'HP:0003131', (118, 128))	('SLC3A1', 'Gene', '6519', (40, 46))	('carrier', 'molecular_function', 'GO:0005215', ('13', '20'))	('SLC3A1', 'Gene', (103, 109))	('SLC3A1', 'Gene', '6519', (103, 109))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('lead to', 'Reg', (110, 117))	('cystinuria', 'Disease', 'MESH:D003555', (118, 128))
45689	31100816	SLC3A1 exit from the endoplasmic reticulum is facilitated by SLC7A9, and mutations in SLC7A9 also result in cystinuria.	('exit', 'MPA', (7, 11))	('SLC7A9', 'Gene', (86, 92))	('cystinuria', 'Phenotype', 'HP:0003131', (108, 118))	('result in', 'Reg', (98, 107))	('cystinuria', 'Disease', 'MESH:D003555', (108, 118))	('SLC3A1', 'Gene', (0, 6))	('SLC7A9', 'Gene', '11136', (61, 67))	('SLC7A9', 'Gene', '11136', (86, 92))	('SLC3A1', 'Gene', '6519', (0, 6))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('21', '42'))	('SLC7A9', 'Gene', (61, 67))	('mutations', 'Var', (73, 82))	('cystinuria', 'Disease', (108, 118))
45719	31100816	Phenotypically, individuals harboring mutations in CBS all share elevated levels of methionine and homocysteine.	('methionine', 'Chemical', 'MESH:D008715', (84, 94))	('levels of methionine', 'MPA', (74, 94))	('elevated levels of methionine', 'Phenotype', 'HP:0003235', (65, 94))	('homocysteine', 'MPA', (99, 111))	('homocysteine', 'Chemical', 'MESH:D006710', (99, 111))	('elevated', 'PosReg', (65, 73))	('mutations', 'Var', (38, 47))	('CBS', 'Gene', (51, 54))
45720	31100816	Disease resulting from CBS mutations range from pneumothorax to mental retardation, thrombosis, ectopia lentis, and skeletal issues similar to Marfan syndrome.	('mutations', 'Var', (27, 36))	('ectopia lentis', 'Disease', 'MESH:C536184', (96, 110))	('pneumothorax', 'Phenotype', 'HP:0002107', (48, 60))	('Marfan syndrome', 'Disease', 'MESH:D008382', (143, 158))	('skeletal issues', 'Phenotype', 'HP:0000924', (116, 131))	('skeletal issues', 'Disease', (116, 131))	('thrombosis', 'Disease', (84, 94))	('CBS', 'Gene', (23, 26))	('Marfan syndrome', 'Disease', (143, 158))	('mental retardation', 'Disease', (64, 82))	('mental retardation', 'Disease', 'MESH:D008607', (64, 82))	('mental retardation', 'Phenotype', 'HP:0001249', (64, 82))	('ectopia lentis', 'Phenotype', 'HP:0001083', (96, 110))	('thrombosis', 'Disease', 'MESH:D013927', (84, 94))	('pneumothorax', 'Disease', (48, 60))	('ectopia lentis', 'Disease', (96, 110))
45724	31100816	Like CBS mutations, CSE mutations result in elevated methionine and homocysteine as well as cystathionine.	('methionine', 'Chemical', 'MESH:D008715', (53, 63))	('elevated', 'PosReg', (44, 52))	('cystathionine', 'MPA', (92, 105))	('mutations', 'Var', (9, 18))	('CBS', 'Gene', (5, 8))	('CSE', 'Gene', (20, 23))	('homocysteine', 'Chemical', 'MESH:D006710', (68, 80))	('elevated methionine', 'Phenotype', 'HP:0003235', (44, 63))	('cystathionine', 'Chemical', 'MESH:D003540', (92, 105))	('mutations', 'Var', (24, 33))
45726	31100816	Treatment of humanized CBS mice, a model mimicking the reduced level of CBS activity caused by mutations in humans, with betaine reduces Hcy levels and ameliorates much of the toxicity induced by Hcy.	('human', 'Species', '9606', (13, 18))	('mice', 'Species', '10090', (27, 31))	('betaine reduces Hcy', 'Phenotype', 'HP:0011905', (121, 140))	('Hcy', 'Chemical', 'MESH:D006710', (137, 140))	('reduces', 'NegReg', (129, 136))	('toxicity', 'Disease', 'MESH:D064420', (176, 184))	('Hcy', 'Chemical', 'MESH:D006710', (196, 199))	('human', 'Species', '9606', (108, 113))	('betaine', 'Chemical', 'MESH:D001622', (121, 128))	('mutations', 'Var', (95, 104))	('toxicity', 'Disease', (176, 184))	('Hcy levels', 'MPA', (137, 147))	('humans', 'Species', '9606', (108, 114))	('ameliorates', 'PosReg', (152, 163))
45731	31100816	Breast cancer cells harboring oncogenic PI3KCA mutations (E545K or H1047R) are dependent on extracellular methionine and cannot regenerate methionine from Hcy.	('PI3KCA', 'Gene', (40, 46))	('E545K', 'Mutation', 'p.E545K', (58, 63))	('methionine', 'Chemical', 'MESH:D008715', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('H1047R', 'Var', (67, 73))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('dependent', 'MPA', (79, 88))	('E545K', 'Var', (58, 63))	('H1047R', 'Mutation', 'p.H1047R', (67, 73))	('methionine', 'Chemical', 'MESH:D008715', (106, 116))	('extracellular', 'cellular_component', 'GO:0005576', ('92', '105'))	('Hcy', 'Chemical', 'MESH:D006710', (155, 158))	('Breast cancer', 'Disease', (0, 13))
45732	31100816	These PI3KCA mutations activate AKT to phosphorylate xCT and suppress cystine/glutamate antiport activity.	('activate', 'PosReg', (23, 31))	('glutamate', 'Chemical', 'MESH:D018698', (78, 87))	('AKT', 'Gene', '207', (32, 35))	('cystine', 'Chemical', 'MESH:D003553', (70, 77))	('PI3KCA', 'Gene', (6, 12))	('phosphorylate xCT', 'MPA', (39, 56))	('AKT', 'Gene', (32, 35))	('antiport', 'biological_process', 'GO:0015982', ('88', '96'))	('suppress', 'NegReg', (61, 69))	('cystine/glutamate antiport activity', 'MPA', (70, 105))	('mutations', 'Var', (13, 22))	('antiport', 'molecular_function', 'GO:0015297', ('88', '96'))
45740	31100816	Inhibition of mTORC2 activity by nutrient deprivation causes export of glutamate by xCT to facilitate the uptake of extracellular cystine and the promotion of cellular survival in times of nutrient scarcity and cellular stress.	('mTORC2', 'Gene', '74343', (14, 20))	('promotion', 'PosReg', (146, 155))	('mTORC2', 'cellular_component', 'GO:0031932', ('14', '20'))	('export of glutamate by', 'MPA', (61, 83))	('cellular survival', 'CPA', (159, 176))	('uptake of extracellular cystine', 'MPA', (106, 137))	('uptake', 'biological_process', 'GO:0098657', ('106', '112'))	('uptake', 'biological_process', 'GO:0098739', ('106', '112'))	('facilitate', 'PosReg', (91, 101))	('Inhibition', 'Var', (0, 10))	('cystine', 'Chemical', 'MESH:D003553', (130, 137))	('extracellular', 'cellular_component', 'GO:0005576', ('116', '129'))	('mTORC2', 'Gene', (14, 20))	('glutamate', 'Chemical', 'MESH:D018698', (71, 80))
45759	31100816	Similarly, beta-mercaptoethanol rescues cysteine starvation induced by xCT inhibition.	('cysteine starvation', 'MPA', (40, 59))	('inhibition', 'Var', (75, 85))	('beta-mercaptoethanol', 'Chemical', 'MESH:D008623', (11, 31))	('cysteine', 'Chemical', 'MESH:D003545', (40, 48))	('xCT', 'Gene', (71, 74))	('rescues', 'PosReg', (32, 39))
45798	31100816	While possible that CHAC1 acts in a manner to scavenge cysteine from intracellular glutathione, knockdown of CHAC1 does not significantly alter cell death induced by erastin treatment.	('knockdown', 'Var', (96, 105))	('cysteine', 'Chemical', 'MESH:D003545', (55, 63))	('erastin', 'Chemical', 'MESH:C477224', (166, 173))	('CHAC1', 'Gene', (109, 114))	('CHAC1', 'Gene', (20, 25))	('glutathione', 'Chemical', 'MESH:D005978', (83, 94))	('CHAC1', 'Gene', '79094', (109, 114))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('CHAC1', 'Gene', '79094', (20, 25))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('scavenge cysteine from intracellular glutathione', 'MPA', (46, 94))
45816	31100816	Mutations in the human cystinosin gene CTNS lead to cystinosis, a disease characterized by rickets, renal failure, growth retardation, and eventually death.	('lead to', 'Reg', (44, 51))	('cystinosin', 'Gene', (23, 33))	('human', 'Species', '9606', (17, 22))	('cystinosin', 'Gene', '1497', (23, 33))	('growth retardation', 'Phenotype', 'HP:0001510', (115, 133))	('renal failure', 'Phenotype', 'HP:0000083', (100, 113))	('CTNS', 'Gene', (39, 43))	('rickets', 'Phenotype', 'HP:0002748', (91, 98))	('Mutations', 'Var', (0, 9))	('CTNS', 'Gene', '1497', (39, 43))	('cystinosis', 'Disease', (52, 62))	('cystinosis', 'Disease', 'MESH:D003554', (52, 62))	('growth retardation', 'Disease', 'MESH:D006130', (115, 133))	('cystinosin', 'molecular_function', 'GO:0015328', ('23', '33'))	('renal failure', 'Disease', 'MESH:D051437', (100, 113))	('growth retardation', 'Disease', (115, 133))	('renal failure', 'Disease', (100, 113))
45818	31100816	The mutations in cystinosin associated with the most severe form of cystinosis also poorly recruit mTOR to the lysosome.	('associated', 'Reg', (28, 38))	('poorly', 'NegReg', (84, 90))	('cystinosin', 'Gene', '1497', (17, 27))	('cystinosis', 'Disease', (68, 78))	('cystinosis', 'Disease', 'MESH:D003554', (68, 78))	('cystinosin', 'molecular_function', 'GO:0015328', ('17', '27'))	('cystinosin', 'Gene', (17, 27))	('mTOR', 'Gene', '2475', (99, 103))	('mutations', 'Var', (4, 13))	('mTOR', 'Gene', (99, 103))	('lysosome', 'cellular_component', 'GO:0005764', ('111', '119'))
45819	31100816	Mutant cystinosin leading to deregulated mTOR signaling could play an unappreciated role in amino acid response.	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('cystinosin', 'Gene', '1497', (7, 17))	('cystinosin', 'Gene', (7, 17))	('cystinosin', 'molecular_function', 'GO:0015328', ('7', '17'))	('Mutant', 'Var', (0, 6))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))
45837	31100816	Another limitation in our understanding of xCT necessity in cancers is a lack of a conditional mouse SLC7A11 knockout allele to study tumor specific deletion of xCT in vivo.	('deletion', 'Var', (149, 157))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('xCT', 'Gene', (161, 164))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (134, 139))	('mouse', 'Species', '10090', (95, 100))
45928	31143211	TQ effect on tracheal responsiveness was significantly enhanced with nordihydroguiaretic acid, quinacrine and also methylene blue.	('methylene', 'Var', (115, 124))	('nordihydroguiaretic acid', 'Chemical', '-', (69, 93))	('TQ', 'Chemical', 'MESH:C003466', (0, 2))	('quinacrine', 'Var', (95, 105))	('enhanced', 'PosReg', (55, 63))	('quinacrine', 'Chemical', 'MESH:D011796', (95, 105))	('nordihydroguiaretic acid', 'Var', (69, 93))	('tracheal responsiveness', 'MPA', (13, 36))	('methylene blue', 'Chemical', 'MESH:D008751', (115, 129))
45989	31143211	Significant increase in the number of monocyte and eosinophil in the LLF in the sensitized group pretreated with antagonists A  2B  compared to sensitized group pretreated with TQ has been observed.	('antagonists A', 'Var', (113, 126))	('TQ', 'Chemical', 'MESH:C003466', (177, 179))	('increase', 'PosReg', (12, 20))
46126	31024698	There was no significant change in tumor volume in the low-dose group compared with the control group.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('low-dose', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
46131	31024698	The IFN-gamma level in the spleen lymphocyte supernatant of the Lewis lung cancer model mice immunized in the control group (784.54 pg/ml) was lower than the low-dose group (832.67 pg/ml) (p > 0.05).	('IFN-gamma', 'Gene', '15978', (4, 13))	('lower', 'NegReg', (143, 148))	('784.54', 'Var', (125, 131))	('Lewis lung cancer', 'Disease', (64, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('Lewis lung cancer', 'Disease', 'MESH:D018827', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mice', 'Species', '10090', (88, 92))	('IFN-gamma', 'Gene', (4, 13))
46164	31024698	The concentration of IFN-gamma in 5 mug/ml group (886.31 pg/ml) was not statistically significant difference from the control group (p > 0.05).	('IFN-gamma', 'Gene', '15978', (21, 30))	('886.31', 'Var', (50, 56))	('mug', 'molecular_function', 'GO:0043739', ('36', '39'))	('IFN-gamma', 'Gene', (21, 30))
46212	31024698	The study has shown that if the TLR2 gene or MyD88 gene was knocked out, the mice were stimulated with the TLR2 agonist, and they were unable to induce DC cell maturation or induce B-cell activation (Fukata et al., 2008).	('mice', 'Species', '10090', (77, 81))	('TLR2', 'Gene', '24088', (32, 36))	('TLR2', 'Gene', (107, 111))	('MyD88', 'Gene', (45, 50))	('B-cell activation', 'CPA', (181, 198))	('TLR2', 'Gene', (32, 36))	('knocked out', 'Var', (60, 71))	('unable', 'NegReg', (135, 141))	('MyD88', 'Gene', '17874', (45, 50))	('B-cell activation', 'biological_process', 'GO:0042113', ('181', '198'))	('TLR2', 'Gene', '24088', (107, 111))	('cell maturation', 'biological_process', 'GO:0048469', ('155', '170'))
46226	30373585	The distribution according to the severity of obstruction in the COPD group was as follows: Grade 1 (FEV1 >= 80%) 35 patients (20.6%), Grade 2 (50% <= FEV1 < 80%) 103 patients (60.6%), Grade 3 (30% <= FEV1 < 50%) 24 patients (14.1%), and Grade 4 (FEV1 < 30%) 8 patients (4.7%).	('COPD', 'Gene', '260431', (65, 69))	('FEV1', 'Phenotype', 'HP:0032342', (247, 251))	('COPD', 'Phenotype', 'HP:0006510', (65, 69))	('FEV1', 'Phenotype', 'HP:0032342', (151, 155))	('COPD', 'Gene', (65, 69))	('patients', 'Species', '9606', (167, 175))	('50% <= FEV1', 'Var', (144, 155))	('patients', 'Species', '9606', (216, 224))	('30% <= FEV1', 'Var', (194, 205))	('FEV1', 'Phenotype', 'HP:0032342', (101, 105))	('patients', 'Species', '9606', (261, 269))	('patients', 'Species', '9606', (117, 125))	('FEV1', 'Phenotype', 'HP:0032342', (201, 205))
46254	30373585	The distribution of patients with COPD according to severity of the obstruction was classified into Grade 1 (FEV1 >= 80%), Grade 2 (50% <= FEV1 < 80%), Grade 3 (30% <= FEV1 < 50%), and Grade 4 (FEV1 < 30%).	('FEV1', 'Phenotype', 'HP:0032342', (109, 113))	('COPD', 'Phenotype', 'HP:0006510', (34, 38))	('COPD', 'Gene', (34, 38))	('FEV1', 'Phenotype', 'HP:0032342', (168, 172))	('patients', 'Species', '9606', (20, 28))	('50', 'Var', (132, 134))	('FEV1', 'Phenotype', 'HP:0032342', (139, 143))	('COPD', 'Gene', '260431', (34, 38))	('FEV1', 'Phenotype', 'HP:0032342', (194, 198))
46270	30373585	The distribution of patients with COPD according to severity of the airway obstruction was Grade 1 (FEV1 >= 80%) 35 patients (20.6%); Grade 2 (50% <= FEV1 < 80%) 103 patients (60.6%); Grade 3 (30% <= FEV1 < 50%) 24 patients (14.1%); and Grade 4 (FEV1 < 30%) 8 patients (4.7%).	('patients', 'Species', '9606', (215, 223))	('FEV1', 'Phenotype', 'HP:0032342', (246, 250))	('airway obstruction', 'Phenotype', 'HP:0002781', (68, 86))	('COPD', 'Phenotype', 'HP:0006510', (34, 38))	('30% <= FEV1', 'Var', (193, 204))	('COPD', 'Gene', (34, 38))	('patients', 'Species', '9606', (116, 124))	('FEV1', 'Phenotype', 'HP:0032342', (100, 104))	('FEV1', 'Phenotype', 'HP:0032342', (150, 154))	('50% <=', 'Var', (143, 149))	('patients', 'Species', '9606', (260, 268))	('patients', 'Species', '9606', (20, 28))	('FEV1', 'Phenotype', 'HP:0032342', (200, 204))	('COPD', 'Gene', '260431', (34, 38))	('patients', 'Species', '9606', (166, 174))
46285	30373585	Smoking is the major cause of lung cancer and is also known to cause various other diseases, including diabetes and cerebral cardiovascular diseases.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('Smoking', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('diabetes and cerebral cardiovascular diseases', 'Disease', 'MESH:D002318', (103, 148))	('cause', 'Reg', (63, 68))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (125, 148))	('cause', 'Reg', (21, 26))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))
46307	30373585	This finding is similar to that of a previous study, which reported that the presence of COPD has no significant effect on prognosis for lung cancer patients.	('patients', 'Species', '9606', (149, 157))	('COPD', 'Phenotype', 'HP:0006510', (89, 93))	('lung cancer', 'Disease', (137, 148))	('COPD', 'Gene', (89, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('presence', 'Var', (77, 85))	('COPD', 'Gene', '260431', (89, 93))
46317	30373585	However, no significant differences in prognosis were observed according to the presence of COPD in patients with advanced NSCLC.	('NSCLC', 'Disease', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('presence', 'Var', (80, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('patients', 'Species', '9606', (100, 108))	('COPD', 'Gene', '260431', (92, 96))	('COPD', 'Phenotype', 'HP:0006510', (92, 96))	('COPD', 'Gene', (92, 96))
46325	30338211	DM-exposed fetal lungs exhibited reduced numbers of alveoli, irregularities in the appearance and thickness of the alveolar septum, increased levels of glycogen and lipids in type II alveolar epithelial cells, fewer microvilli and mature lamellar bodies, and swollen mitochondria.	('lipids', 'Chemical', 'MESH:D008055', (165, 171))	('DM', 'Phenotype', 'HP:0000819', (0, 2))	('mitochondria', 'cellular_component', 'GO:0005739', ('267', '279'))	('fewer', 'NegReg', (210, 215))	('septum', 'cellular_component', 'GO:0030428', ('124', '130'))	('appearance', 'CPA', (83, 93))	('DM', 'Disease', 'MESH:D009223', (0, 2))	('increased', 'PosReg', (132, 141))	('glycogen', 'Chemical', 'MESH:D006003', (152, 160))	('irregularities', 'Var', (61, 75))	('reduced', 'NegReg', (33, 40))	('microvilli', 'CPA', (216, 226))	('microvilli', 'cellular_component', 'GO:0005902', ('216', '226'))
46328	30338211	In murine lung epithelial (MLE) 12 cells, p-AKT levels were increased by high glucose/insulin, but decreased by the Akt inhibitor MK2206 (P < 0.05).	('decreased', 'NegReg', (99, 108))	('high glucose', 'Phenotype', 'HP:0003074', (73, 85))	('insulin', 'molecular_function', 'GO:0016088', ('86', '93'))	('glucose', 'Chemical', 'MESH:D005947', (78, 85))	('insulin', 'Gene', (86, 93))	('AKT', 'Gene', (44, 47))	('murine', 'Species', '10090', (3, 9))	('MK2206', 'Chemical', 'MESH:C548887', (130, 136))	('AKT', 'Gene', '24185', (44, 47))	('insulin', 'Gene', '3630', (86, 93))	('high', 'Var', (73, 77))	('increased', 'PosReg', (60, 69))
46329	30338211	Expression of nuclear FOXA2 was increased by MK2206 compared with the high glucose/insulin group (P < 0.05).	('MK2206', 'Chemical', 'MESH:C548887', (45, 51))	('high glucose', 'Phenotype', 'HP:0003074', (70, 82))	('insulin', 'molecular_function', 'GO:0016088', ('83', '90'))	('Expression', 'MPA', (0, 10))	('glucose', 'Chemical', 'MESH:D005947', (75, 82))	('FOXA2', 'Gene', (22, 27))	('increased', 'PosReg', (32, 41))	('insulin', 'Gene', (83, 90))	('MK2206', 'Var', (45, 51))	('insulin', 'Gene', '3630', (83, 90))
46348	30338211	Akt/PKB can phosphorylate FOXA2 directly, resulting in p-FOXA2 being released from the nucleus into the cytoplasm 27, inhibiting the transcriptional activity of FOXA2 28.	('PKB', 'Gene', (4, 7))	('nucleus', 'cellular_component', 'GO:0005634', ('87', '94'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('104', '113'))	('p-FOXA2', 'Var', (55, 62))	('PKB', 'Gene', '11651;24185', (4, 7))	('inhibiting', 'NegReg', (118, 128))	('transcriptional activity', 'MPA', (133, 157))
46369	30338211	In order to study the effects of insulin resistance on FOXA2, an insulin resistance cell model was induced by different conditions of insulin and glucose [no treatment; 30 mm glucose and 25 nm insulin; 30 mm glucose; 25 nm insulin; and 5 mum MK22062 2HCl (Selleckchem, Houston, TX, USA)].	('insulin', 'molecular_function', 'GO:0016088', ('134', '141'))	('insulin', 'molecular_function', 'GO:0016088', ('65', '72'))	('insulin', 'Gene', '3630', (193, 200))	('insulin', 'Gene', '3630', (65, 72))	('MK22062 2HCl', 'Chemical', '-', (242, 254))	('insulin', 'Gene', '3630', (33, 40))	('insulin', 'Gene', '3630', (134, 141))	('insulin', 'molecular_function', 'GO:0016088', ('33', '40'))	('insulin', 'molecular_function', 'GO:0016088', ('223', '230'))	('insulin', 'Gene', '3630', (223, 230))	('insulin', 'Gene', (193, 200))	('MK22062', 'Var', (242, 249))	('glucose', 'Chemical', 'MESH:D005947', (146, 153))	('insulin resistance', 'Phenotype', 'HP:0000855', (33, 51))	('insulin', 'Gene', (65, 72))	('insulin resistance', 'Phenotype', 'HP:0000855', (65, 83))	('insulin', 'Gene', (33, 40))	('insulin', 'Gene', (134, 141))	('glucose', 'Chemical', 'MESH:D005947', (208, 215))	('insulin', 'molecular_function', 'GO:0016088', ('193', '200'))	('insulin', 'Gene', (223, 230))	('glucose', 'Chemical', 'MESH:D005947', (175, 182))
46422	30338211	The levels of p-AKT were the highest in the high glucose/insulin group and were decreased when cells under high glucose and insulin condition were treated with MK2206 (P < 0.05) (Fig.	('glucose', 'Chemical', 'MESH:D005947', (49, 56))	('insulin condition', 'Disease', (124, 141))	('insulin', 'Gene', (57, 64))	('MK2206', 'Var', (160, 166))	('high glucose', 'Phenotype', 'HP:0003074', (107, 119))	('insulin condition', 'Disease', 'MESH:D007333', (124, 141))	('insulin', 'Gene', '3630', (57, 64))	('insulin', 'molecular_function', 'GO:0016088', ('57', '64'))	('decreased', 'NegReg', (80, 89))	('AKT', 'Gene', (16, 19))	('AKT', 'Gene', '24185', (16, 19))	('glucose', 'Chemical', 'MESH:D005947', (112, 119))	('MK2206', 'Chemical', 'MESH:C548887', (160, 166))	('insulin', 'Gene', (124, 131))	('high glucose', 'Phenotype', 'HP:0003074', (44, 56))	('insulin', 'molecular_function', 'GO:0016088', ('124', '131'))	('insulin', 'Gene', '3630', (124, 131))
46424	30338211	Interestingly, the expression of nuclear FOXA2 was increased in the MK2206 group compared with the high glucose and insulin group (P < 0.05) (Fig.	('MK2206', 'Chemical', 'MESH:C548887', (68, 74))	('expression', 'MPA', (19, 29))	('FOXA2', 'Gene', (41, 46))	('increased', 'PosReg', (51, 60))	('MK2206', 'Var', (68, 74))	('insulin', 'Gene', (116, 123))	('high glucose', 'Phenotype', 'HP:0003074', (99, 111))	('insulin', 'Gene', '3630', (116, 123))	('insulin', 'molecular_function', 'GO:0016088', ('116', '123'))	('glucose', 'Chemical', 'MESH:D005947', (104, 111))
46426	30338211	The results suggested that changes in nuclear FOXA2 and p-FOXA2 in cells of the high glucose and insulin group could be partly reversed by MK2206.	('insulin', 'Gene', '3630', (97, 104))	('MK2206', 'Chemical', 'MESH:C548887', (139, 145))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('p-FOXA2', 'Gene', (56, 63))	('insulin', 'molecular_function', 'GO:0016088', ('97', '104'))	('MK2206', 'Var', (139, 145))	('insulin', 'Gene', (97, 104))
46427	30338211	The analysis of PARP and caspase 3 cleavage suggested that apoptosis was increased compared with controls under high glucose/insulin (P < 0.05), but was decreased by the addition of MK2206 (P < 0.05) (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('caspase 3', 'Gene', (25, 34))	('glucose', 'Chemical', 'MESH:D005947', (117, 124))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('insulin', 'Gene', '3630', (125, 132))	('MK2206', 'Chemical', 'MESH:C548887', (182, 188))	('insulin', 'molecular_function', 'GO:0016088', ('125', '132'))	('caspase 3', 'Gene', '25402', (25, 34))	('apoptosis', 'CPA', (59, 68))	('decreased', 'NegReg', (153, 162))	('MK2206', 'Var', (182, 188))	('high glucose', 'Phenotype', 'HP:0003074', (112, 124))	('insulin', 'Gene', (125, 132))
46428	30338211	Western blot and RT-PCR showed that the protein and mRNA expression levels of SP-B and SP-C in the high glucose and insulin group were lower compared with the control group (P < 0.05), but were increased after inhibition of the Akt pathway by MK-2206 (P < 0.05) (Fig.	('glucose', 'Chemical', 'MESH:D005947', (104, 111))	('Akt pathway', 'Pathway', (228, 239))	('protein', 'MPA', (40, 47))	('MK-2206', 'Chemical', 'MESH:C548887', (243, 250))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('SP-C', 'Gene', (87, 91))	('SP-C', 'Gene', '50683', (87, 91))	('increased', 'PosReg', (194, 203))	('SP-B', 'Gene', (78, 82))	('lower', 'NegReg', (135, 140))	('insulin', 'Gene', (116, 123))	('high glucose', 'Phenotype', 'HP:0003074', (99, 111))	('insulin', 'Gene', '3630', (116, 123))	('mRNA expression levels', 'MPA', (52, 74))	('insulin', 'molecular_function', 'GO:0016088', ('116', '123'))	('inhibition', 'NegReg', (210, 220))	('SP-B', 'Gene', '192155', (78, 82))	('MK-2206', 'Var', (243, 250))
46429	30338211	The results suggested that lower expression levels of SP-B and SP-C in the high glucose and insulin group could be partly reversed by MK2206.	('MK2206', 'Chemical', 'MESH:C548887', (134, 140))	('insulin', 'molecular_function', 'GO:0016088', ('92', '99'))	('insulin', 'Gene', (92, 99))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('SP-C', 'Gene', '50683', (63, 67))	('insulin', 'Gene', '3630', (92, 99))	('MK2206', 'Var', (134, 140))	('lower', 'NegReg', (27, 32))	('SP-B', 'Gene', (54, 58))	('SP-C', 'Gene', (63, 67))	('expression levels', 'MPA', (33, 50))	('SP-B', 'Gene', '192155', (54, 58))	('high glucose', 'Phenotype', 'HP:0003074', (75, 87))
46442	30338211	p-FOXA2 without transcriptional regulation could then be found in the plasma, affecting the differentiation of AECII and SP synthesis.	('affecting', 'Reg', (78, 87))	('SP', 'Chemical', '-', (121, 123))	('differentiation of AECII', 'CPA', (92, 116))	('SP synthesis', 'CPA', (121, 133))	('p-FOXA2', 'Var', (0, 7))	('synthesis', 'biological_process', 'GO:0009058', ('124', '133'))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))
46445	30338211	In the in vitro experiments, in which short-term high glucose and insulin induction were used, the protein and mRNA expression levels of both SP-B and SP-C in the high glucose and insulin group were lower compared with the control group, but were increased by MK2206.	('high glucose', 'Phenotype', 'HP:0003074', (49, 61))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('mRNA expression levels', 'MPA', (111, 133))	('insulin', 'Gene', (180, 187))	('MK2206', 'Var', (260, 266))	('insulin', 'molecular_function', 'GO:0016088', ('180', '187'))	('insulin', 'Gene', (66, 73))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('lower', 'NegReg', (199, 204))	('SP-C', 'Gene', (151, 155))	('high glucose', 'Phenotype', 'HP:0003074', (163, 175))	('glucose', 'Chemical', 'MESH:D005947', (168, 175))	('SP-C', 'Gene', '50683', (151, 155))	('protein', 'MPA', (99, 106))	('insulin', 'Gene', '3630', (180, 187))	('SP-B', 'Gene', '192155', (142, 146))	('insulin', 'molecular_function', 'GO:0016088', ('66', '73'))	('insulin', 'Gene', '3630', (66, 73))	('MK2206', 'Chemical', 'MESH:C548887', (260, 266))	('SP-B', 'Gene', (142, 146))
46446	30338211	The present study confirms that MK2206 reduces the phosphorylation of Akt, as supported by a previous study 27.	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('MK2206', 'Var', (32, 38))	('Akt', 'Pathway', (70, 73))	('phosphorylation', 'MPA', (51, 66))	('MK2206', 'Chemical', 'MESH:C548887', (32, 38))	('reduces', 'NegReg', (39, 46))
46460	30237723	Functional experiments showed knockdown of hsa_circ_0003998 restrained cell proliferation and invasion in NSCLC cells.	('hsa_circ_0003998', 'Gene', (43, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('restrained', 'NegReg', (60, 70))	('knockdown', 'Var', (30, 39))	('cell proliferation', 'CPA', (71, 89))	('NSCLC', 'Disease', (106, 111))
46461	30237723	In particular, hsa_circ_0003998 upregulated the expression of miR-326 target gene Notch1 through sponging miR-326.	('miR-326', 'Gene', (62, 69))	('hsa_circ_0003998', 'Var', (15, 31))	('Notch1', 'Gene', '4851', (82, 88))	('miR-326', 'Gene', '442900', (106, 113))	('miR-326', 'Gene', '442900', (62, 69))	('expression', 'MPA', (48, 58))	('miR-326', 'Gene', (106, 113))	('Notch1', 'Gene', (82, 88))	('upregulated', 'PosReg', (32, 43))
46471	30237723	Our data indicate that hsa_circ_0003998 exerts oncogenic functions in NSCLC.	('hsa_circ_0003998', 'Var', (23, 39))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('oncogenic functions', 'CPA', (47, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
46485	30237723	The wild-type and mutant hsa_circ_0003998 were cloned into pGL3-control vector.	('pGL3', 'Gene', '6391', (59, 63))	('hsa_circ_0003998', 'Gene', (25, 41))	('mutant', 'Var', (18, 24))	('pGL', 'molecular_function', 'GO:0004598', ('59', '62'))	('pGL3', 'Gene', (59, 63))
46497	30237723	As shown in Figure 1B, hsa_circ_0003998 was significantly upregulated in NSCLC tissues compared with normal tissue.	('hsa_circ_0003998', 'Var', (23, 39))	('upregulated', 'PosReg', (58, 69))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
46500	30237723	To confirm the functional role of hsa_circ_0003998 in NSCLC, siRNA for hsa_circ_0003998 was transfected into A549 and H1299 cells.	('hsa_circ_0003998', 'Var', (71, 87))	('H1299', 'CellLine', 'CVCL:0060', (118, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('NSCLC', 'Disease', (54, 59))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
46502	30237723	In addition, invasion assays indicated that hsa_circ_0003998 knockdown significantly reduced the invasive capacity of A549 and H1299 cells (Figure 2E).	('hsa_circ_0003998', 'Gene', (44, 60))	('knockdown', 'Var', (61, 70))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('reduced', 'NegReg', (85, 92))	('H1299', 'CellLine', 'CVCL:0060', (127, 132))
46506	30237723	After knockdown of hsa_circ_0003998, miR-326 expression was increased compared with control (Figure 3D).	('miR-326', 'Gene', '442900', (37, 44))	('expression', 'MPA', (45, 55))	('miR-326', 'Gene', (37, 44))	('knockdown', 'Var', (6, 15))	('increased', 'PosReg', (60, 69))	('hsa_circ_0003998', 'Var', (19, 35))
46512	30237723	CCK-8, colony formation, and invasion assays showed that the miR-326 inhibitor rescued the suppressive roles of si-hsa_circ_0003998 (Figure 4C-E).	('miR-326', 'Gene', (61, 68))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))	('suppressive roles', 'MPA', (91, 108))	('si-hsa_circ_0003998', 'Var', (112, 131))	('miR-326', 'Gene', '442900', (61, 68))
46514	30237723	As shown in Figure 5A and B, silencing of hsa_circ_0003998 significantly reduced the mRNA and protein expression levels of Notch1, while the miR-326 inhibitor increased the mRNA and protein expression levels of Notch1 in H1299 cells.	('miR-326', 'Gene', (141, 148))	('Notch1', 'Gene', '4851', (123, 129))	('silencing', 'Var', (29, 38))	('miR-326', 'Gene', '442900', (141, 148))	('reduced', 'NegReg', (73, 80))	('H1299', 'CellLine', 'CVCL:0060', (221, 226))	('increased', 'PosReg', (159, 168))	('hsa_circ_0003998', 'Gene', (42, 58))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('Notch1', 'Gene', (211, 217))	('Notch1', 'Gene', '4851', (211, 217))	('Notch1', 'Gene', (123, 129))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
46518	30237723	These results suggest that hsa_circ_0003998 may exert oncogenic functions by modulating miR-326/Notch1.	('miR-326', 'Gene', '442900', (88, 95))	('Notch1', 'Gene', (96, 102))	('Notch1', 'Gene', '4851', (96, 102))	('oncogenic functions', 'CPA', (54, 73))	('hsa_circ_0003998', 'Var', (27, 43))	('miR-326', 'Gene', (88, 95))	('modulating', 'Reg', (77, 87))
46520	30237723	In this report, we demonstrated that a high expression level of hsa_circ_0003998 in NSCLC patients was associated with larger tumor size and lymph-node metastasis.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('hsa_circ_0003998', 'Var', (64, 80))	('associated', 'Reg', (103, 113))	('expression level', 'MPA', (44, 60))	('NSCLC', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('lymph-node metastasis', 'CPA', (141, 162))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', (126, 131))
46521	30237723	These results suggest that hsa_circ_0003998 may be used as a potential predictor of prognosis in NSCLC.	('NSCLC', 'Disease', (97, 102))	('hsa_circ_0003998', 'Var', (27, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))
46527	30237723	Here, we employed bioinformatics analysis and provide evidence that the hsa_circ_0003998 plays an oncogenic role in lung pathogenesis via the modulation of miR-326.	('modulation', 'Reg', (142, 152))	('miR-326', 'Gene', (156, 163))	('lung pathogenesis', 'Disease', (116, 133))	('pathogenesis', 'biological_process', 'GO:0009405', ('121', '133'))	('hsa_circ_0003998', 'Var', (72, 88))	('miR-326', 'Gene', '442900', (156, 163))
46534	30237723	Functional experiments showed hsa_circ_0003998 acted as an oncogene in NSCLC via modulating miR-326/Notch1.	('miR-326', 'Gene', '442900', (92, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('Notch1', 'Gene', (100, 106))	('hsa_circ_0003998', 'Var', (30, 46))	('Notch1', 'Gene', '4851', (100, 106))	('miR-326', 'Gene', (92, 99))	('NSCLC', 'Disease', (71, 76))	('modulating', 'Reg', (81, 91))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
46535	30237723	Our data suggest that hsa_circ_0003998 may have considerable potential as a prognostic predictor and therapeutic target in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Disease', (123, 128))	('hsa_circ_0003998', 'Var', (22, 38))
46542	29441722	Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung.	('lung', 'Disease', (82, 86))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('KPS', 'Var', (7, 10))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
46554	29441722	Recent trials have shown the addition of WBRT to SRS does not improve survival outcomes, and WBRT causes significant declines in neurocognition and overall quality of life (QOL) for patients with 1-3 BM 6, 7.	('declines in neurocognition', 'Disease', 'MESH:D060825', (117, 143))	('WBRT', 'Var', (93, 97))	('patients', 'Species', '9606', (182, 190))	('declines in neurocognition', 'Disease', (117, 143))
46610	29441722	We found those with total tumor volume >10 cc and KPS <80 had a median OS of 1.63 months compared to 7.87 months for all patients that did not meet all these criteria (P = 0.02).	('to 7', 'Species', '1214577', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('KPS <80', 'Var', (50, 57))	('OS', 'Chemical', '-', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('patients', 'Species', '9606', (121, 129))
46626	29441722	Secondary factors including female sex, age <65, KPS >=80, stable extracranial disease, and the absence of neurologic symptoms were significantly associated with longer OS in JLGK0901 10.	('JLGK0901', 'Gene', (175, 183))	('absence of neurologic symptoms', 'Disease', (96, 126))	('OS', 'Chemical', '-', (169, 171))	('absence of neurologic symptoms', 'Disease', 'MESH:D009422', (96, 126))	('KPS >=80', 'Var', (49, 57))	('stable extracranial disease', 'Disease', (59, 86))
46627	29441722	In our analysis, histology and KPS (along with tumor volume) were significantly associated with OS on MVA.	('OS on MVA', 'Disease', (96, 105))	('KPS', 'Var', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('associated', 'Reg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('OS', 'Chemical', '-', (96, 98))
46630	29441722	Additionally, we identified a high-risk cohort, namely histology other than breast cancer, tumor volume >10 cc, and KPS <80.	('KPS <80', 'Var', (116, 123))	('>10', 'Var', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('tumor', 'Disease', (91, 96))
46648	29503876	PIK3CA mutation is associated with increased local failure in lung stereotactic body radiation therapy (SBRT) An examination of mutations in PIK3CA signaling pathways and radioresistance.	('failure in lung', 'Phenotype', 'HP:0010444', (51, 66))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('increased local failure', 'Disease', (35, 58))	('PIK3CA', 'Gene', (0, 6))	('increased local failure', 'Disease', 'MESH:D012594', (35, 58))	('PIK3CA', 'Gene', (141, 147))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))	('stereotactic body', 'Phenotype', 'HP:0000733', (67, 84))	('PIK3CA', 'Gene', '5290', (141, 147))	('associated with', 'Reg', (19, 34))
46649	29503876	PIK3CA mutation was found to be associated with local failure after lung SBRT.	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))	('associated with', 'Reg', (32, 47))	('local failure', 'Disease', (48, 61))	('local failure', 'Disease', 'MESH:D012594', (48, 61))
46651	29503876	Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT.	('associated with', 'Reg', (92, 107))	('local failure', 'Disease', (108, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('signaling pathway', 'biological_process', 'GO:0007165', ('70', '87'))	('local failure', 'Disease', 'MESH:D012594', (108, 121))	('AKT', 'Gene', (59, 62))	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', '1956', (54, 58))	('PIK3CA', 'Gene', (63, 69))	('AKT', 'Gene', '207', (59, 62))	('PIK3CA', 'Gene', '5290', (63, 69))	('EGFR', 'Gene', (54, 58))
46653	29503876	Six patients (4%) had PIK3CA mutation, 36 patients (22%) had EGFR mutation, and one patient (0.6%) had AKT1 mutation.	('mutation', 'Var', (29, 37))	('PIK3CA', 'Gene', '5290', (22, 28))	('AKT1', 'Gene', '207', (103, 107))	('AKT1', 'Gene', (103, 107))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (42, 49))	('patient', 'Species', '9606', (84, 91))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (4, 12))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('patients', 'Species', '9606', (42, 50))	('PIK3CA', 'Gene', (22, 28))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
46655	29503876	On univariate analysis, PIK3CA mutation was associated with LF (HR 10.44 [95% CI 2.16-50.46], p = .003), while tumor histology, tumor size, primary tumor site, BED and EGFR mutation were not.	('associated', 'Reg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('EGFR', 'Gene', '1956', (168, 172))	('PIK3CA', 'Gene', (24, 30))	('EGFR', 'Gene', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('tumor', 'Disease', (148, 153))	('mutation', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (111, 116))	('PIK3CA', 'Gene', '5290', (24, 30))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
46656	29503876	At one year, probability of LF in lesions with PIK3CA mutation was 20.0% vs. 2.9% in lesions without mutation (p < .001 by log rank test).	('mutation', 'Var', (54, 62))	('PIK3CA', 'Gene', (47, 53))	('PIK3CA', 'Gene', '5290', (47, 53))
46657	29503876	Although the number of patients affected was small, PIK3CA mutation was significantly associated with higher risk of LF in patients undergoing lung SBRT.	('patients', 'Species', '9606', (23, 31))	('PIK3CA', 'Gene', (52, 58))	('patients', 'Species', '9606', (123, 131))	('associated', 'Reg', (86, 96))	('mutation', 'Var', (59, 67))	('PIK3CA', 'Gene', '5290', (52, 58))
46659	29503876	Following growth factor stimulation and activation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), PI3K (consisting of regulatory and catalytic subunits) is recruited to the cellular membrane.	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('cellular membrane', 'cellular_component', 'GO:0005886', ('204', '221'))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('PI3K', 'Var', (129, 133))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('88', '111'))	('EGFR', 'Gene', '1956', (122, 126))	('epidermal growth factor receptor', 'Gene', (88, 120))	('EGFR', 'Gene', (122, 126))
46661	29503876	Mutations in PIK3CA, the gene that encodes the catalytic subunit of PI3K, have been reported in 2-5% of non-small cell lung cancers in 6-40% of other solid tumors such as breast, liver, and colon.	('solid tumors', 'Disease', (150, 162))	('PIK3CA', 'Gene', (13, 19))	('breast', 'Disease', (171, 177))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (108, 131))	('liver', 'Disease', (179, 184))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (104, 131))	('Mutations', 'Var', (0, 9))	('solid tumors', 'Disease', 'MESH:D009369', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('lung cancers', 'Phenotype', 'HP:0100526', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PIK3CA', 'Gene', '5290', (13, 19))	('colon', 'Disease', (190, 195))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('non-small cell lung cancers', 'Disease', (104, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (104, 131))	('reported', 'Reg', (84, 92))
46662	29503876	It is unknown whether mutations in the PI3K pathway confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT).	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('patients', 'Species', '9606', (88, 96))	('stereotactic body', 'Phenotype', 'HP:0000733', (114, 131))	('PI3K pathway', 'Pathway', (39, 51))	('local control', 'MPA', (70, 83))	('mutations', 'Var', (22, 31))
46675	29503876	Six patients (4%) had PIK3CA mutation, 36 patients (21%) had EGFR mutation, and one patient (0.6%) had AKT mutation.	('mutation', 'Var', (29, 37))	('AKT', 'Gene', '207', (103, 106))	('PIK3CA', 'Gene', '5290', (22, 28))	('AKT', 'Gene', (103, 106))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (42, 49))	('patient', 'Species', '9606', (84, 91))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (4, 12))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('patients', 'Species', '9606', (42, 50))	('PIK3CA', 'Gene', (22, 28))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
46677	29503876	On univariate analysis, PIK3CA mutation was associated with increased LF (HR 10.44 [95% CI 2.16-50.46]), p = .003 (and remained p < .05 after Bonferroni multiple testing correction), while tumor histology (adenocarcinoma vs. other), tumor size (<=2 cm vs. >2 cm), primary tumor site (lung vs. other), prescription biologically effective dose (BED) (<100 Gy versus >=100 Gy) and EGFR mutation presence were not, Table 2.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('EGFR', 'Gene', '1956', (378, 382))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (189, 194))	('PIK3CA', 'Gene', (24, 30))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (272, 277))	('EGFR', 'Gene', (378, 382))	('mutation', 'Var', (31, 39))	('adenocarcinoma', 'Disease', (206, 220))	('EGFR', 'molecular_function', 'GO:0005006', ('378', '382'))	('PIK3CA', 'Gene', '5290', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('adenocarcinoma', 'Disease', 'MESH:D000230', (206, 220))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('increased', 'PosReg', (60, 69))
46678	29503876	There were too few events for multivariate analysis, but all tumors with PIK3CA mutation were <=3.2 cm in size and all but one of the tumors with PIK3CA mutation received BED >100 Gy.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('PIK3CA', 'Gene', '5290', (73, 79))	('PIK3CA', 'Gene', '5290', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PIK3CA', 'Gene', (73, 79))	('PIK3CA', 'Gene', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutation', 'Var', (80, 88))
46680	29503876	At one year, probability of LF in lesions with PIK3CA mutations was 20.0% vs. 2.9% in lesions without mutations (p < .001 by log-rank test), Fig.	('PIK3CA', 'Gene', (47, 53))	('mutations', 'Var', (54, 63))	('PIK3CA', 'Gene', '5290', (47, 53))
46683	29503876	PIK3CA mutations are an attractive area of study due to the opportunity for pharmacokinetic inhibition.	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
46685	29503876	Associations between PIK3CA mutations and outcomes have shown conflicting results in the literature.	('Associations', 'Interaction', (0, 12))	('mutations', 'Var', (28, 37))	('PIK3CA', 'Gene', (21, 27))	('PIK3CA', 'Gene', '5290', (21, 27))
46686	29503876	PIK3CA mutations have demonstrated association with improved overall survival in squamous cell lung cancer and breast cancer yet decreased progression-free survival in lung adenocarcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (81, 106))	('improved', 'PosReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('progression-free', 'MPA', (139, 155))	('PIK3CA', 'Gene', (0, 6))	('squamous cell lung cancer', 'Disease', (81, 106))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('PIK3CA', 'Gene', '5290', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('breast cancer', 'Disease', (111, 124))	('lung adenocarcinoma', 'Disease', (168, 187))	('overall', 'MPA', (61, 68))	('decreased', 'NegReg', (129, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (168, 187))	('mutations', 'Var', (7, 16))
46688	29503876	reported that following chemoradiation, overall survival was not significantly different among the three groups of wild-type versus EGFR-ALK versus other mutations.	('EGFR', 'Gene', '1956', (132, 136))	('ALK', 'Gene', (137, 140))	('EGFR', 'Gene', (132, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('mutations', 'Var', (154, 163))	('ALK', 'Gene', '238', (137, 140))
46690	29503876	We found PIK3CA mutation was significantly associated with higher risk of LF in patients undergoing lung SBRT.	('mutation', 'Var', (16, 24))	('patients', 'Species', '9606', (80, 88))	('associated', 'Reg', (43, 53))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))
46692	29503876	Association between PIK3CA mutation and outcome after lung SBRT has not previously been reported.	('mutation', 'Var', (27, 35))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))
46694	29503876	Hyperactivation of the PI3K pathway has been associated with radioresistance in vitro; it is unclear whether PIK3CA mutations confer increased local failure following lung SBRT.	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('local failure', 'Disease', (143, 156))	('PI3K pathway', 'Pathway', (23, 35))	('mutations', 'Var', (116, 125))	('local failure', 'Disease', 'MESH:D012594', (143, 156))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))
46695	29503876	We found PIK3CA mutation was associated with higher local failure following lung SBRT.	('local failure', 'Disease', 'MESH:D012594', (52, 65))	('mutation', 'Var', (16, 24))	('local failure', 'Disease', (52, 65))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))
46720	29296228	Among 208 primary pulmonary adenocarcinomas, 84 nodules staged as T1aN0M0, 96 T1bN0M0and 28 T1cN0M0 (Table 3).	('T1aN0M0', 'Var', (66, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('T1bN0M0and', 'Var', (78, 88))	('pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (18, 43))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (18, 42))	('pulmonary adenocarcinomas', 'Disease', (18, 43))
46852	28878195	As shown in Figure 3A-D, compared with TGF-beta-treated cells, 1alpha,25(OH)2D3 increased the expression of E-cadherin, and decreased the expressions of N-cadherin and Vimentin.	('E-cadherin', 'Gene', (108, 118))	('Vimentin', 'Gene', (168, 176))	('E-cadherin', 'Gene', '999', (108, 118))	('cadherin', 'molecular_function', 'GO:0008014', ('155', '163'))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (63, 79))	('Vimentin', 'cellular_component', 'GO:0045099', ('168', '176'))	('increased', 'PosReg', (80, 89))	('Vimentin', 'Gene', '7431', (168, 176))	('Vimentin', 'cellular_component', 'GO:0045098', ('168', '176'))	('decreased', 'NegReg', (124, 133))	('expressions', 'MPA', (138, 149))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('expression', 'MPA', (94, 104))	('N-cadherin', 'Gene', (153, 163))	('1alpha,25(OH)2D3', 'Var', (63, 79))	('N-cadherin', 'Gene', '1000', (153, 163))
46898	28878195	Our present study found that TGF-beta stimulated the total expression of beta-catenin in a time-dependent manner and the combination of 1alpha,25(OH)2D3 and TGF-beta constrained the expression the beta-catenin.	('beta-catenin', 'Gene', (73, 85))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (136, 152))	('expression', 'MPA', (182, 192))	('combination', 'Var', (121, 132))	('beta-catenin', 'Gene', (197, 209))	('TGF-beta', 'Gene', (29, 37))	('beta-catenin', 'Gene', '1499', (73, 85))	('expression', 'MPA', (59, 69))	('stimulated', 'PosReg', (38, 48))	('beta-catenin', 'Gene', '1499', (197, 209))	('TGF-beta', 'Gene', (157, 165))
46905	28878195	In addition, we previously found that 1,25(OH)2D3 could inhibit cell growth at a dose of 50 nM or higher in other cell lines.	('1,25(OH)2D3', 'Var', (38, 49))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('cell growth', 'CPA', (64, 75))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (38, 49))	('inhibit', 'NegReg', (56, 63))
46917	28918047	Moreover, BC032913 enhanced the mRNA and protein expression of TIMP3 and inhibited Wnt/beta-catenin pathway activity, thus suppressing CRC metastasis in vitro and in vivo.	('BC032913', 'Chemical', '-', (10, 18))	('si', 'Chemical', 'MESH:D012825', (146, 148))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('BC032913', 'Var', (10, 18))	('suppressing', 'NegReg', (123, 134))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('CRC metastasis', 'CPA', (135, 149))	('inhibited', 'NegReg', (73, 82))	('TIMP3', 'Gene', (63, 68))	('CRC', 'Phenotype', 'HP:0003003', (135, 138))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('Wnt/beta-catenin pathway', 'Pathway', (83, 107))	('enhanced', 'PosReg', (19, 27))
46918	28918047	Collectively, the obtained data show that BC032913 plays an inhibitory role in CRC aggression by upregulating TIMP3, followed by inactivation of the Wnt/beta-catenin pathway.	('CRC aggression', 'Disease', 'MESH:D015179', (79, 93))	('BC032913', 'Chemical', '-', (42, 50))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('Wnt/beta-catenin pathway', 'Pathway', (149, 173))	('BC032913', 'Var', (42, 50))	('inactivation', 'NegReg', (129, 141))	('CRC aggression', 'Disease', (79, 93))	('upregulating', 'PosReg', (97, 109))	('TIMP3', 'MPA', (110, 115))	('aggression', 'Phenotype', 'HP:0000718', (83, 93))	('aggression', 'biological_process', 'GO:0002118', ('83', '93'))
46919	28918047	Our findings indicate that the novel lncRNA BC032913 could serve as a novel prognostic marker and effective therapeutic target for CRC.	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('BC032913', 'Chemical', '-', (44, 52))	('CRC', 'Disease', (131, 134))	('BC032913', 'Var', (44, 52))
46927	28918047	In recent years, increasing evidence has demonstrated that lncRNAs participate in the pathogenesis of multiple diseases through various mechanisms of downstream gene regulation, such as epigenetic, post-transcriptional, and transcriptional regulation.	('epigenetic', 'Var', (186, 196))	('regulation', 'biological_process', 'GO:0065007', ('166', '176'))	('participate', 'Reg', (67, 78))	('multiple diseases', 'Disease', (102, 119))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('regulation', 'biological_process', 'GO:0065007', ('240', '250'))	('pathogenesis', 'biological_process', 'GO:0009405', ('86', '98'))	('lncRNAs', 'Gene', (59, 66))
46938	28918047	Previous studies have indicated that alternative factors are involved in CRC pathogenesis, including genetic alternations in oncogenes or tumor suppressor genes, as well as changes in the transforming growth factor beta (TGF-beta) and Wnt signaling pathways.	('tumor', 'Disease', (138, 143))	('alternations', 'Var', (109, 121))	('Wnt signaling pathways', 'Pathway', (235, 257))	('transforming growth factor beta', 'Gene', (188, 219))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('changes', 'Reg', (173, 180))	('si', 'Chemical', 'MESH:D012825', (239, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('transforming growth factor beta', 'Gene', '7040', (188, 219))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CRC', 'Disease', (73, 76))	('genetic alternations', 'Var', (101, 121))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('TGF-beta', 'Gene', '7040', (221, 229))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('oncogenes', 'Gene', (125, 134))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('188', '219'))	('TGF-beta', 'Gene', (221, 229))	('pathogenesis', 'biological_process', 'GO:0009405', ('77', '89'))
46945	28918047	It has been documented that aberrant methylation of TIMP-3 occurs in primary cancers of the colon, lung, breast, kidney, and brain.	('lung', 'Disease', (99, 103))	('brain', 'Disease', (125, 130))	('cancers of the colon', 'Disease', 'MESH:D015179', (77, 97))	('kidney', 'Disease', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('TIMP-3', 'Gene', (52, 58))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('aberrant', 'Var', (28, 36))	('TIMP-3', 'Gene', '7078', (52, 58))	('occurs', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast', 'Disease', (105, 111))	('cancers of the colon', 'Disease', (77, 97))	('methylation', 'MPA', (37, 48))
46946	28918047	Such tumor-specific methylation is associated with a lack of the TIMP-3 protein.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('TIMP-3', 'Gene', (65, 71))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('methylation', 'Var', (20, 31))	('tumor', 'Disease', (5, 10))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('lack', 'NegReg', (53, 57))	('TIMP-3', 'Gene', '7078', (65, 71))
46954	28918047	Here we demonstrate for the first time that lncRNA BC032913 suppresses CRC metastasis through upregulating TIMP3 expression, followed by inhibition of the nuclear translocation of beta-catenin, which inactivates the Wnt/beta-catenin pathway.	('expression', 'MPA', (113, 123))	('beta-catenin', 'Protein', (180, 192))	('CRC', 'Disease', (71, 74))	('suppresses', 'NegReg', (60, 70))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('nuclear translocation', 'MPA', (155, 176))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('BC032913', 'Chemical', '-', (51, 59))	('inhibition', 'NegReg', (137, 147))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('upregulating', 'PosReg', (94, 106))	('TIMP3', 'Gene', (107, 112))	('Wnt/beta-catenin', 'Pathway', (216, 232))	('lncRNA BC032913', 'Var', (44, 59))
46962	28918047	The results indicated that ENST00000502715 and ENST00000418454 were increased in CRC, whereas the levels of BC029135, NR_003191, and BC032913 were decreased (Figure 1B).	('ENST00000418454', 'Var', (47, 62))	('CRC', 'Disease', (81, 84))	('BC032913', 'Chemical', '-', (133, 141))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('ENST00000502715', 'Var', (27, 42))	('increased', 'PosReg', (68, 77))
46970	28918047	Kaplan-Meier survival analysis showed that the low-level group was associated with poor OS in CRC patients (p = 0.028' Figure 1D).	('patients', 'Species', '9606', (98, 106))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('poor OS', 'Disease', (83, 90))	('low-level', 'Var', (47, 56))	('CRC', 'Disease', (94, 97))	('si', 'Chemical', 'MESH:D012825', (27, 29))
46971	28918047	These clinical data suggested that BC032913 could affect CRC metastasis and serve as a novel prognostic marker for CRC.	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('BC032913', 'Chemical', '-', (35, 43))	('CRC', 'Disease', (115, 118))	('BC032913', 'Var', (35, 43))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('affect', 'Reg', (50, 56))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('CRC', 'Disease', (57, 60))
46974	28918047	Thus, we conducted migration, invasion, and sphere-forming assays, and the results demonstrated that ectopic BC032913 expression caused significant suppression of cell migration in both HCT116 and DLD-1 cells compared with cells transfected with an empty vector (p < 0.05; Figure 2A).	('cell migration', 'biological_process', 'GO:0016477', ('163', '177'))	('ectopic', 'Var', (101, 108))	('BC032913', 'Gene', (109, 117))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('cell migration', 'CPA', (163, 177))	('suppression', 'NegReg', (148, 159))	('BC032913', 'Chemical', '-', (109, 117))	('HCT116', 'CellLine', 'CVCL:0291', (186, 192))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('si', 'Chemical', 'MESH:D012825', (155, 157))
46976	28918047	Overexpression of BC032913 resulted in the formation of fewer and smaller spheres (p < 0.05; Figure 2C).	('BC032913', 'Chemical', '-', (18, 26))	('fewer', 'NegReg', (56, 61))	('smaller', 'NegReg', (66, 73))	('BC032913', 'Var', (18, 26))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('si', 'Chemical', 'MESH:D012825', (10, 12))
46978	28918047	To explore the mechanism underlying the inhibition of an aggressive phenotype by BC032913, metastasis-related genes that were deregulated between HCT116 cells stably transfected with pLNCX2-BC032913 (HCT116-BC032913) or pLNCX2 (HCT116-control) were determined using a human tumor metastasis PCR array.	('pLNCX2-BC032913', 'Var', (183, 198))	('tumor metastasis', 'Disease', (274, 290))	('si', 'Chemical', 'MESH:D012825', (287, 289))	('human', 'Species', '9606', (268, 273))	('BC032913', 'Chemical', '-', (207, 215))	('BC032913', 'Gene', (81, 89))	('BC032913', 'Chemical', '-', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('HCT116', 'CellLine', 'CVCL:0291', (200, 206))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('BC032913', 'Chemical', '-', (81, 89))	('HCT116', 'CellLine', 'CVCL:0291', (146, 152))	('deregulated', 'PosReg', (126, 137))	('metastasis-related genes', 'Gene', (91, 115))	('HCT116', 'CellLine', 'CVCL:0291', (228, 234))	('tumor metastasis', 'Disease', 'MESH:D009362', (274, 290))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (261, 263))
46984	28918047	Western blot analyses showed that the protein levels of TIMP3 were elevated in both the HCT116-BC032913 and DLD-1-BC032913 cell lines compared with the corresponding control cell lines (Figure 3E).	('BC032913', 'Chemical', '-', (114, 122))	('elevated', 'PosReg', (67, 75))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('BC032913', 'Chemical', '-', (95, 103))	('protein levels', 'MPA', (38, 52))	('HCT116', 'CellLine', 'CVCL:0291', (88, 94))	('HCT116-BC032913', 'Var', (88, 103))
46987	28918047	The above data indicate that BC032913 could upregulate TIMP3 expression and inhibit the activity of the Wnt/beta-catenin pathway.	('TIMP3', 'Gene', (55, 60))	('inhibit', 'NegReg', (76, 83))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('BC032913', 'Chemical', '-', (29, 37))	('upregulate', 'PosReg', (44, 54))	('activity', 'MPA', (88, 96))	('BC032913', 'Var', (29, 37))	('Wnt/beta-catenin pathway', 'Pathway', (104, 128))	('expression', 'MPA', (61, 71))
46988	28918047	First, it was confirmed that overexpression of TIMP3 suppressed the invasion capability (p < 0.05; Figure 4A), whereas knockdown of TIMP3 promoted invasion (p < 0.05; Figure 4B) in HCT-116 and DLD-1 cells.	('TIMP3', 'Gene', (132, 137))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('invasion', 'CPA', (147, 155))	('promoted', 'PosReg', (138, 146))	('knockdown', 'Var', (119, 128))	('invasion capability', 'CPA', (68, 87))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('HCT-116', 'CellLine', 'CVCL:0291', (181, 188))	('suppressed', 'NegReg', (53, 63))
46990	28918047	Compared with the negative control (HCT116-control/DLD1-control), stably expressed BC032913 (HCT116-BC032913/DLD1-BC032913) markedly reduced the number of invasive cells (p < 0.05; Figures 4C and 4D).	('si', 'Chemical', 'MESH:D012825', (159, 161))	('BC032913', 'Chemical', '-', (83, 91))	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('HCT116-BC032913/DLD1-BC032913', 'Var', (93, 122))	('BC032913', 'Chemical', '-', (114, 122))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))	('reduced', 'NegReg', (133, 140))	('BC032913', 'Chemical', '-', (100, 108))
46993	28918047	The results showed a clear decrease in luciferase activity in the presence of BC032913 and partial rescue by TIMP3 knockdown.	('BC032913', 'Var', (78, 86))	('luciferase', 'Enzyme', (39, 49))	('decrease', 'NegReg', (27, 35))	('luciferase activity', 'molecular_function', 'GO:0047077', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('39', '58'))	('TIMP3', 'Gene', (109, 114))	('activity', 'MPA', (50, 58))	('luciferase activity', 'molecular_function', 'GO:0047712', ('39', '58'))	('BC032913', 'Chemical', '-', (78, 86))	('luciferase activity', 'molecular_function', 'GO:0050248', ('39', '58'))
46994	28918047	Moreover, the western blot analysis shown in Figure 4F revealed that BC032913 increased TIMP3 and E-cadherin expression levels and decreased nuclear beta-catenin and CD44 expression levels compared with the corresponding negative control.	('BC032913', 'Chemical', '-', (69, 77))	('CD44', 'Gene', (166, 170))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('E-cadherin', 'Gene', (98, 108))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('BC032913', 'Var', (69, 77))	('decreased', 'NegReg', (131, 140))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('nuclear beta-catenin', 'MPA', (141, 161))	('E-cadherin', 'Gene', '999', (98, 108))	('increased', 'PosReg', (78, 87))	('CD44', 'Gene', '960', (166, 170))
46998	28918047	Compared with the control, fewer and much smaller lung micrometastases were observed in the HCT116-BC032913 group (p < 0.01; Figure 5A).	('HCT116', 'CellLine', 'CVCL:0291', (92, 98))	('smaller', 'NegReg', (42, 49))	('metastases', 'Disease', (60, 70))	('smaller lung', 'Phenotype', 'HP:0002089', (42, 54))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('BC032913', 'Chemical', '-', (99, 107))	('HCT116-BC032913', 'Var', (92, 107))
47001	28918047	Furthermore, we assessed the expression of TIPM3 and beta-catenin by real-time qPCR in lung and liver metastases originating from mice in the HCT116-control and HCT116-BC032913 groups.	('mice', 'Species', '10090', (130, 134))	('liver metastases', 'Disease', (96, 112))	('HCT116-BC032913', 'Var', (161, 176))	('beta-catenin', 'Protein', (53, 65))	('TIPM3', 'Gene', (43, 48))	('liver metastases', 'Disease', 'MESH:D009362', (96, 112))	('HCT116', 'CellLine', 'CVCL:0291', (161, 167))	('HCT116', 'CellLine', 'CVCL:0291', (142, 148))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('BC032913', 'Chemical', '-', (168, 176))
47002	28918047	The mRNA levels of TIMP3 and beta-catenin were increased and decreased, respectively, in mice in the HCT116-BC032913 group compared with mice in the HCT116-control group (p < 0.01; Figure 5C).	('mRNA levels', 'MPA', (4, 15))	('BC032913', 'Chemical', '-', (108, 116))	('mice', 'Species', '10090', (137, 141))	('mice', 'Species', '10090', (89, 93))	('increased', 'PosReg', (47, 56))	('HCT116-BC032913', 'Var', (101, 116))	('decreased', 'NegReg', (61, 70))	('HCT116', 'CellLine', 'CVCL:0291', (149, 155))	('TIMP3', 'MPA', (19, 24))	('beta-catenin', 'MPA', (29, 41))	('HCT116', 'CellLine', 'CVCL:0291', (101, 107))
47004	28918047	In conclusion, lncRNA BC032913 inhibited CRC metastasis through inactivation of the Wnt/beta-catenin pathway, which was followed by modulation of TIMP3, nuclear beta-catenin, E-cadherin, and CD44 expression.	('lncRNA BC032913', 'Var', (15, 30))	('CD44', 'Gene', '960', (191, 195))	('CD44', 'Gene', (191, 195))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('CRC', 'Disease', (41, 44))	('BC032913', 'Chemical', '-', (22, 30))	('inactivation', 'NegReg', (64, 76))	('modulation', 'Reg', (132, 142))	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('TIMP3', 'Protein', (146, 151))	('nuclear', 'Protein', (153, 160))	('cadherin', 'molecular_function', 'GO:0008014', ('177', '185'))	('E-cadherin', 'Gene', (175, 185))	('E-cadherin', 'Gene', '999', (175, 185))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('Wnt/beta-catenin pathway', 'Pathway', (84, 108))	('expression', 'MPA', (196, 206))	('si', 'Chemical', 'MESH:D012825', (202, 204))	('inhibited', 'NegReg', (31, 40))	('BC032913', 'Var', (22, 30))
47005	28918047	Emerging research has shown that lncRNAs play important roles in cancer carcinogenesis and progression, and aberrant lncRNA expression has been identified in CRC.	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('lncRNA expression', 'Protein', (117, 134))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('aberrant', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CRC', 'Disease', (158, 161))	('cancer carcinogenesis', 'Disease', (65, 86))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('cancer carcinogenesis', 'Disease', 'MESH:D063646', (65, 86))	('identified', 'Reg', (144, 154))
47008	28918047	CCAT2 is elevated in microsatellite-stable CRC and promotes tumor growth, metastasis, and chromosomal instability.	('elevated', 'PosReg', (9, 17))	('CCAT2', 'Gene', (0, 5))	('microsatellite-stable', 'Var', (21, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('metastasis', 'CPA', (74, 84))	('chromosomal instability', 'Phenotype', 'HP:0040012', (90, 113))	('promotes', 'PosReg', (51, 59))	('CCAT2', 'Gene', '101805488', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('tumor', 'Disease', (60, 65))	('chromosomal instability', 'CPA', (90, 113))
47011	28918047	Five selected lncRNAs were further validated in an additional 20 pairs of CRC tissues via real-time qPCR (Figure 1), and we found that the novel lncRNA BC032913 was markedly downregulated in 115 CRC tissues.	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('BC032913', 'Chemical', '-', (152, 160))	('downregulated', 'NegReg', (174, 187))	('BC032913', 'Var', (152, 160))	('CRC', 'Disease', (195, 198))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))
47013	28918047	Low BC032913 levels were positively correlated with an advanced TNM stage and a higher risk of lymph node and distant metastases, suggesting that the downregulation of BC032913 in CRC may facilitate the invasive/metastatic phenotype (Figure 1; Table 1).	('facilitate', 'PosReg', (188, 198))	('BC032913', 'Chemical', '-', (4, 12))	('BC032913', 'Var', (168, 176))	('si', 'Chemical', 'MESH:D012825', (207, 209))	('downregulation', 'NegReg', (150, 164))	('metastases', 'Disease', (118, 128))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('CRC', 'Phenotype', 'HP:0003003', (180, 183))	('invasive/metastatic phenotype', 'CPA', (203, 232))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('BC032913', 'Chemical', '-', (168, 176))
47018	28918047	In humans, LOC389023 recruits polycomb 2 (PRC2) and other transcriptional repressors in cis, thereby inhibiting the expression of the sense transcript DPP10.	('LOC389023', 'Var', (11, 20))	('expression', 'MPA', (116, 126))	('PRC2', 'Gene', (42, 46))	('DPP10', 'Gene', (151, 156))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('DPP10', 'Gene', '57628', (151, 156))	('humans', 'Species', '9606', (3, 9))	('inhibiting', 'NegReg', (101, 111))
47019	28918047	This research suggests that BC032913 may also play a functional role in CRC through regulating DPP10 transcription.	('DPP10', 'Gene', '57628', (95, 100))	('CRC', 'Disease', (72, 75))	('BC032913', 'Chemical', '-', (28, 36))	('BC032913', 'Var', (28, 36))	('CRC', 'Phenotype', 'HP:0003003', (72, 75))	('transcription', 'biological_process', 'GO:0006351', ('101', '114'))	('transcription', 'MPA', (101, 114))	('DPP10', 'Gene', (95, 100))	('regulating', 'Reg', (84, 94))
47025	28918047	To explore the underlying mechanism, metastasis-related genes that were deregulated in HCT116-BC032913 versus HCT116-control cells were identified using a human tumor metastasis PCR array.	('tumor metastasis', 'Disease', 'MESH:D009362', (161, 177))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('human', 'Species', '9606', (155, 160))	('tumor metastasis', 'Disease', (161, 177))	('BC032913', 'Chemical', '-', (94, 102))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('HCT116-BC032913', 'Var', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HCT116', 'CellLine', 'CVCL:0291', (87, 93))	('HCT116', 'CellLine', 'CVCL:0291', (110, 116))	('deregulated', 'PosReg', (72, 83))	('metastasis-related genes', 'Gene', (37, 61))
47026	28918047	BC032913 was verified to elevate TIMP3 at both the mRNA and protein levels.	('BC032913', 'Var', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('elevate', 'PosReg', (25, 32))	('TIMP3', 'Gene', (33, 38))	('BC032913', 'Chemical', '-', (0, 8))
47027	28918047	Subsequently, we demonstrated that BC032913 inactivated the Wnt/beta-catenin pathway by upregulating TIMP3 (Figures 3 and 4).	('BC032913', 'Chemical', '-', (35, 43))	('Wnt/beta-catenin pathway', 'Pathway', (60, 84))	('BC032913', 'Var', (35, 43))	('inactivated', 'NegReg', (44, 55))	('upregulating', 'PosReg', (88, 100))	('TIMP3', 'Gene', (101, 106))
47032	28918047	In mammary epithelial cells, extracellular TIMP3 functions to inactivate the Wnt-beta-catenin pathway, followed by increasing phosphorylated beta-catenin levels and decreasing nuclear beta-catenin levels.	('phosphorylated beta-catenin levels', 'MPA', (126, 160))	('nuclear beta-catenin levels', 'MPA', (176, 203))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('extracellular TIMP3', 'Var', (29, 48))	('decreasing', 'NegReg', (165, 175))	('inactivate', 'NegReg', (62, 72))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('increasing', 'PosReg', (115, 125))	('Wnt-beta-catenin pathway', 'Pathway', (77, 101))	('extracellular', 'cellular_component', 'GO:0005576', ('29', '42'))
47033	28918047	In accord with the above studies, TIMP3, upregulated by BC032913, inhibits nuclear translocation of beta-catenin, followed by inactivating the Wnt/beta-catenin pathway in our research.	('inhibits', 'NegReg', (66, 74))	('BC032913', 'Chemical', '-', (56, 64))	('upregulated', 'PosReg', (41, 52))	('nuclear translocation of beta-catenin', 'MPA', (75, 112))	('Wnt/beta-catenin pathway', 'Pathway', (143, 167))	('inactivating', 'NegReg', (126, 138))	('BC032913', 'Var', (56, 64))	('TIMP3', 'Gene', (34, 39))
47034	28918047	A downstream target gene of the Wnt pathway, CD44, was also identified to be downregulated by BC032913 using a human tumor metastasis PCR array (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('downregulated', 'NegReg', (77, 90))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('CD44', 'Gene', '960', (45, 49))	('human', 'Species', '9606', (111, 116))	('BC032913', 'Chemical', '-', (94, 102))	('tumor metastasis', 'Disease', 'MESH:D009362', (117, 133))	('CD44', 'Gene', (45, 49))	('BC032913', 'Var', (94, 102))	('tumor metastasis', 'Disease', (117, 133))	('Wnt pathway', 'Pathway', (32, 43))
47035	28918047	Hence, we hypothesized that the BC032913/TIMP3 axis may inhibit CRC metastasis by inactivating Wnt/beta-catenin signaling and subsequently blocking CD44 transcription.	('si', 'Chemical', 'MESH:D012825', (75, 77))	('inactivating', 'NegReg', (82, 94))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('Wnt/beta-catenin signaling', 'MPA', (95, 121))	('BC032913', 'Chemical', '-', (32, 40))	('BC032913/TIMP3', 'Var', (32, 46))	('CRC', 'Disease', (64, 67))	('blocking', 'NegReg', (139, 147))	('CD44', 'Gene', '960', (148, 152))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('transcription', 'MPA', (153, 166))	('transcription', 'biological_process', 'GO:0006351', ('153', '166'))	('CD44', 'Gene', (148, 152))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('inhibit', 'NegReg', (56, 63))
47036	28918047	The data revealed that the BC032913/TIMP3 axis decreased the levels of nuclear beta-catenin and CD44, which are important molecules in the Wnt/beta-catenin pathway (Figure 4F).	('BC032913/TIMP3', 'Var', (27, 41))	('CD44', 'Gene', '960', (96, 100))	('levels of nuclear beta-catenin', 'MPA', (61, 91))	('CD44', 'Gene', (96, 100))	('BC032913', 'Chemical', '-', (27, 35))	('decreased', 'NegReg', (47, 56))
47040	28918047	As shown in Figure 4F, BC032913 promoted E-cadherin expression levels and suppressed CD44 expression levels compared with the corresponding negative control.	('promoted', 'PosReg', (32, 40))	('suppressed', 'NegReg', (74, 84))	('CD44', 'Gene', '960', (85, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('CD44', 'Gene', (85, 89))	('BC032913', 'Chemical', '-', (23, 31))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('BC032913', 'Var', (23, 31))	('si', 'Chemical', 'MESH:D012825', (96, 98))
47041	28918047	Moreover, TIMP3 knockdown reversed the effect of BC032913 on the expression of E-cadherin and CD44.	('CD44', 'Gene', (94, 98))	('BC032913', 'Chemical', '-', (49, 57))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('BC032913', 'Var', (49, 57))	('E-cadherin', 'Gene', (79, 89))	('CD44', 'Gene', '960', (94, 98))	('E-cadherin', 'Gene', '999', (79, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))
47051	28918047	For example, TNFSF10 was downregulated by BC032913, indicating that BC032913 may influence CRC carcinogenesis and progression by modulating TNFSF10.	('modulating', 'Reg', (129, 139))	('TNFSF10', 'Gene', '8743', (13, 20))	('BC032913', 'Var', (68, 76))	('BC032913', 'Chemical', '-', (42, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))	('CRC', 'Disease', (91, 94))	('influence', 'Reg', (81, 90))	('carcinogenesis', 'Disease', (95, 109))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('downregulated', 'NegReg', (25, 38))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('BC032913', 'Chemical', '-', (68, 76))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('TNFSF10', 'Gene', (140, 147))	('progression', 'CPA', (114, 125))	('TNFSF10', 'Gene', (13, 20))	('TNFSF10', 'Gene', '8743', (140, 147))
47077	28918047	GP293 cells were transfected with pLNCX2-BC032913 or pLNCX2 and the package plasmids according to the manufacturer's instructions.	('pLNCX2', 'Var', (53, 59))	('BC032913', 'Chemical', '-', (41, 49))	('pLNCX2-BC032913', 'Var', (34, 49))	('GP293', 'CellLine', 'CVCL:E072', (0, 5))
47096	28918047	The primary antibodies used included anti-TIMP3 (sc-9906, Santa Cruz), anti-GAPDH (sc-32233), anti-Histone H3 (sc-8654), anti-beta-catenin (8480, Cell Signaling Technology), and anti-E-cadherin (3195, Cell Signaling Technology).	('anti-TIMP3', 'Var', (37, 47))	('Signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('E-cadherin', 'Gene', '999', (183, 193))	('GAPDH', 'Gene', '2597', (76, 81))	('GAPDH', 'Gene', (76, 81))	('anti-Histone', 'Var', (94, 106))	('Signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('sc-32233', 'Var', (83, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('185', '193'))	('E-cadherin', 'Gene', (183, 193))
47105	28918047	For the hepatic metastasis model, tumor cell suspensions (HCT116-BC032913 or HCT116-control, 1 x 106 cells/mouse/100 muL) were injected into the distal tip of the spleen.	('HCT116', 'CellLine', 'CVCL:0291', (77, 83))	('hepatic metastasis', 'Disease', (8, 26))	('HCT116-BC032913', 'Var', (58, 73))	('tumor', 'Disease', (34, 39))	('mouse', 'Species', '10090', (107, 112))	('hepatic metastasis', 'Disease', 'MESH:D009362', (8, 26))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('BC032913', 'Chemical', '-', (65, 73))
47130	28460459	In some cases, mesothelin expression has been associated with increased tumor aggressiveness and poor clinical outcome, however, its impact on the clinical outcome of malignant pleural mesothelioma patients has not been extensively evaluated.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (72, 92))	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('malignant pleural mesothelioma', 'Disease', (167, 197))	('patients', 'Species', '9606', (198, 206))	('mesothelin', 'Protein', (15, 25))	('expression', 'Var', (26, 36))	('aggressiveness', 'Phenotype', 'HP:0000718', (78, 92))	('tumor aggressiveness', 'Disease', (72, 92))	('associated', 'Reg', (46, 56))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (177, 197))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (167, 197))
47133	28460459	Although the mechanism(s) and/or tumor biological significances were unclear, high mesothelin expression was associated with KRAS gene mutation in lung adenocarcinoma.	('associated', 'Reg', (109, 119))	('KRAS', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('high', 'PosReg', (78, 82))	('KRAS', 'Gene', '3845', (125, 129))	('mesothelin', 'Protein', (83, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('expression', 'MPA', (94, 104))	('tumor', 'Disease', (33, 38))	('mutation', 'Var', (135, 143))	('lung adenocarcinoma', 'Disease', (147, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))
47164	28460459	Multivariable Cox hazards regression analysis revealed diffuse membranous mesothelin expression in mesothelioma tumor cells to be a favorable prognostic factor (HR, 0.36; 95% CI, 0.21-0.64; P < 0.001) (Table 4).	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mesothelioma tumor', 'Disease', (99, 117))	('diffuse', 'Var', (55, 62))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (99, 117))
47167	28460459	Arbitrary selected 75 colorectal tumors were analyzed for BRAF, KRAS, and NRAS gene mutations.	('NRAS', 'Gene', (74, 78))	('KRAS', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (84, 93))	('NRAS', 'Gene', '4893', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal tumors', 'Disease', (22, 39))	('colorectal tumors', 'Disease', 'MESH:D015179', (22, 39))	('BRAF', 'Gene', '673', (58, 62))	('KRAS', 'Gene', '3845', (64, 68))	('BRAF', 'Gene', (58, 62))
47200	28460459	In case of lung adenocarcinoma high-level of mesothelin expression is associated with aggressiveness, poor prognosis and KRAS gene mutation status.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (11, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('KRAS', 'Gene', (121, 125))	('KRAS', 'Gene', '3845', (121, 125))	('high-level', 'Var', (31, 41))	('aggressiveness', 'Disease', 'MESH:D001523', (86, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (11, 30))	('associated', 'Reg', (70, 80))	('expression', 'MPA', (56, 66))	('aggressiveness', 'Disease', (86, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('lung adenocarcinoma', 'Disease', (11, 30))
47201	28460459	Based on these observations, in the present study, gene mutation analyses were performed in colorectal adenocarcinomas since they commonly harbor KRAS mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('KRAS', 'Gene', (146, 150))	('harbor', 'Reg', (139, 145))	('KRAS', 'Gene', '3845', (146, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colorectal adenocarcinomas', 'Disease', (92, 118))	('mutations', 'Var', (151, 160))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (92, 118))
47202	28460459	Among 75 arbitrarily selected colorectal adenocarcinomas, 20 and 31 tumors carried BRAF and RAS mutations, respectively.	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (30, 56))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('RAS', 'Gene', (92, 95))	('carried', 'Reg', (75, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('colorectal adenocarcinomas', 'Disease', (30, 56))	('BRAF', 'Gene', '673', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('BRAF', 'Gene', (83, 87))	('mutations', 'Var', (96, 105))
47227	28376735	Central nervous system progression in advanced non-small cell lung cancer patients with EGFR mutations in response to first-line treatment with two EGFR-TKIs, gefitinib and erlotinib: a comparative study Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer (NSCLC) patients confers a worse quality of life and prognosis.	('gefitinib', 'Chemical', 'MESH:D000077156', (159, 168))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (266, 288))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (262, 288))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (51, 73))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (47, 73))	('EGFR', 'Gene', '1956', (148, 152))	('non-small cell lung cancer', 'Disease', (262, 288))	('EGFR', 'Gene', (88, 92))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('mutations', 'Var', (93, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (297, 305))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('non-small cell lung cancer', 'Disease', (47, 73))	('NSCLC', 'Disease', (290, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('NSCLC', 'Phenotype', 'HP:0030358', (290, 295))	('EGFR', 'Gene', (148, 152))	('erlotinib', 'Chemical', 'MESH:D000069347', (173, 182))	('Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer', 'Disease', 'MESH:D002289', (204, 288))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (262, 288))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('EGFR', 'Gene', '1956', (88, 92))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (47, 73))
47228	28376735	The efficacy comparison of two first-generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib as first-line treatment for CNS metastasis NSCLC patients with EGFR-sensitizing mutations is yet to be elucidated.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('48', '71'))	('EGFR', 'Gene', (82, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('metastasis NSCLC', 'Disease', 'MESH:D009362', (154, 170))	('EGFR', 'Gene', (185, 189))	('metastasis NSCLC', 'Disease', (154, 170))	('epidermal growth factor receptor', 'Gene', (48, 80))	('EGFR', 'Gene', '1956', (185, 189))	('patients', 'Species', '9606', (171, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('erlotinib', 'Chemical', 'MESH:D000069347', (99, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('185', '189'))	('EGFR', 'Gene', '1956', (82, 86))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))	('gefitinib', 'Chemical', 'MESH:D000077156', (112, 121))	('mutations', 'Var', (202, 211))
47229	28376735	A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefitinib as first-line treatment for advanced NSCLC patients with EGFR-sensitizing mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('patients', 'Species', '9606', (134, 142))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('NSCLC', 'Disease', (128, 133))	('cerebral metastasis', 'CPA', (37, 56))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('erlotinib', 'Chemical', 'MESH:D000069347', (68, 77))	('mutations', 'Var', (165, 174))	('gefitinib', 'Chemical', 'MESH:D000077156', (81, 90))
47234	28376735	The 6-, 12- and 18-month cumulative CNS progression rates were 0.9, 3.7 and 12% for erlotinib compared with corresponding rates of 5.8, 9.4 and 17% for gefitinib (P = 0.181).	('erlotinib', 'Var', (84, 93))	('CNS', 'Disease', (36, 39))	('gefitinib', 'Chemical', 'MESH:D000077156', (152, 161))	('erlotinib', 'Chemical', 'MESH:D000069347', (84, 93))
47236	28376735	Our data show that nTTP can be effectively extended in preexisting brain metastases patients with EGFR-sensitizing mutations initially treated with erlotinib compared with gefitinib.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (115, 124))	('nTTP', 'Chemical', '-', (19, 23))	('gefitinib', 'Chemical', 'MESH:D000077156', (172, 181))	('patients', 'Species', '9606', (84, 92))	('brain metastases', 'Disease', 'MESH:D009362', (67, 83))	('brain metastases', 'Disease', (67, 83))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('erlotinib', 'Chemical', 'MESH:D000069347', (148, 157))
47237	28376735	If confirmed, our results indicate that erlotinib may play an important role in controlling CNS progression from EGFR mutation-positive NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('mutation-positive', 'Var', (118, 135))	('erlotinib', 'Chemical', 'MESH:D000069347', (40, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('CNS', 'Disease', (92, 95))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('NSCLC', 'Disease', (136, 141))
47239	28376735	In particular, EGFR mutations show a strong association with the risk of brain metastases at the initial time of diagnosis and follow up in lung adenocarcinoma patients.	('patients', 'Species', '9606', (160, 168))	('brain metastases', 'Disease', 'MESH:D009362', (73, 89))	('brain metastases', 'Disease', (73, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('association', 'Reg', (44, 55))	('lung adenocarcinoma', 'Disease', (140, 159))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (140, 159))	('mutations', 'Var', (20, 29))
47243	28376735	The outcomes from multiple prospective phase III clinical trials have shown significantly better clinical efficacy in EGFR mutant advanced NSCLC patients initially treated with first- generation EGFR inhibitors (gefitinib or erlotinib) compared with upfront chemotherapy, with an objective response rate (ORR) of 71-83% and PFS of 9-13 months.	('patients', 'Species', '9606', (145, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('195', '199'))	('EGFR', 'Gene', (195, 199))	('erlotinib', 'Chemical', 'MESH:D000069347', (225, 234))	('NSCLC', 'Disease', (139, 144))	('better', 'PosReg', (90, 96))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('gefitinib', 'Chemical', 'MESH:D000077156', (212, 221))	('EGFR', 'Gene', '1956', (195, 199))	('mutant', 'Var', (123, 129))
47244	28376735	Recently published data showed that erlotinib and gefitinib could efficiently pass through the blood brain barrier and target brain metastases of NSCLC patients harboring sensitive EGFR mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('brain metastases', 'Disease', (126, 142))	('EGFR', 'Gene', (181, 185))	('mutations', 'Var', (186, 195))	('NSCLC', 'Disease', (146, 151))	('erlotinib', 'Chemical', 'MESH:D000069347', (36, 45))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('gefitinib', 'Chemical', 'MESH:D000077156', (50, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('EGFR', 'Gene', '1956', (181, 185))	('patients', 'Species', '9606', (152, 160))	('brain metastases', 'Disease', 'MESH:D009362', (126, 142))
47246	28376735	reported that first-line TKI gefitinib/erlotinib treatment for EGFR mutant advanced NSCLC patients resulted in lower rates of CNS progression compared with first-line chemotherapy.	('EGFR', 'Gene', '1956', (63, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('EGFR', 'Gene', (63, 67))	('erlotinib', 'Chemical', 'MESH:D000069347', (39, 48))	('CNS progression', 'CPA', (126, 141))	('NSCLC', 'Disease', (84, 89))	('gefitinib', 'Chemical', 'MESH:D000077156', (29, 38))	('lower', 'NegReg', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('patients', 'Species', '9606', (90, 98))	('mutant', 'Var', (68, 74))
47247	28376735	These results indicated that gefitinib and erlotinib might have an effective role in prevention and treatment of CNS metastases in NSCLS patients harboring sensitive EGFR mutations.	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('EGFR', 'Gene', '1956', (166, 170))	('erlotinib', 'Chemical', 'MESH:D000069347', (43, 52))	('EGFR', 'Gene', (166, 170))	('patients', 'Species', '9606', (137, 145))	('gefitinib', 'Chemical', 'MESH:D000077156', (29, 38))	('mutations', 'Var', (171, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('metastases', 'Disease', (117, 127))	('NSCLS', 'Disease', 'None', (131, 136))	('NSCLS', 'Disease', (131, 136))
47248	28376735	However, there is currently no definitive conclusion regarding comparative effectiveness between the two first generation TKIs gefitinib and erlotinib in the prevention and treatment of brain metastases in NSCLS with EGFR mutations.	('erlotinib', 'Chemical', 'MESH:D000069347', (141, 150))	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (217, 221))	('gefitinib', 'Chemical', 'MESH:D000077156', (127, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('brain metastases', 'Disease', 'MESH:D009362', (186, 202))	('brain metastases', 'Disease', (186, 202))	('mutations', 'Var', (222, 231))	('NSCLS', 'Disease', 'None', (206, 211))	('NSCLS', 'Disease', (206, 211))
47249	28376735	Erlotinib might be more effective in the prevention and treatment for brain metastases than gefitinib since the concentration of erlotinib in the cerebro-spinal fluid (CSF) reaches higher levels than that of gefitinib.	('brain metastases', 'Disease', 'MESH:D009362', (70, 86))	('erlotinib', 'Chemical', 'MESH:D000069347', (129, 138))	('brain metastases', 'Disease', (70, 86))	('higher', 'PosReg', (181, 187))	('gefitinib', 'Chemical', 'MESH:D000077156', (208, 217))	('gefitinib', 'Chemical', 'MESH:D000077156', (92, 101))	('erlotinib', 'Var', (129, 138))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
47250	28376735	To our knowledge, there are no reports that directly compare erlotinib with gefitinib in preventing and controlling brain metastases in NSCLC patients harboring EGFR-sensitive mutations.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))	('mutations', 'Var', (176, 185))	('EGFR', 'Gene', (161, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('gefitinib', 'Chemical', 'MESH:D000077156', (76, 85))	('erlotinib', 'Chemical', 'MESH:D000069347', (61, 70))	('EGFR', 'Gene', '1956', (161, 165))	('patients', 'Species', '9606', (142, 150))	('brain metastases', 'Disease', 'MESH:D009362', (116, 132))	('NSCLC', 'Disease', (136, 141))	('brain metastases', 'Disease', (116, 132))
47251	28376735	The aim of this retrospective study is to analyze the prevention and control of brain metastases in a cohort of EGFR mutant NSCLC patients initially treated with erlotinib in comparison to that in a cohort initially treated with gefitinib.	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('mutant', 'Var', (117, 123))	('NSCLC', 'Disease', (124, 129))	('brain metastases', 'Disease', 'MESH:D009362', (80, 96))	('gefitinib', 'Chemical', 'MESH:D000077156', (229, 238))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('patients', 'Species', '9606', (130, 138))	('brain metastases', 'Disease', (80, 96))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('EGFR', 'Gene', '1956', (112, 116))	('erlotinib', 'Chemical', 'MESH:D000069347', (162, 171))
47256	28376735	NSCLC patients with EGFR-sensitizing mutations and stage IV or systemic recurrent stage I-IIIB disease were eligible for this study.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('EGFR', 'Gene', (20, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (6, 14))	('NSCLC', 'Disease', (0, 5))	('EGFR', 'Gene', '1956', (20, 24))
47266	28376735	Consistent with previous methods using the ADx-ARMS EGFR Mutation Test Kit (AmoyDx), the tumor specimens were detected using the amplification refractory mutation system (ARMS) that can detect a total of 29 EGFR gene mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('detect', 'Reg', (186, 192))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('EGFR', 'Gene', (207, 211))	('mutations', 'Var', (217, 226))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
47267	28376735	In this study, the following EGFR mutations were defined as sensitive mutations: deletion or deletion-insertion of exon 19, point mutations of L858R, L861Q in exon 21, and missense point mutations of G719(G719S or G719C) in exon 18.	('L858R', 'Var', (143, 148))	('G719S', 'Mutation', 'rs28929495', (205, 210))	('L861Q', 'Var', (150, 155))	('deletion', 'Var', (81, 89))	('G719', 'Var', (200, 204))	('G719C', 'Mutation', 'rs28929495', (214, 219))	('L861Q', 'Mutation', 'rs121913444', (150, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))	('G719C', 'Var', (214, 219))	('L858R', 'Mutation', 'rs121434568', (143, 148))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (29, 33))	('deletion-insertion', 'Var', (93, 111))	('point mutations', 'Var', (124, 139))	('mutations', 'Var', (34, 43))	('missense point mutations', 'Var', (172, 196))
47273	28376735	Between January 1, 2009, and December 31, 2013, 358 NSCLC patients with EGFR mutations from the CFC database were screened.	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('NSCLC', 'Disease', (52, 57))	('EGFR', 'Gene', '1956', (72, 76))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('EGFR', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (58, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
47274	28376735	Two hundred and seventy-nine patients with stage IV disease or relapsed metastatic NSCLC harboring sensitizing EGFR mutations were included in the final analysis and were treated with either gefitinib (n = 171) or erlotinib (n = 108) as their initial systemic therapy.	('patients', 'Species', '9606', (29, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('NSCLC', 'Disease', (83, 88))	('EGFR', 'Gene', '1956', (111, 115))	('erlotinib', 'Chemical', 'MESH:D000069347', (214, 223))	('stage IV disease', 'Disease', 'MESH:D058625', (43, 59))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('EGFR', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('gefitinib', 'Chemical', 'MESH:D000077156', (191, 200))	('stage IV disease', 'Disease', (43, 59))
47275	28376735	Another 79 patients with EGFR-sensitizing mutations were excluded from the study, including 49 patients with less than 1 year of follow-up and 30 patients who received gefitinib/erlotinib treatment for recurrent lesions less than 12 months after completing neoadjuvant/adjuvant chemotherapy.	('gefitinib', 'Chemical', 'MESH:D000077156', (168, 177))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (95, 103))	('mutations', 'Var', (42, 51))	('erlotinib', 'Chemical', 'MESH:D000069347', (178, 187))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (146, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('EGFR', 'Gene', '1956', (25, 29))
47282	28376735	The EGFR mutation status of all patients was suitable for this analysis (Table 2).	('mutation', 'Var', (9, 17))	('patients', 'Species', '9606', (32, 40))	('EGFR', 'Gene', (4, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (4, 8))
47283	28376735	The EGFR mutations were detected in pretreatment tissue specimens (surgical specimens, puncture specimens or fiber bronchoscopic specimens) in 268/279 patients, whereas malignant pleural effusion cytology specimens were tested in 11/279 patients following treatment with an EGFR-TKI.	('pleural effusion', 'Phenotype', 'HP:0002202', (179, 195))	('EGFR', 'Gene', (4, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('274', '278'))	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (151, 159))	('malignant pleural effusion', 'Disease', (169, 195))	('malignant pleural effusion', 'Disease', 'MESH:D016066', (169, 195))	('EGFR', 'Gene', '1956', (274, 278))	('patients', 'Species', '9606', (237, 245))	('EGFR', 'Gene', (274, 278))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (4, 8))
47284	28376735	The proportion of the classical sensitive mutations (deletion or deletion- insertion mutations of exon 19, L858R point mutation of exon 21) was similar in the two groups.	('L858R point mutation', 'Var', (107, 127))	('classical sensitive', 'Disease', (22, 41))	('deletion', 'Var', (53, 61))	('L858R', 'Mutation', 'rs121434568', (107, 112))	('deletion- insertion mutations', 'Var', (65, 94))
47285	28376735	In the gefitinib group, 1 patient with a G719Ab mutation of exon 18 was combined with a deletion mutation of exon 19; another patient with a G719Ab mutation of exon 18 was combined with a L858R point mutation of exon 21.	('patient', 'Species', '9606', (26, 33))	('gefitinib', 'Chemical', 'MESH:D000077156', (7, 16))	('L858R', 'Var', (188, 193))	('L858R', 'Mutation', 'rs121434568', (188, 193))	('patient', 'Species', '9606', (126, 133))	('G719Ab', 'Var', (141, 147))	('G719Ab', 'Var', (41, 47))
47296	28376735	The median nTTP was significantly longer in the erlotinib group than in the gefitinib group (24 months vs 16 months, p = 0.014).	('erlotinib', 'Chemical', 'MESH:D000069347', (48, 57))	('nTTP', 'MPA', (11, 15))	('longer', 'PosReg', (34, 40))	('erlotinib', 'Var', (48, 57))	('gefitinib', 'Chemical', 'MESH:D000077156', (76, 85))	('nTTP', 'Chemical', '-', (11, 15))
47303	28376735	In the study, the effects of erlotinib versus gefitinib as first-line treatment on the risk of CNS progression in advanced NSCLC patients with EGFR mutations was retrospectively analyzed.	('EGFR', 'Gene', (143, 147))	('mutations', 'Var', (148, 157))	('NSCLC', 'Disease', (123, 128))	('erlotinib', 'Chemical', 'MESH:D000069347', (29, 38))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('EGFR', 'Gene', '1956', (143, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))
47307	28376735	The two first generation EGFR-TKIs have not yet been demonstrated to be the therapeutic choice for treatment of patients with CNS progression carrying EGFR mutations.	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (151, 155))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('CNS', 'Disease', (126, 129))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (151, 155))
47309	28376735	However, there is no data to compare these two first generation TKIs with respect to CNS progression in advanced EGFR mutant NSCLC patients.	('patients', 'Species', '9606', (131, 139))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('mutant', 'Var', (118, 124))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))
47311	28376735	However, for the advanced EGFR mutant NSCLC patients with prior CNS involvement, the time to occurrence of CNS progression was significantly prolonged after first-line erlotinib compared with gefitinib (30.0 months vs 15.8 months, P = 0.024), indicating the greater potential of erlotinib at slowing development of established CNS metastases from NSCLC than gefitinib.	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('metastases', 'Disease', (331, 341))	('gefitinib', 'Chemical', 'MESH:D000077156', (192, 201))	('NSCLC', 'Disease', 'MESH:D002289', (347, 352))	('gefitinib', 'Chemical', 'MESH:D000077156', (358, 367))	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', (347, 352))	('prolonged', 'PosReg', (141, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('slowing development', 'Phenotype', 'HP:0001263', (292, 311))	('NSCLC', 'Phenotype', 'HP:0030358', (347, 352))	('erlotinib', 'Chemical', 'MESH:D000069347', (168, 177))	('EGFR', 'Gene', (26, 30))	('mutant', 'Var', (31, 37))	('erlotinib', 'Chemical', 'MESH:D000069347', (279, 288))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('metastases', 'Disease', 'MESH:D009362', (331, 341))	('EGFR', 'Gene', '1956', (26, 30))
47313	28376735	Erlotinib significantly prolonged nTTP compared with gefitinib in the treatment of CNS metastases in NSCLC patients with preexisting brain metastasis.	('metastases', 'Disease', (87, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('prolonged', 'PosReg', (24, 33))	('NSCLC', 'Disease', (101, 106))	('Erlotinib', 'Var', (0, 9))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('nTTP', 'Chemical', '-', (34, 38))	('gefitinib', 'Chemical', 'MESH:D000077156', (53, 62))	('patients', 'Species', '9606', (107, 115))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('nTTP', 'MPA', (34, 38))
47317	28376735	using kinetic analysis showed that erlotinib has a stronger antitumor effect than gefitinib when using the conventional recommended dose.	('erlotinib', 'Chemical', 'MESH:D000069347', (35, 44))	('tumor', 'Disease', (64, 69))	('erlotinib', 'Var', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('gefitinib', 'Chemical', 'MESH:D000077156', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
47318	28376735	showed clinical improvements following the change to erlotinib therapy in lung adenocarcinoma patients with EGFR mutations who developed leptomeningeal metastases during gefitinib therapy.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('improvements', 'PosReg', (16, 28))	('metastases', 'Disease', (152, 162))	('erlotinib', 'Chemical', 'MESH:D000069347', (53, 62))	('gefitinib', 'Chemical', 'MESH:D000077156', (170, 179))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('mutations', 'Var', (113, 122))	('lung adenocarcinoma', 'Disease', (74, 93))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))
47321	28376735	Notably, EGFR mutation status as a poor prognostic factor for the risk of brain metastasis in NSCLC has previously been demonstrated.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('NSCLC', 'Disease', (94, 99))	('EGFR', 'Gene', '1956', (9, 13))	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('brain metastasis', 'CPA', (74, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
47322	28376735	In a retrospective trial of 314 lung adenocarcinoma patients with EGFR mutations, the multivariate model analysis showed a strong association between EGFR mutation status and brain metastasis (adjusted odds ratio = 3.83, 95% CI: 1.72-8.55, P = 0.001).	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('lung adenocarcinoma', 'Disease', (32, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('150', '154'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (32, 51))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (52, 60))	('mutation', 'Var', (155, 163))	('EGFR', 'Gene', '1956', (150, 154))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 51))	('brain metastasis', 'CPA', (175, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
47323	28376735	While resistance to continued EGFR inhibition is common, acquired systemic resistance through the selection of resistance mutations or amplification of other oncogenes is usually detected after 6 to 12 months of therapy.	('systemic', 'MPA', (66, 74))	('EGFR', 'Gene', (30, 34))	('amplification', 'Var', (135, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('mutations', 'Var', (122, 131))	('EGFR', 'Gene', '1956', (30, 34))	('inhibition', 'NegReg', (35, 45))
47335	28376735	In addition, we did not evaluate other clinically important genetic changes besides EGFR mutations, for example, KRAS mutation, c-Met amplification, or the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (ALK) translocation.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (205, 224))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('anaplastic lymphoma', 'Disease', (205, 224))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('lymphoma', 'Phenotype', 'HP:0002665', (216, 224))	('ALK', 'Gene', (233, 236))	('c-Met', 'Gene', (128, 133))	('KRAS', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (84, 88))	('c-Met', 'Gene', '4233', (128, 133))	('mutations', 'Var', (89, 98))	('translocation', 'Var', (238, 251))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (205, 224))	('KRAS', 'Gene', '3845', (113, 117))	('EGFR', 'Gene', (84, 88))	('microtubule', 'cellular_component', 'GO:0005874', ('167', '178'))	('ALK', 'Gene', '238', (233, 236))
47338	28376735	Our findings provide a rationale for physicians to use erlotinib for the treatment of CNS progression in EGFR mutant NSCLC.	('NSCLC', 'Disease', (117, 122))	('erlotinib', 'Chemical', 'MESH:D000069347', (55, 64))	('mutant', 'Var', (110, 116))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('EGFR', 'Gene', (105, 109))	('CNS', 'Disease', (86, 89))
47341	28376735	If validated, our findings suggest that erlotinib might be more effective at delaying CNS metastases from NSCLC in patients with sensitizing EGFR mutations.	('delaying', 'NegReg', (77, 85))	('patients', 'Species', '9606', (115, 123))	('metastases', 'Disease', (90, 100))	('mutations', 'Var', (146, 155))	('CNS', 'Disease', (86, 89))	('EGFR', 'Gene', '1956', (141, 145))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('erlotinib', 'Chemical', 'MESH:D000069347', (40, 49))	('EGFR', 'Gene', (141, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('NSCLC', 'Disease', (106, 111))
47349	27377534	The cytotoxicity against OVA-expressing tumor cells increased by combining OT-I-CTLs and A-NK cells, but the increase was additive rather than synergistic.	('rat', 'Species', '10116', (131, 134))	('increased', 'PosReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cytotoxicity', 'Disease', (4, 16))	('OT-I-CTLs', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('combining', 'Interaction', (65, 74))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
47374	27377534	The MC38 colon carcinoma was a gift from Dr. M. Shurin, University of Pittsburgh.	('colon carcinoma', 'Disease', (9, 24))	('MC38', 'Var', (4, 8))	('colon carcinoma', 'Disease', 'MESH:D015179', (9, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))
47375	27377534	MC38 and Panc02 tumor cells were transfected to produce OVA-expressing variants, MC38OVA and Panc02 OVA, respectively.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MC38OVA', 'Var', (81, 88))	('tumor', 'Disease', (16, 21))	('Panc02', 'CellLine', 'CVCL:D627', (9, 15))	('Panc02', 'CellLine', 'CVCL:D627', (93, 99))
47386	27377534	Routinely, on day 5 of culture, the A-NK cells were >95% CD45.1+ (or CD45.2+), >95% Thy1.2+, >95% asGM1+, >90% NK1.1+, >90% NKp46+ <2% CD8+, <2% CD4+.	('Thy1.2', 'Gene', '21838', (84, 90))	('Thy1.2', 'Gene', (84, 90))	('CD45', 'Gene', '19264', (57, 61))	('>95% asGM1+', 'Var', (93, 104))	('asGM1+', 'Var', (98, 104))	('>90% NK1.1+', 'Var', (106, 117))	('CD4', 'Gene', (69, 72))	('CD4', 'Gene', '12504', (57, 60))	('NKp46', 'Gene', '17086', (124, 129))	('CD45', 'Gene', (57, 61))	('CD45', 'Gene', '19264', (69, 73))	('NK1.1+', 'Var', (111, 117))	('CD4', 'Gene', (145, 148))	('CD4', 'Gene', '12504', (69, 72))	('CD45', 'Gene', (69, 73))	('>90%', 'Var', (119, 123))	('NKp46', 'Gene', (124, 129))	('CD4', 'Gene', '12504', (145, 148))	('CD4', 'Gene', (57, 60))
47421	27377534	Eight-micron thick sections were cut from ten randomly chosen areas of each set of lungs and stained with PE-anti-H-2Kb (553570, BD Pharmingen ).	('H-2Kb', 'Gene', '14972', (114, 119))	('H-2Kb', 'Gene', (114, 119))	('PE', 'Chemical', '-', (106, 108))	('553570', 'Var', (121, 127))
47427	27377534	The average dry weight of the lungs from Adv-mock and Adv-IL-12 transduced ANK groups were 0.189g+-0.01g versus 0.163g+-0.03g, respectively, ensuring that the mice, upon sacrifice, had reached roughly the same stage of tumor development.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Adv-IL', 'Gene', (54, 60))	('tumor', 'Disease', (219, 224))	('0.163g+-0.03g', 'Var', (112, 125))	('ANK', 'Gene', '11732', (75, 78))	('IL-12', 'molecular_function', 'GO:0005143', ('58', '63'))	('Adv-IL', 'Gene', '11567', (54, 60))	('ANK', 'Gene', (75, 78))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
47443	27377534	MIP-1alpha and GM-CSF production also increased, especially after IL-18 gene-transduction.	('GM-CSF', 'Gene', (15, 21))	('IL-18', 'Gene', (66, 71))	('transduction', 'biological_process', 'GO:0009293', ('77', '89'))	('MIP', 'molecular_function', 'GO:0004243', ('0', '3'))	('GM-CSF', 'Gene', '12981', (15, 21))	('IL-18', 'Gene', '16173', (66, 71))	('MIP-1alpha', 'Gene', '20302', (0, 10))	('GM-CSF production', 'biological_process', 'GO:0032604', ('15', '32'))	('MIP-1alpha', 'Gene', (0, 10))	('gene-transduction', 'Var', (72, 89))	('IL-18', 'molecular_function', 'GO:0045515', ('66', '71'))	('increased', 'PosReg', (38, 47))
47444	27377534	While IL-12, but not IL-18 gene-transduction increased the NK cells' secretion of IL-10 by nearly 100 fold, only IL-18 gene-transduction increased the A-NK cells' secretion of IL-6 and RANTES.	('IL-6', 'Gene', '16193', (176, 180))	('secretion', 'biological_process', 'GO:0046903', ('69', '78'))	('IL-18', 'Gene', '16173', (113, 118))	('IL-12', 'molecular_function', 'GO:0005143', ('6', '11'))	('RANTES', 'Gene', '20304', (185, 191))	('transduction', 'biological_process', 'GO:0009293', ('124', '136'))	('IL-10', 'Gene', '16153', (82, 87))	('secretion', 'biological_process', 'GO:0046903', ('163', '172'))	('transduction', 'biological_process', 'GO:0009293', ('32', '44'))	('IL-18', 'molecular_function', 'GO:0045515', ('21', '26'))	('RANTES', 'Gene', (185, 191))	('increased', 'PosReg', (137, 146))	('IL-18', 'Gene', (21, 26))	('IL-6', 'molecular_function', 'GO:0005138', ('176', '180'))	('IL-18', 'molecular_function', 'GO:0045515', ('113', '118'))	('IL-18', 'Gene', '16173', (21, 26))	('IL-10', 'molecular_function', 'GO:0005141', ('82', '87'))	('IL-6', 'Gene', (176, 180))	('IL-10', 'Gene', (82, 87))	('gene-transduction', 'Var', (119, 136))	('IL-18', 'Gene', (113, 118))
47454	27377534	The increase in CTL-mediated lysis was even more pronounced against tumor cells pre-incubated in medium from IL-12 (and IL-18 - data not shown) gene-transduced A-NK cells (Figure 4A).	('tumor', 'Disease', (68, 73))	('pre', 'molecular_function', 'GO:0003904', ('80', '83'))	('IL-18', 'molecular_function', 'GO:0045515', ('120', '125'))	('CTL-mediated', 'MPA', (16, 28))	('IL-18', 'Gene', '16173', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('IL-12', 'molecular_function', 'GO:0005143', ('109', '114'))	('lysis', 'biological_process', 'GO:0019835', ('29', '34'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('IL-18', 'Gene', (120, 125))	('gene-transduced', 'Var', (144, 159))
47484	27377534	Survival after treatment with IL-12 gene-transduced A-NK cells plus one injection of PegIL-2 was clearly prolonged (by 11.5 days), but it was 5 days shorter (p=0.007) than treatment with the CTLs + A-NKIL-12 + PegIL-2.	('NKIL-12', 'Chemical', '-', (200, 207))	('IL-12', 'molecular_function', 'GO:0005143', ('30', '35'))	('prolonged', 'PosReg', (105, 114))	('PegIL', 'Chemical', '-', (85, 90))	('IL-2', 'Gene', (213, 217))	('Survival', 'CPA', (0, 8))	('PegIL', 'Chemical', '-', (210, 215))	('shorter', 'NegReg', (149, 156))	('IL-2', 'Gene', '16183', (88, 92))	('gene-transduced', 'Var', (36, 51))	('IL-2', 'Gene', (88, 92))	('IL-12', 'Gene', (30, 35))	('IL-2', 'Gene', '16183', (213, 217))
47496	27377534	Since NK cells transduced with the gene for IL-12 produce 10-fold higher amounts of IFNgamma, but only 2-3 fold higher amounts of TNFalpha than mock-transduced NK cells, it is not surprising that IFNgamma appears to be the main cytokine responsible for this effect.	('IL-12', 'Gene', (44, 49))	('IL-12', 'molecular_function', 'GO:0005143', ('44', '49'))	('IFNgamma', 'Gene', (84, 92))	('IFNgamma', 'Gene', '15978', (84, 92))	('IFNgamma', 'Gene', (196, 204))	('IFNgamma', 'Gene', '15978', (196, 204))	('TNFalpha', 'Gene', '21926', (130, 138))	('gene', 'Var', (35, 39))	('higher', 'PosReg', (66, 72))	('TNFalpha', 'Gene', (130, 138))
47500	27377534	The A-NK cell accumulation translates into a significant delay in tumor growth and increase in survival.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('increase', 'PosReg', (83, 91))	('tumor', 'Disease', (66, 71))	('A-NK', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('survival', 'CPA', (95, 103))	('delay', 'NegReg', (57, 62))
47526	33972506	Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified.	('NOTCH2', 'Gene', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('NOTCH2', 'Gene', '4853', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('patients', 'Species', '9606', (199, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('patients', 'Species', '9606', (117, 125))	('miR-296', 'Var', (25, 32))	('AGAP2-AS1', 'Gene', (14, 23))
47532	33972506	Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296.	('NOTCH2', 'Gene', '4853', (57, 63))	('miR-296', 'Var', (80, 87))	('regulated', 'MPA', (34, 43))	('miR-296', 'Protein', (44, 51))	('NOTCH2', 'Gene', (57, 63))	('negatively', 'NegReg', (23, 33))	('AGAP2-AS1', 'Gene', (13, 22))
47549	33972506	MiR-296 is one of the miRNAs that has been verified to modulate chemo-sensitivity of lung cancer cells, and the role of exosomal miR-296 has been unraveled in hepatocellular carcinoma.	('modulate', 'Reg', (55, 63))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('hepatocellular carcinoma', 'Disease', (159, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('miR-296', 'Var', (129, 136))	('MiR-296', 'Gene', (0, 7))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('exo', 'Gene', (120, 123))	('MiR-296', 'Gene', '407022', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('exo', 'Gene', '24127', (120, 123))
47554	33972506	Based on the aforementioned evidence, we could speculate that miR-296 and NOTCH2 might be used as the downstream of AGAP2-AS1 to affect the immune function of lung cancer radiotherapy.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('NOTCH2', 'Gene', '4853', (74, 80))	('immune', 'MPA', (140, 146))	('affect', 'Reg', (129, 135))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('miR-296', 'Var', (62, 69))	('NOTCH2', 'Gene', (74, 80))
47568	33972506	Moreover, patients with high miR-296 expression had high OS and DFS (Supplementary Fig.	('high miR-296 expression', 'Var', (24, 47))	('DFS', 'CPA', (64, 67))	('patients', 'Species', '9606', (10, 18))	('high', 'Disease', (52, 56))
47569	33972506	2A-C), suggesting that AGAP2-AS1, miR-296, and NOTCH2 are associated with the prognosis of lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('NOTCH2', 'Gene', '4853', (47, 53))	('associated with', 'Reg', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('AGAP2-AS1', 'Gene', (23, 32))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('NOTCH2', 'Gene', (47, 53))	('patients', 'Species', '9606', (103, 111))	('miR-296', 'Var', (34, 41))	('lung cancer', 'Disease', (91, 102))
47572	33972506	3H) contrasted to the mimic NC group, the luciferase activity of cells with the NOTCH2-WT in the miR-296 mimic group was suppressed, showing that miR-296 specifically bound to NOTCH2.	('luciferase activity', 'molecular_function', 'GO:0047712', ('42', '61'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('42', '61'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('42', '61'))	('miR-296', 'Var', (146, 153))	('NOTCH2', 'Gene', (176, 182))	('luciferase activity', 'molecular_function', 'GO:0050397', ('42', '61'))	('NOTCH2', 'Gene', (80, 86))	('activity', 'MPA', (53, 61))	('luciferase', 'Enzyme', (42, 52))	('suppressed', 'NegReg', (121, 131))	('NOTCH2', 'Gene', '4853', (80, 86))	('luciferase activity', 'molecular_function', 'GO:0047077', ('42', '61'))	('NOTCH2', 'Gene', '4853', (176, 182))	('bound', 'Interaction', (167, 172))
47574	33972506	4A, B) with the radiation dose increased, the viability and survival rate of cells reduced; treated with the same radiation dose, the proliferation and survival rate of A549R26-1 and H157R24-1 cells were promoted in relation to A549P and H157P cells.	('A549P', 'CellLine', 'CVCL:0023', (228, 233))	('A549R26-1', 'Var', (169, 178))	('A549R26-1', 'CellLine', 'CVCL:0023', (169, 178))	('survival rate', 'CPA', (152, 165))	('H157R24-1', 'Var', (183, 192))	('proliferation', 'CPA', (134, 147))	('H157P', 'Mutation', 'p.H157P', (238, 243))	('promoted', 'PosReg', (204, 212))
47575	33972506	4C) an increased radiation dose resulted in a higher apoptosis rate; exposed to the same radiation dose, the apoptosis rate of A549R26-1 and H157R24-1 cells was suppressed relative to A549P and H157P cells.	('A549P', 'CellLine', 'CVCL:0023', (184, 189))	('A549R26-1', 'Var', (127, 136))	('suppressed', 'NegReg', (161, 171))	('apoptosis rate', 'CPA', (109, 123))	('A549R26-1', 'CellLine', 'CVCL:0023', (127, 136))	('H157P', 'Mutation', 'p.H157P', (194, 199))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))
47578	33972506	4D, E) volume and weight of xenografts from nude mice that had been injected with A549R26-1 and H157R24-1 cells were increased compared with nude mice that had been injected with A549P and H157P cells.	('nude mice', 'Species', '10090', (141, 150))	('H157P', 'Mutation', 'p.H157P', (189, 194))	('A549R26-1', 'Var', (82, 91))	('increased', 'PosReg', (117, 126))	('A549R26-1', 'CellLine', 'CVCL:0023', (82, 91))	('A549P', 'CellLine', 'CVCL:0023', (179, 184))	('H157R24-1 cells', 'Var', (96, 111))	('nude mice', 'Species', '10090', (44, 53))
47584	33972506	5F, G) the tumor volume and weight of xenografts in the sh-AGAP2-AS1 group were suppressed in relation to the sh-NC group.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('sh-AGAP2-AS1', 'Var', (56, 68))	('suppressed', 'NegReg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
47591	33972506	To measure whether macrophage-derived exosomes maintained the activity when entering cells, the PKH26-labeled exosomes were co-cultured with A549R26-1 and H157R24-1 cells, and DAPI staining reflected that the exosomes had the activity entering A549R26-1 and H157R24-1.	('activity', 'MPA', (226, 234))	('A549R26-1', 'CellLine', 'CVCL:0023', (141, 150))	('exo', 'Gene', (110, 113))	('exo', 'Gene', '24127', (110, 113))	('activity', 'MPA', (62, 70))	('DAPI', 'Chemical', '-', (176, 180))	('PKH26', 'Chemical', 'MESH:C070080', (96, 101))	('H157R24-1', 'Var', (258, 267))	('A549R26-1', 'Var', (244, 253))	('exo', 'Gene', (209, 212))	('exo', 'Gene', '24127', (209, 212))	('exo', 'Gene', '24127', (38, 41))	('A549R26-1', 'CellLine', 'CVCL:0023', (244, 253))	('exo', 'Gene', (38, 41))
47616	33972506	By comparison with the miR-296 mimic + Oe-NC group, enhanced cell viability and cell survival rate, as well as inhibited cell apoptosis was found in the miR-296 mimic + Oe-NOTCH2 group (Fig.	('miR-296', 'Var', (153, 160))	('NOTCH2', 'Gene', (172, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('cell viability', 'CPA', (61, 75))	('cell survival rate', 'CPA', (80, 98))	('NOTCH2', 'Gene', '4853', (172, 178))	('enhanced', 'PosReg', (52, 60))	('inhibited', 'NegReg', (111, 120))	('cell apoptosis', 'CPA', (121, 135))
47617	33972506	It was implied that NOTCH2 could be used as a downstream target of AGAP2-AS1 and miR-296 in radioresistant lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('NOTCH2', 'Gene', '4853', (20, 26))	('miR-296', 'Var', (81, 88))	('AGAP2-AS1', 'Gene', (67, 76))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NOTCH2', 'Gene', (20, 26))
47623	33972506	In addition, miR-296-5p has been found to be downregulated in both NSCLC tissues and cell lines, and Qian et al.	('miR-296-5p', 'Var', (13, 23))	('downregulated', 'NegReg', (45, 58))	('NSCLC', 'Disease', (67, 72))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
47629	33972506	We also confirmed the target relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2, both of which have been seldom studied.	('AGAP2-AS1', 'Gene', (51, 60))	('miR-296', 'Gene', (65, 72))	('NOTCH2', 'Gene', '4853', (98, 104))	('miR-296', 'Var', (86, 93))	('NOTCH2', 'Gene', (98, 104))
47633	33972506	have unveiled that degradation of AGAP2-AS1 represses NSCLC cell growth, and also constrains tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SCLC', 'Phenotype', 'HP:0030357', (55, 59))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('represses', 'NegReg', (44, 53))	('tumor', 'Disease', (93, 98))	('degradation', 'biological_process', 'GO:0009056', ('19', '30'))	('constrains', 'NegReg', (82, 92))	('NSCLC', 'Disease', (54, 59))	('AGAP2-AS1', 'Gene', (34, 43))	('degradation', 'Var', (19, 30))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
47635	33972506	have unearthed that miR-296-3p restricts NSCLC cell proliferation, and promotes drug resistance and apoptosis, and it has been recently reported that miR-296 restoration restrains malignant behaviors of breast cancer cells and also inhibits in vivo breast cancer cell growth.	('promotes', 'PosReg', (71, 79))	('NSCLC', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('miR-296-3p', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('cell growth', 'biological_process', 'GO:0016049', ('263', '274'))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('restricts', 'NegReg', (31, 40))	('malignant behaviors of breast cancer', 'Disease', (180, 216))	('apoptosis', 'CPA', (100, 109))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('drug resistance', 'biological_process', 'GO:0009315', ('80', '95'))	('restrains', 'NegReg', (170, 179))	('SCLC', 'Phenotype', 'HP:0030357', (42, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('drug resistance', 'biological_process', 'GO:0042493', ('80', '95'))	('drug resistance', 'Phenotype', 'HP:0020174', (80, 95))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('breast cancer', 'Disease', (249, 262))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('drug', 'CPA', (80, 84))	('miR-296', 'Var', (150, 157))	('malignant behaviors of breast cancer', 'Disease', 'MESH:D001943', (180, 216))	('inhibits', 'NegReg', (232, 240))
47637	33972506	Mechanistically, decreased NOTCH2 could suppress the cancer stem cell-like properties and chemoresistance in non-small cell lung cancer and inactivation of NOTCH signaling subdue stemness and chemoresistance in colorectal cancer.	('small cell lung cancer', 'Disease', (113, 135))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('cancer', 'Disease', (129, 135))	('NOTCH2', 'Gene', '4853', (27, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inactivation', 'Var', (140, 152))	('decreased', 'NegReg', (17, 26))	('cancer', 'Disease', (222, 228))	('suppress', 'NegReg', (40, 48))	('subdue', 'NegReg', (172, 178))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('chemoresistance', 'CPA', (90, 105))	('NOTCH2', 'Gene', (27, 33))	('cancer', 'Disease', (53, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (211, 228))	('NOTCH', 'Gene', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal cancer', 'Disease', (211, 228))	('NOTCH', 'Gene', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('NOTCH', 'Gene', '4851;4853', (156, 161))	('small cell lung cancer', 'Disease', 'MESH:D055752', (113, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('NOTCH', 'Gene', '4851;4853', (27, 32))
47667	33972506	A549R26-1 and H157R24-1 cells were separated into several groups: the blank group (no treatment), the short hairpin RNA (sh)-NC group (cells were introduced with NC of AGAP2-AS1 silenced vector), the sh-AGAP2-AS1 group (cells were introduced with AGAP2-AS1 silenced vector), the exo group (cells were co-cultured with untreated macrophage-derived exosomes), the Oe-NC-exo group (cells were co-cultured with exosomes that released from macrophages in the oe-NC group), the Oe-AGAP2-AS1-exo group (cells were cocultured with exosomes that released from macrophages in the Oe-AGAP2-AS1 group), the inhibitor-NC-exo group (cells were cocultured with exosomes that released from macrophages in the inhibitor-NC group), the miR-296 inhibitor-exo group (cells were cocultured with exosomes that released from macrophages in the miR-296 inhibitor group), Oe-AGAP2-AS1 + sh-NC group (cells were cocultured with exosomes that released from macrophages in the Oe-AGAP2-AS1 + sh-NC group), Oe-AGAP2-AS1 + sh-NOTCH2 group (cells were cocultured with exosomes that released from macrophages in the Oe-AGAP2-AS1 + sh-NOTCH2 group), miR-296 mimic + Oe-NC group (cells were cocultured with exosomes that released from macrophages in the miR-296 mimic + Oe-NC group), and miR-296 mimic + Oe-NOTCH2 group (cells were cocultured with exosomes that released from macrophages in the miR-296 mimic + Oe-NOTCH2 group).	('NOTCH2', 'Gene', (1102, 1108))	('exo', 'Gene', (736, 739))	('exo', 'Gene', (347, 350))	('exo', 'Gene', '24127', (523, 526))	('exo', 'Gene', (1314, 1317))	('exo', 'Gene', (902, 905))	('exo', 'Gene', '24127', (1173, 1176))	('NOTCH2', 'Gene', '4853', (1273, 1279))	('exo', 'Gene', '24127', (1037, 1040))	('exo', 'Gene', (646, 649))	('exo', 'Gene', (608, 611))	('exo', 'Gene', (368, 371))	('exo', 'Gene', '24127', (736, 739))	('exo', 'Gene', '24127', (347, 350))	('exo', 'Gene', (774, 777))	('exo', 'Gene', (407, 410))	('NOTCH2', 'Gene', (996, 1002))	('exo', 'Gene', '24127', (1314, 1317))	('exo', 'Gene', '24127', (902, 905))	('exo', 'Gene', '24127', (646, 649))	('exo', 'Gene', (279, 282))	('exo', 'Gene', (485, 488))	('exo', 'Gene', '24127', (608, 611))	('NOTCH2', 'Gene', (1273, 1279))	('RNA', 'cellular_component', 'GO:0005562', ('116', '119'))	('exo', 'Gene', '24127', (368, 371))	('NOTCH2', 'Gene', '4853', (1380, 1386))	('exo', 'Gene', '24127', (407, 410))	('exo', 'Gene', '24127', (774, 777))	('NOTCH2', 'Gene', '4853', (1102, 1108))	('exo', 'Gene', '24127', (485, 488))	('exo', 'Gene', '24127', (279, 282))	('exo', 'Gene', (523, 526))	('miR-296', 'Var', (1254, 1261))	('exo', 'Gene', (1173, 1176))	('A549R26-1', 'CellLine', 'CVCL:0023', (0, 9))	('NOTCH2', 'Gene', '4853', (996, 1002))	('exo', 'Gene', (1037, 1040))	('NOTCH2', 'Gene', (1380, 1386))
47671	33972506	The isolated cells were kept in IL-2 containing NK cell media and stained with anti-CD56-PE (e-Bioscience, CA, USA) and anti-CD3-Cy7 (BioLegend, CA, USA).	('IL-2', 'molecular_function', 'GO:0005134', ('32', '36'))	('IL-2', 'Gene', '3558', (32, 36))	('CD56', 'Gene', '4684', (84, 88))	('anti-CD3-Cy7', 'Var', (120, 132))	('IL-2', 'Gene', (32, 36))	('CD56', 'Gene', (84, 88))
47681	33972506	The sequenced luciferase reporter plasmids WT and mutant type (MUT) were co-transfected with miR-296 into A549 and H157 cells for 48 h, and the cells were lysed.	('A549', 'CellLine', 'CVCL:0023', (106, 110))	('mutant', 'Var', (50, 56))	('luciferase', 'Enzyme', (14, 24))
47931	33671996	Results of the pH showed that it was observed that as concentrations increased for DOX, pH decreased: (-0.034, -0.036, and -0.044 pH/h for 5, 7.5, and 10 muM DOX, respectively).	('pH', 'Gene', '5053', (15, 17))	('pH', 'Gene', '5053', (88, 90))	('-0.034', 'Var', (103, 109))	('DOX', 'Chemical', 'MESH:D004317', (83, 86))	('rat', 'Species', '10116', (61, 64))	('DOX', 'Chemical', 'MESH:D004317', (158, 161))	('decreased', 'NegReg', (91, 100))	('pH', 'Gene', '5053', (130, 132))
47962	33671996	The results showed bleomycin did not cause cessation of cardiac organoid beating, indicating that bleomycin may induce production of a secondary factor from one of the other tissues in the platform, which would later be found to be lung organoid.	('bleomycin', 'Chemical', 'MESH:D001761', (19, 28))	('bleomycin', 'Var', (98, 107))	('production', 'MPA', (119, 129))	('bleomycin', 'Chemical', 'MESH:D001761', (98, 107))
48203	33671996	The device was tested for its capacity to discriminate between low and higher glucose levels (G3 vs. G11 and G15).	('G3', 'Chemical', '-', (94, 96))	('G11', 'Var', (101, 104))	('G15', 'Var', (109, 112))	('glucose', 'Chemical', 'MESH:D005947', (78, 85))
48356	33463035	In conclusion, oral administration of tegafur-uracil might cause pericardial effusion.	('tegafur-uracil', 'Chemical', 'MESH:D005641', (38, 52))	('pericardial effusion', 'Disease', (65, 85))	('cause', 'Reg', (59, 64))	('pericardial effusion', 'Disease', 'MESH:D010490', (65, 85))	('tegafur-uracil', 'Var', (38, 52))	('pericardial effusion', 'Phenotype', 'HP:0001698', (65, 85))
48376	33665255	Our study shows that serum CCL18 levels, indirectly indicative of the amount of TAMs, increases with the increasing SUVmax.	('CCL18', 'Gene', (27, 32))	('increases', 'PosReg', (86, 95))	('CCL', 'molecular_function', 'GO:0044101', ('27', '30'))	('TAMs', 'Chemical', '-', (80, 84))	('CCL18', 'Gene', '6362', (27, 32))	('SUVmax', 'Var', (116, 122))
48424	33380833	Defects in the autophagy mechanism are associated with many diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, infectious diseases and metabolic diseases.	('cardiovascular diseases', 'Disease', 'MESH:D002318', (116, 139))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (116, 139))	('autophagy', 'biological_process', 'GO:0006914', ('15', '24'))	('metabolic diseases', 'Disease', (165, 183))	('autophagy mechanism', 'CPA', (15, 34))	('neurodegenerative diseases', 'Disease', (80, 106))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (80, 106))	('Defects', 'Var', (0, 7))	('infectious diseases', 'Disease', 'MESH:D003141', (141, 160))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('associated', 'Reg', (39, 49))	('metabolic diseases', 'Disease', 'MESH:D008659', (165, 183))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (80, 106))	('autophagy', 'biological_process', 'GO:0016236', ('15', '24'))	('infectious diseases', 'Disease', (141, 160))	('cardiovascular diseases', 'Disease', (116, 139))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
48445	33380833	Therefore, lack of key genes in autophagy can lead to carcinogenesis.	('lead to', 'Reg', (46, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('carcinogenesis', 'Disease', (54, 68))	('autophagy', 'biological_process', 'GO:0016236', ('32', '41'))	('autophagy', 'CPA', (32, 41))	('lack', 'Var', (11, 15))	('autophagy', 'biological_process', 'GO:0006914', ('32', '41'))
48446	33380833	For instance, deletion of ATG5 and ATG7 could develop benign liver adenomas from autophagy-deficient hepatocytes due to mitochondrial swelling and oxidative stress.	('swelling', 'Disease', (134, 142))	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('swelling', 'Disease', 'MESH:D004487', (134, 142))	('ATG7', 'Gene', (35, 39))	('liver adenomas', 'Disease', 'MESH:D018248', (61, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (147, 163))	('mitochondrial swelling', 'Phenotype', 'HP:0030774', (120, 142))	('develop', 'PosReg', (46, 53))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('ATG7', 'Gene', '10533', (35, 39))	('ATG5', 'Gene', '9474', (26, 30))	('deletion', 'Var', (14, 22))	('liver adenomas', 'Disease', (61, 75))	('liver adenomas', 'Phenotype', 'HP:0012028', (61, 75))	('ATG5', 'Gene', (26, 30))
48448	33380833	Loss of autophagy-related gene Beclin 1 could develop spontaneous tumors and cause an increase in cell proliferation in different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cell proliferation', 'CPA', (98, 116))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('increase', 'PosReg', (86, 94))	('Beclin 1', 'Gene', '8678', (31, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('develop', 'PosReg', (46, 53))	('autophagy', 'biological_process', 'GO:0016236', ('8', '17'))	('Loss', 'Var', (0, 4))	('Beclin 1', 'Gene', (31, 39))	('autophagy', 'biological_process', 'GO:0006914', ('8', '17'))	('cancer', 'Disease', (139, 145))
48451	33380833	Emerging studies have shown that autophagy was an integral component of the tumor suppressive crisis mechanism and that loss of autophagy could promote continued proliferation and accumulation of genome instability, which was required for the initiation of cancer.	('genome instability', 'MPA', (196, 214))	('autophagy', 'biological_process', 'GO:0006914', ('128', '137'))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('autophagy', 'biological_process', 'GO:0016236', ('128', '137'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('autophagy', 'CPA', (128, 137))	('tumor', 'Disease', (76, 81))	('promote', 'PosReg', (144, 151))	('autophagy', 'CPA', (33, 42))	('autophagy', 'biological_process', 'GO:0016236', ('33', '42'))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('accumulation', 'PosReg', (180, 192))	('autophagy', 'biological_process', 'GO:0006914', ('33', '42'))	('cancer', 'Disease', (257, 263))	('loss', 'Var', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
48455	33380833	Genetic ablation of essential autophagy genes in genetically engineered mouse models (GEMMs) for cancer has revealed an important role of autophagy in promoting tumor to a malignant stage.	('tumor', 'Disease', (161, 166))	('autophagy', 'CPA', (138, 147))	('cancer', 'Disease', (97, 103))	('promoting', 'PosReg', (151, 160))	('mouse', 'Species', '10090', (72, 77))	('autophagy', 'biological_process', 'GO:0016236', ('30', '39'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('autophagy', 'biological_process', 'GO:0006914', ('30', '39'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('autophagy', 'biological_process', 'GO:0016236', ('138', '147'))	('ablation', 'Var', (8, 16))	('autophagy', 'biological_process', 'GO:0006914', ('138', '147'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
48477	33380833	As a result, abnormally high aerobic glycolysis has been recognized as one of the "hallmarks of cancer".	('aerobic glycolysis', 'MPA', (29, 47))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('abnormally', 'Var', (13, 23))	('glycolysis', 'biological_process', 'GO:0006096', ('37', '47'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
48487	33380833	Ji Hye Kim et al demonstrated that EGFR mutation-mediated enhancement of glycolysis sustains EGFR stability and is critical to EGFR-mutant NSCLC survival.	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('mutation-mediated', 'Var', (40, 57))	('glycolysis', 'MPA', (73, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('EGFR stability', 'MPA', (93, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('sustains', 'PosReg', (84, 92))	('glycolysis', 'biological_process', 'GO:0006096', ('73', '83'))	('EGFR', 'Gene', (35, 39))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))	('enhancement', 'PosReg', (58, 69))
48498	33380833	Human NSCLC with activating mutations in EGFR was resistant to EGFR-targeted tyrosine kinase inhibitors (TKIs).	('Human', 'Species', '9606', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('EGFR', 'Gene', (41, 45))	('SCLC', 'Phenotype', 'HP:0030357', (7, 11))	('activating', 'PosReg', (17, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('mutations', 'Var', (28, 37))	('NSCLC', 'Disease', (6, 11))
48512	33380833	In the lung cancer cell lines KP2 and H23, inhibition of HK2 enzyme activity with 2-DG could inhibit tumor growth, induce cell cycle arrest, and regulate autophagy and apoptotic pathways.	('inhibition', 'Var', (43, 53))	('HK2', 'molecular_function', 'GO:0008256', ('57', '60'))	('lung cancer', 'Disease', (7, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('autophagy', 'biological_process', 'GO:0006914', ('154', '163'))	('arrest', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('2-DG', 'Chemical', 'MESH:D003847', (82, 86))	('HK2', 'Gene', (57, 60))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('122', '139'))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('apoptotic pathways', 'CPA', (168, 186))	('inhibit', 'NegReg', (93, 100))	('enzyme activity', 'molecular_function', 'GO:0003824', ('61', '76'))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('activity', 'MPA', (68, 76))	('arrest', 'Disease', 'MESH:D006323', (133, 139))	('autophagy', 'CPA', (154, 163))	('regulate', 'Reg', (145, 153))	('tumor', 'Disease', (101, 106))	('autophagy', 'biological_process', 'GO:0016236', ('154', '163'))	('induce', 'PosReg', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
48516	33380833	Previous studies demonstrated that inhibition of PFKFB3 suppressed autophagy, which showed an important role of PFKFBs in regulating autophagy.	('PFKFB3', 'Gene', '5209', (49, 55))	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('autophagy', 'biological_process', 'GO:0016236', ('133', '142'))	('PFKFB3', 'Gene', (49, 55))	('suppressed', 'NegReg', (56, 66))	('autophagy', 'CPA', (67, 76))	('autophagy', 'biological_process', 'GO:0006914', ('133', '142'))	('inhibition', 'Var', (35, 45))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
48528	33380833	Mitochondrial uncoupling protein 2 (UCP2) inhibition triggered ROS/Akt/mTOR axis in pancreatic adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (84, 109))	('Akt', 'Gene', (67, 70))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('UCP2', 'Gene', (36, 40))	('inhibition', 'Var', (42, 52))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (84, 109))	('Mitochondrial uncoupling protein 2', 'Gene', (0, 34))	('Mitochondrial uncoupling protein 2', 'Gene', '7351', (0, 34))	('triggered', 'Reg', (53, 62))	('UCP2', 'Gene', '7351', (36, 40))	('pancreatic adenocarcinoma', 'Disease', (84, 109))	('Akt', 'Gene', '207', (67, 70))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
48534	33380833	Glutamine deprivation or hypoxia condition resulted in inhibition of mTOR and mTOR-mediated the acetyltransferase NAA10 S228 phosphorylation, then PGK1 was acetylated at K388 by NAA10.	('NAA10', 'Gene', (114, 119))	('mTOR-mediated', 'Enzyme', (78, 91))	('hypoxia', 'Disease', (25, 32))	('PGK', 'molecular_function', 'GO:0004618', ('147', '150'))	('inhibition', 'NegReg', (55, 65))	('NAA10', 'Gene', '8260', (178, 183))	('S228', 'Var', (120, 124))	('hypoxia', 'Disease', 'MESH:D000860', (25, 32))	('phosphorylation', 'MPA', (125, 140))	('NAA10', 'Gene', '8260', (114, 119))	('K388', 'Chemical', '-', (170, 174))	('Glutamine', 'Chemical', 'MESH:D005973', (0, 9))	('mTOR', 'Enzyme', (69, 73))	('K388', 'Var', (170, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('acetyltransferase', 'Enzyme', (96, 113))	('PGK1', 'Gene', '5230', (147, 151))	('NAA10', 'Gene', (178, 183))	('PGK1', 'Gene', (147, 151))
48545	33380833	Studies demonstrated that PKM2 knockdown could enhance the radiosensitivity of lung cancer cell lines and xenografts via enhancing ionizing radiation (IR)-induced apoptosis and autophagy both in vitro and in vivo.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('enhance', 'PosReg', (47, 54))	('PKM2', 'Gene', '5315', (26, 30))	('ionizing radiation', 'MPA', (131, 149))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('radiosensitivity of lung', 'Phenotype', 'HP:0010997', (59, 83))	('autophagy', 'biological_process', 'GO:0016236', ('177', '186'))	('autophagy', 'biological_process', 'GO:0006914', ('177', '186'))	('lung cancer', 'Disease', (79, 90))	('autophagy', 'CPA', (177, 186))	('enhancing', 'PosReg', (121, 130))	('knockdown', 'Var', (31, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('PKM2', 'Gene', (26, 30))	('radiosensitivity', 'CPA', (59, 75))
48548	33380833	Phosphorylation of S202/203 of AKT1S1 by PKM2 dissociated AKT1S1 from raptor and facilitated its binding to 14-3-3, which resulted in activation of mTORC1 signaling independent of growth factors and amino acids signals and led to autophagy inhibition in cancer cells.	('mTORC1', 'Gene', (148, 154))	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('mTORC1', 'cellular_component', 'GO:0031931', ('148', '154'))	('mTORC1', 'Gene', '382056', (148, 154))	('14-3-3', 'Gene', '10971', (108, 114))	('cancer', 'Disease', (254, 260))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('raptor', 'Gene', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('autophagy', 'biological_process', 'GO:0006914', ('230', '239'))	('facilitated', 'PosReg', (81, 92))	('AKT1S1', 'Gene', (31, 37))	('Phosphorylation', 'CPA', (0, 15))	('activation', 'PosReg', (134, 144))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('binding', 'Interaction', (97, 104))	('14-3-3', 'Gene', (108, 114))	('PKM2', 'Gene', (41, 45))	('raptor', 'Gene', '57521', (70, 76))	('AKT1S1', 'Gene', (58, 64))	('S202/203', 'Var', (19, 27))	('PKM2', 'Gene', '5315', (41, 45))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('autophagy', 'biological_process', 'GO:0016236', ('230', '239'))	('autophagy', 'CPA', (230, 239))
48560	33380833	These observations indicated that LDHA inhibition could trigger protective autophagy against apoptosis in NSCLC.	('inhibition', 'Var', (39, 49))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('LDHA', 'Gene', (34, 38))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('autophagy against apoptosis', 'CPA', (75, 102))	('autophagy', 'biological_process', 'GO:0016236', ('75', '84'))	('LDHA', 'Gene', '3939', (34, 38))	('SCLC', 'Phenotype', 'HP:0030357', (107, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('autophagy', 'biological_process', 'GO:0006914', ('75', '84'))	('NSCLC', 'Disease', (106, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
48563	33380833	Research showed that SIRT5 induced deacetylated LDHB triggered hyperactivation of autophagy in tumor cells, facilitated lysosomal acidification and autolysosomal maturation, which was a key event in tumorigenesis.	('tumor', 'Disease', (199, 204))	('SIRT5', 'Gene', (21, 26))	('hyperactivation', 'PosReg', (63, 78))	('autophagy', 'biological_process', 'GO:0016236', ('82', '91'))	('deacetylated', 'Var', (35, 47))	('acidification', 'biological_process', 'GO:0045851', ('130', '143'))	('LDHB', 'Gene', (48, 52))	('autophagy', 'biological_process', 'GO:0006914', ('82', '91'))	('SIRT5', 'Gene', '23408', (21, 26))	('LDHB', 'Gene', '3945', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('autolysosomal maturation', 'CPA', (148, 172))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('lysosomal acidification', 'MPA', (120, 143))	('tumor', 'Disease', (95, 100))	('facilitated', 'PosReg', (108, 119))
48568	33380833	Evidence indicates that lactate and/or protons leading to pH 6-6.5 in tumor microenvironment, a characteristic phenotype of more aggressive tumors, modulate cell proliferation and promote angiogenesis, invasion, metastasis and poor prognosis.	('modulate', 'Reg', (148, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('157', '175'))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('invasion', 'CPA', (202, 210))	('pH 6-6.5', 'Var', (58, 66))	('lactate', 'Chemical', 'MESH:D019344', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('iron', 'Chemical', 'MESH:D007501', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('metastasis', 'CPA', (212, 222))	('tumors', 'Disease', (140, 146))	('angiogenesis', 'biological_process', 'GO:0001525', ('188', '200'))	('angiogenesis', 'CPA', (188, 200))	('promote', 'PosReg', (180, 187))	('poor prognosis', 'CPA', (227, 241))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('cell proliferation', 'CPA', (157, 175))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (140, 145))
48573	33380833	GPR119 agonists enhanced glycolysis accompanied by reduced mitochondrial oxidative phosphorylation, which inhibited gefitinib-induced autophagosome formation due to increased intracellular and extracellular lactate in MCF-7 and MDA-MB-231 cells.	('GPR119', 'Gene', (0, 6))	('reduced', 'NegReg', (51, 58))	('lactate', 'Chemical', 'MESH:D019344', (207, 214))	('autophagosome formation', 'biological_process', 'GO:0000045', ('134', '157'))	('GPR119', 'Gene', '139760', (0, 6))	('increased intracellular and extracellular lactate', 'Phenotype', 'HP:0002151', (165, 214))	('glycolysis', 'biological_process', 'GO:0006096', ('25', '35'))	('agonists', 'Var', (7, 15))	('intracellular', 'cellular_component', 'GO:0005622', ('175', '188'))	('inhibited', 'NegReg', (106, 115))	('gefitinib', 'Chemical', 'MESH:D000077156', (116, 125))	('enhanced', 'PosReg', (16, 24))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('73', '98'))	('autophagosome', 'cellular_component', 'GO:0005776', ('134', '147'))	('glycolysis', 'CPA', (25, 35))	('autophagosome formation', 'CPA', (134, 157))	('MCF-7', 'CellLine', 'CVCL:0031', (218, 223))	('mitochondrial oxidative phosphorylation', 'MPA', (59, 98))	('extracellular', 'cellular_component', 'GO:0005576', ('193', '206'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (228, 238))	('increased', 'PosReg', (165, 174))
48582	33380833	MCT4 depletion enhanced the cytotoxicity of NK cells by blocking lactate flux and reversing the acidified tumor microenvironment, of note, the MCT4 inhibition with a pronounced impact on autophagy induction.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('depletion', 'Var', (5, 14))	('MCT4', 'Gene', (143, 147))	('autophagy', 'biological_process', 'GO:0006914', ('187', '196'))	('MCT4', 'Gene', (0, 4))	('MCT4', 'Gene', '9123', (143, 147))	('tumor', 'Disease', (106, 111))	('MCT4', 'Gene', '9123', (0, 4))	('lactate flux', 'MPA', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('enhanced', 'PosReg', (15, 23))	('inhibition', 'NegReg', (148, 158))	('blocking', 'NegReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MCT', 'biological_process', 'GO:0120197', ('143', '146'))	('MCT', 'biological_process', 'GO:0120197', ('0', '3'))	('autophagy', 'biological_process', 'GO:0016236', ('187', '196'))	('autophagy induction', 'CPA', (187, 206))	('cytotoxicity', 'Disease', (28, 40))	('lactate', 'Chemical', 'MESH:D019344', (65, 72))	('iron', 'Chemical', 'MESH:D007501', (120, 124))
48591	33380833	HIF-1alpha dysregulation blocked hypoxia-induced autophagy, glycolysis and pentose phosphate pathway (PPP) activation.	('glycolysis', 'CPA', (60, 70))	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('hypoxia', 'Disease', (33, 40))	('hypoxia', 'Disease', 'MESH:D000860', (33, 40))	('pentose phosphate pathway', 'CPA', (75, 100))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('glycolysis', 'biological_process', 'GO:0006096', ('60', '70'))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('75', '100'))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('dysregulation', 'Var', (11, 24))	('blocked', 'NegReg', (25, 32))	('pentose phosphate', 'Chemical', 'MESH:D010428', (75, 92))	('activation', 'PosReg', (107, 117))	('HIF-1alpha', 'Gene', (0, 10))
48592	33380833	HIF-1alpha knockdown in A549 cells (human alveolar type II epithelial cell line) reduced glycolysis by regulating transcription of glycolysis-related enzymes, which subsequently activated the AMPKalpha-ULK1 signalling pathway to promote autophagy.	('AMPK', 'Gene', '5563', (192, 196))	('glycolysis', 'biological_process', 'GO:0006096', ('89', '99'))	('reduced', 'NegReg', (81, 88))	('ULK1', 'Gene', '8408', (202, 206))	('autophagy', 'CPA', (237, 246))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('glycolysis-related enzymes', 'Gene', (131, 157))	('autophagy', 'biological_process', 'GO:0006914', ('237', '246'))	('AMPK', 'Gene', (192, 196))	('activated', 'PosReg', (178, 187))	('ULK1', 'Gene', (202, 206))	('glycolysis', 'biological_process', 'GO:0006096', ('131', '141'))	('knockdown', 'Var', (11, 20))	('signalling pathway', 'biological_process', 'GO:0007165', ('207', '225'))	('promote', 'PosReg', (229, 236))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('glycolysis', 'MPA', (89, 99))	('regulating', 'Reg', (103, 113))	('transcription', 'MPA', (114, 127))	('human', 'Species', '9606', (36, 41))	('autophagy', 'biological_process', 'GO:0016236', ('237', '246'))	('HIF-1alpha', 'Gene', (0, 10))
48612	33194731	Recently, increasing evidence shows that imbalanced O-GlcNAcylation directly or indirectly impacts the process of cancer metastasis.	('impacts', 'Reg', (91, 98))	('imbalanced', 'Var', (41, 51))	('imbalance', 'Phenotype', 'HP:0002172', (41, 50))	('O-GlcNAcylation', 'Protein', (52, 67))	('O-GlcNAcylation', 'Chemical', '-', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer metastasis', 'Disease', (114, 131))	('cancer metastasis', 'Disease', 'MESH:D009362', (114, 131))
48632	33194731	In view of the important roles of O-GlcNAcylation in multiple fundamental cellular processes, it is unsurprising that imbalanced profiles of OGT/O-GlcNAcylation frequently lead to the occurrence of many diseases such as diabetes, neurological disorders, cardiovascular disease, and even cancer.	('cardiovascular disease', 'Disease', (254, 276))	('diabetes', 'Disease', (220, 228))	('diabetes', 'Disease', 'MESH:D003920', (220, 228))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (254, 276))	('neurological disorders', 'Disease', 'MESH:D009422', (230, 252))	('O-GlcNAcylation', 'Chemical', '-', (145, 160))	('imbalanced', 'Var', (118, 128))	('lead to', 'Reg', (172, 179))	('cardiovascular disease', 'Disease', 'MESH:D002318', (254, 276))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('imbalance', 'Phenotype', 'HP:0002172', (118, 127))	('neurological disorders', 'Disease', (230, 252))	('occurrence', 'Reg', (184, 194))	('O-GlcNAcylation', 'Chemical', '-', (34, 49))
48633	33194731	In many types of cancer such as breast, prostate, lung, colorectal, and esophageal cancers, higher levels of OGT/O-GlcNAcylation are observed, suggesting that alterations of the intracellular level of OGT and O-GlcNAcylation are tightly associated with tumorigenesis, which might further participate directly or indirectly in the regulation of the biological processes associated with cancer metastasis.	('intracellular', 'cellular_component', 'GO:0005622', ('178', '191'))	('cancer metastasis', 'Disease', (385, 402))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Disease', (17, 23))	('colorectal', 'Disease', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('associated', 'Reg', (237, 247))	('cancer metastasis', 'Disease', 'MESH:D009362', (385, 402))	('esophageal cancers', 'Disease', (72, 90))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('alterations', 'Var', (159, 170))	('regulation', 'biological_process', 'GO:0065007', ('330', '340'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('esophageal cancers', 'Disease', 'MESH:D004938', (72, 90))	('tumor', 'Disease', (253, 258))	('breast', 'Disease', (32, 38))	('O-GlcNAcylation', 'Chemical', '-', (209, 224))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Disease', (385, 391))	('O-GlcNAcylation', 'Chemical', '-', (113, 128))	('cancer', 'Disease', (83, 89))
48640	33194731	In addition, downregulation of O-GlcNAcylation induced by OGT silencing results in cell cycle arrest, as well as the induction of autophagy and apoptosis, in bladder cancer cells.	('autophagy', 'biological_process', 'GO:0016236', ('130', '139'))	('arrest', 'Disease', (94, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('silencing', 'Var', (62, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('O-GlcNAcylation', 'Chemical', '-', (31, 46))	('autophagy', 'biological_process', 'GO:0006914', ('130', '139'))	('OGT', 'Gene', (58, 61))	('downregulation', 'NegReg', (13, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('induction', 'Reg', (117, 126))	('O-GlcNAcylation', 'MPA', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('autophagy', 'CPA', (130, 139))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('83', '100'))	('apoptosis', 'CPA', (144, 153))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))
48641	33194731	However, in rare cases, O-GlcNAcylation is decreased in cancer tissues such as ovarian cancer tissues which harbor high rates of p53 mutations.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('O-GlcNAcylation', 'Chemical', '-', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('O-GlcNAcylation', 'MPA', (24, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('mutations', 'Var', (133, 142))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('ovarian cancer', 'Disease', (79, 93))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('decreased', 'NegReg', (43, 52))
48648	33194731	There are already research data confirming that CRC patients with high O-GlcNAcylation are typically diagnosed with greater lymph node metastasis potential.	('CRC', 'Disease', (48, 51))	('high O-GlcNAcylation', 'Var', (66, 86))	('CRC', 'Disease', 'MESH:D015179', (48, 51))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('lymph node metastasis potential', 'CPA', (124, 155))	('O-GlcNAcylation', 'Chemical', '-', (71, 86))	('patients', 'Species', '9606', (52, 60))
48650	33194731	Moreover, decreasing O-GlcNAcylation levels via OGT knockdown or microRNA (miRNA; e.g., miR-483 and miR-24-1)-mediated depletion suppresses the growth, migration, and invasive capability of cancer cells.	('miR-24-1', 'Gene', '407012', (100, 108))	('cancer', 'Disease', (190, 196))	('O-GlcNAcylation', 'Chemical', '-', (21, 36))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('miR-24-1', 'Gene', (100, 108))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('suppresses', 'NegReg', (129, 139))	('miR-483', 'Gene', '619552', (88, 95))	('depletion', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('miR-483', 'Gene', (88, 95))	('decreasing', 'NegReg', (10, 20))	('O-GlcNAcylation levels', 'MPA', (21, 43))	('growth', 'CPA', (144, 150))
48656	33194731	Thereby O-GlcNAcylation stabilizes HIF-1alpha and activates its transcriptional activity.	('O-GlcNAcylation', 'Var', (8, 23))	('activates', 'PosReg', (50, 59))	('O-GlcNAcylation', 'Chemical', '-', (8, 23))	('transcriptional activity', 'MPA', (64, 88))	('HIF-1alpha', 'Protein', (35, 45))
48668	33194731	In breast cancer cells, one of the most common NF-kappaB dimeric forms, RELA (p65)/p50, can be O-GlcNAcylated at Thr322 and Thr352 residues of p65, which competitively inhibits p65 Ser536 phosphorylation, thus facilitating activated NF-kappaB-mediated gene transcription.	('inhibits', 'NegReg', (168, 176))	('NF-kappaB', 'Gene', '4790', (233, 242))	('Thr352', 'Var', (124, 130))	('p65', 'Gene', '5970', (78, 81))	('transcription', 'biological_process', 'GO:0006351', ('257', '270'))	('p65', 'Gene', (177, 180))	('O-GlcNAc', 'Gene', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('NF-kappaB', 'Gene', (47, 56))	('Ser', 'cellular_component', 'GO:0005790', ('181', '184'))	('Ser536', 'Chemical', '-', (181, 187))	('p50', 'Gene', '4790', (83, 86))	('NF-kappaB', 'Gene', '4790', (47, 56))	('Thr352', 'Chemical', '-', (124, 130))	('O-GlcNAc', 'Gene', '8473', (95, 103))	('p65', 'Gene', '5970', (177, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('phosphorylation', 'biological_process', 'GO:0016310', ('188', '203'))	('p65', 'Gene', (143, 146))	('facilitating activated', 'PosReg', (210, 232))	('p50', 'Gene', (83, 86))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('p65', 'Gene', (78, 81))	('breast cancer', 'Disease', (3, 16))	('NF-kappaB', 'Gene', (233, 242))	('p65', 'Gene', '5970', (143, 146))	('RELA', 'Gene', (72, 76))	('RELA', 'Gene', '5970', (72, 76))	('Thr322', 'Chemical', '-', (113, 119))
48673	33194731	Phosphorylation can activate STAT3, resulting in its translocation to the nucleus to regulate gene expression, further enhancing tumor angiogenic and invasive capability.	('activate', 'PosReg', (20, 28))	('STAT3', 'Gene', '6774', (29, 34))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('invasive capability', 'CPA', (150, 169))	('enhancing', 'PosReg', (119, 128))	('Phosphorylation', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('STAT3', 'Gene', (29, 34))	('translocation to the nucleus', 'MPA', (53, 81))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('regulate gene expression', 'MPA', (85, 109))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('nucleus', 'cellular_component', 'GO:0005634', ('74', '81'))	('tumor', 'Disease', (129, 134))
48674	33194731	For instance, phosphorylated STAT3 promotes proliferation and metastasis in epithelial ovarian cancer.	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (76, 101))	('STAT3', 'Gene', '6774', (29, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('metastasis in epithelial ovarian cancer', 'Disease', (62, 101))	('promotes', 'PosReg', (35, 43))	('STAT3', 'Gene', (29, 34))	('phosphorylated', 'Var', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('metastasis in epithelial ovarian cancer', 'Disease', 'MESH:D009362', (62, 101))	('proliferation', 'CPA', (44, 57))
48676	33194731	Phosphorylation targets STAT3 residues, Tyr705 and Ser727, and these two modifications demonstrate a negative relationship to maintain its activity.	('Ser727', 'Var', (51, 57))	('activity', 'MPA', (139, 147))	('Tyr705', 'Var', (40, 46))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('STAT3', 'Gene', '6774', (24, 29))	('Ser727', 'Chemical', '-', (51, 57))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('Tyr705', 'Chemical', '-', (40, 46))	('STAT3', 'Gene', (24, 29))
48680	33194731	Nrf-2 activation is likely modulated by OGT, cause in Caenorhabditis elegans, the ortholog of human Nrf-2, is O-GlcNAcylated at Ser470 and Thr493.	('Ser470', 'Chemical', '-', (128, 134))	('Thr493', 'Chemical', '-', (139, 145))	('Nrf-2', 'Gene', '4780', (100, 105))	('Thr493', 'Var', (139, 145))	('Ser470', 'Var', (128, 134))	('Caenorhabditis elegans', 'Species', '6239', (54, 76))	('human', 'Species', '9606', (94, 99))	('Nrf-2', 'Gene', (0, 5))	('O-GlcNAc', 'Gene', (110, 118))	('Nrf-2', 'Gene', (100, 105))	('Ser', 'cellular_component', 'GO:0005790', ('128', '131'))	('O-GlcNAc', 'Gene', '8473', (110, 118))	('Nrf-2', 'Gene', '4780', (0, 5))
48691	33194731	For instance, Snail as an E-cadherin repressor can stabilize E-cadherin via Ser112 O-GlcNAcylation and enhance the migration and invasive capability of cancer cells.	('cadherin', 'molecular_function', 'GO:0008014', ('63', '71'))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('E-cadherin', 'Gene', (61, 71))	('migration', 'CPA', (115, 124))	('stabilize', 'MPA', (51, 60))	('E-cadherin', 'Gene', (26, 36))	('O-GlcNAcylation', 'Chemical', '-', (83, 98))	('Snail', 'Gene', (14, 19))	('enhance', 'PosReg', (103, 110))	('Ser112', 'Var', (76, 82))	('E-cadherin', 'Gene', '999', (61, 71))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('E-cadherin', 'Gene', '999', (26, 36))	('Snail', 'Gene', '6615', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Ser112', 'Chemical', '-', (76, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
48693	33194731	Moreover, E-cadherin can be directly O-GlcNAcylated in breast cancer cells during drug-induced apoptosis, and this modification inhibits its transport to the cell surface, thereby decreasing cell-cell interactions and promoting EMT.	('O-GlcNAc', 'Gene', '8473', (37, 45))	('EMT', 'CPA', (228, 231))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('modification', 'Var', (115, 127))	('cell-cell interactions', 'CPA', (191, 213))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('promoting', 'PosReg', (218, 227))	('breast cancer', 'Disease', (55, 68))	('transport', 'biological_process', 'GO:0006810', ('141', '150'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('EMT', 'biological_process', 'GO:0001837', ('228', '231'))	('cadherin', 'molecular_function', 'GO:0008014', ('12', '20'))	('E-cadherin', 'Gene', (10, 20))	('E-cadherin', 'Gene', '999', (10, 20))	('O-GlcNAc', 'Gene', (37, 45))	('inhibits', 'NegReg', (128, 136))	('transport to the cell surface', 'MPA', (141, 170))	('cell surface', 'cellular_component', 'GO:0009986', ('158', '170'))	('decreasing', 'NegReg', (180, 190))
48695	33194731	O-GlcNAcylation of EMT-Related Proteins in Cancer Metastasis During EMT, reduced E-cadherin expression and elevated snail, vimentin, fibronectin, and N-cadherin expression levels can be observed, thus these proteins are considered EMT markers.	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('snail', 'Gene', '6615', (116, 121))	('EMT', 'biological_process', 'GO:0001837', ('231', '234'))	('O-GlcNAcylation', 'Var', (0, 15))	('elevated', 'PosReg', (107, 115))	('O-GlcNAcylation', 'Chemical', '-', (0, 15))	('vimentin', 'cellular_component', 'GO:0045098', ('123', '131'))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('reduced', 'NegReg', (73, 80))	('Cancer Metastasis', 'Disease', 'MESH:D009362', (43, 60))	('snail', 'Gene', (116, 121))	('fibronectin', 'Gene', (133, 144))	('Cancer Metastasis', 'Disease', (43, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('EMT', 'biological_process', 'GO:0001837', ('19', '22'))	('E-cadherin', 'Gene', (81, 91))	('E-cadherin', 'Gene', '999', (81, 91))	('expression levels', 'MPA', (161, 178))	('expression', 'MPA', (92, 102))	('vimentin', 'cellular_component', 'GO:0045099', ('123', '131'))	('N-cadherin', 'Gene', (150, 160))	('fibronectin', 'Gene', '2335', (133, 144))	('N-cadherin', 'Gene', '1000', (150, 160))	('vimentin', 'Gene', '7431', (123, 131))	('vimentin', 'Gene', (123, 131))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
48697	33194731	Moreover, O-GlcNAcylation of RACK1 by OGT stabilizes RACK1, and results in a reduction of N-cadherin and upregulation of E-cadherin, indicating the induction of EMT and suppression of metastasis in chemoresistant gastric cancer.	('O-GlcNAcylation', 'Chemical', '-', (10, 25))	('reduction', 'NegReg', (77, 86))	('EMT', 'biological_process', 'GO:0001837', ('161', '164'))	('chemoresistant gastric cancer', 'Disease', 'MESH:D013274', (198, 227))	('cadherin', 'molecular_function', 'GO:0008014', ('123', '131'))	('N-cadherin', 'Gene', (90, 100))	('E-cadherin', 'Gene', (121, 131))	('E-cadherin', 'Gene', '999', (121, 131))	('RACK1', 'Gene', '10399', (53, 58))	('N-cadherin', 'Gene', '1000', (90, 100))	('RACK1', 'Gene', '10399', (29, 34))	('RACK1', 'Gene', (29, 34))	('RACK1', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('O-GlcNAcylation', 'Var', (10, 25))	('EMT', 'CPA', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (213, 227))	('metastasis', 'CPA', (184, 194))	('upregulation', 'PosReg', (105, 117))	('stabilizes', 'Reg', (42, 52))	('chemoresistant gastric cancer', 'Disease', (198, 227))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))
48699	33194731	For example, STAT3 regulates the expression of mesenchymal-related molecules including vimentin, the inhibition of which suppresses EMT-mediated lung cancer cell invasion.	('vimentin', 'cellular_component', 'GO:0045098', ('87', '95'))	('vimentin', 'Gene', '7431', (87, 95))	('inhibition', 'Var', (101, 111))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('vimentin', 'Gene', (87, 95))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('lung cancer', 'Disease', (145, 156))	('STAT3', 'Gene', '6774', (13, 18))	('expression', 'MPA', (33, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('vimentin', 'cellular_component', 'GO:0045099', ('87', '95'))	('suppresses', 'NegReg', (121, 131))	('STAT3', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
48704	33194731	Sirtuin1 (SIRT1) is a histone de-acetylase and O-GlcNAcylation of SIRT1/Ser549 promotes its enzymatic activity.	('Sirtuin1', 'Gene', '23411', (0, 8))	('Ser549', 'Chemical', '-', (72, 78))	('SIRT1', 'Gene', '23411', (10, 15))	('promotes', 'PosReg', (79, 87))	('enzymatic activity', 'MPA', (92, 110))	('O-GlcNAcylation', 'Var', (47, 62))	('SIRT1', 'Gene', (10, 15))	('Sirtuin1', 'Gene', (0, 8))	('SIRT1', 'Gene', '23411', (66, 71))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('SIRT1', 'Gene', (66, 71))	('O-GlcNAcylation', 'Chemical', '-', (47, 62))
48705	33194731	Decreasing O-GlcNAcylation of this protein via OGT inhibition or knockdown in breast cancer cells increases both SIRT1 level and activity, thereby regulating forkhead box M1 (FOXM1), MMP-2, and MMP-9 protein level, and modulating breast cancer cell invasive and metastatic capability in vitro and in vivo.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('MMP-2', 'molecular_function', 'GO:0004228', ('183', '188'))	('breast cancer', 'Disease', (230, 243))	('O-GlcNAcylation', 'MPA', (11, 26))	('MMP-2', 'Gene', (183, 188))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('FOXM1', 'Gene', '2305', (175, 180))	('increases', 'PosReg', (98, 107))	('breast cancer', 'Disease', (78, 91))	('SIRT1', 'Gene', '23411', (113, 118))	('MMP-9', 'Gene', (194, 199))	('MMP-9', 'Gene', '4318', (194, 199))	('knockdown', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('regulating', 'Reg', (147, 157))	('forkhead box M1', 'Gene', (158, 173))	('SIRT1', 'Gene', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('FOXM1', 'Gene', (175, 180))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('MMP-9', 'molecular_function', 'GO:0004229', ('194', '199'))	('modulating', 'Reg', (219, 229))	('O-GlcNAcylation', 'Chemical', '-', (11, 26))	('MMP-2', 'Gene', '4313', (183, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('activity', 'MPA', (129, 137))	('metastatic capability', 'CPA', (262, 283))	('forkhead box M1', 'Gene', '2305', (158, 173))
48707	33194731	In summary, based on substrates of OGT, as well as their downstream effectors, which have key roles in regulating hypoxia, gene transcription, EMT, and metastasis, O-GlcNAcylation significantly modulates cancer progression.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('O-GlcNAcylation', 'Var', (164, 179))	('modulates', 'Reg', (194, 203))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('O-GlcNAcylation', 'Chemical', '-', (164, 179))
48712	33194731	The enhancer of zeste homolog (EZH2) is responsible for H3K27me3, which promotes the metastasis of cancers such as melanoma and breast cancer.	('H3K27me3', 'Var', (56, 64))	('metastasis of cancers', 'Disease', (85, 106))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('EZH2', 'Gene', '2146', (31, 35))	('metastasis of cancers', 'Disease', 'MESH:D009362', (85, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('EZH2', 'Gene', (31, 35))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (115, 141))	('promotes', 'PosReg', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
48713	33194731	O-GlcNAcylation at Ser729 of EZH2 plays a key role in maintaining the stabilization and methylation activity of its target protein.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('methylation activity', 'MPA', (88, 108))	('O-GlcNAcylation', 'Chemical', '-', (0, 15))	('Ser729', 'Var', (19, 25))	('Ser729', 'Chemical', '-', (19, 25))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('Ser', 'cellular_component', 'GO:0005790', ('19', '22'))	('stabilization', 'MPA', (70, 83))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))
48718	33194731	In breast cancer cells, Nrf1 can be stabilized by OGT through O-GlcNAcylation at Ser448 and Ser451, a modification that suppresses the ubiquitin-proteasome mediated degradation of Nrf1.	('Ser', 'cellular_component', 'GO:0005790', ('81', '84'))	('Ser448', 'Chemical', '-', (81, 87))	('proteasome', 'cellular_component', 'GO:0000502', ('145', '155'))	('Nrf1', 'Gene', '4899', (180, 184))	('Ser448', 'Var', (81, 87))	('Nrf1', 'Gene', (24, 28))	('Ser', 'cellular_component', 'GO:0005790', ('92', '95'))	('O-GlcNAcylation', 'Chemical', '-', (62, 77))	('Ser451', 'Var', (92, 98))	('degradation', 'biological_process', 'GO:0009056', ('165', '176'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('suppresses', 'NegReg', (120, 130))	('ubiquitin-proteasome mediated degradation', 'MPA', (135, 176))	('Nrf1', 'Gene', (180, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('ubiquitin', 'molecular_function', 'GO:0031386', ('135', '144'))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('Nrf1', 'Gene', '4899', (24, 28))	('proteasome', 'molecular_function', 'GO:0004299', ('145', '155'))	('Ser451', 'Chemical', '-', (92, 98))
48725	33194731	Knocking down OGT results in cell cycle arrest as well as induction of autophagy and apoptosis.	('Knocking down', 'Var', (0, 13))	('autophagy', 'biological_process', 'GO:0006914', ('71', '80'))	('induction', 'Reg', (58, 67))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (29, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'CPA', (85, 94))	('OGT', 'Gene', (14, 17))	('arrest', 'Disease', 'MESH:D006323', (40, 46))	('autophagy', 'CPA', (71, 80))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('29', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('arrest', 'Disease', (40, 46))	('autophagy', 'biological_process', 'GO:0016236', ('71', '80'))
48729	33194731	For example, miRNA-24, miRNA-101, and miRNA-483, all of which decrease OGT transcription, have been shown to inhibit the invasive ability of breast cancer, CRC, and gastric cancer, respectively.	('CRC', 'Disease', (156, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('decrease OGT', 'Phenotype', 'HP:0032198', (62, 74))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('decrease', 'NegReg', (62, 70))	('miRNA-483', 'Var', (38, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('inhibit', 'NegReg', (109, 116))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('gastric cancer', 'Disease', (165, 179))	('CRC', 'Disease', 'MESH:D015179', (156, 159))	('transcription', 'biological_process', 'GO:0006351', ('75', '88'))	('invasive ability', 'CPA', (121, 137))	('miRNA-24', 'Var', (13, 21))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('miRNA-101', 'Var', (23, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('OGT transcription', 'MPA', (71, 88))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
48730	33194731	Similarly, ST045849, an OGT inhibitor, suppresses prostate cancer cell proliferation via metabolic reprogramming, and has been shown to inhibit hepatocellular carcinoma (HCC) cell proliferation.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (144, 168))	('suppresses', 'NegReg', (39, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('hepatocellular carcinoma', 'Disease', (144, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (144, 168))	('ST045849', 'Var', (11, 19))	('inhibit', 'NegReg', (136, 143))	('prostate cancer', 'Disease', (50, 65))	('ST045849', 'Chemical', '-', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('metabolic reprogramming', 'CPA', (89, 112))	('HCC', 'Phenotype', 'HP:0001402', (170, 173))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
48739	33194731	Thus, studies focused on correcting aberrant O-GlcNAcylation to normal levels will need, to prevent or mitigate such off-target and potentially adverse effects.	('O-GlcNAcylation', 'MPA', (45, 60))	('O-GlcNAcylation', 'Chemical', '-', (45, 60))	('aberrant', 'Var', (36, 44))
48742	33194731	Elucidating the functional mechanisms through which O-GlcNAcylation promotes cancer metastasis will provide a theoretical basis for future rational research.	('cancer metastasis', 'Disease', 'MESH:D009362', (77, 94))	('O-GlcNAcylation', 'Var', (52, 67))	('promotes', 'PosReg', (68, 76))	('O-GlcNAcylation', 'Chemical', '-', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer metastasis', 'Disease', (77, 94))
48871	33097743	Systematic investigation of promoter substitutions resulting from somatic intrachromosomal structural alterations in diverse human cancers One of the ways in which genes can become activated in tumors is by somatic structural genomic rearrangements leading to promoter swapping events, typically in the context of gene fusions that cause a weak promoter to be substituted for a strong promoter.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('rearrangements', 'Var', (234, 248))	('human', 'Species', '9606', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('leading to', 'Reg', (249, 259))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (194, 200))	('promoter swapping', 'MPA', (260, 277))
48874	33097743	Copy number alterations (CNAs) significantly contribute to cancer development, usually by causing oncogene amplification or tumor suppressor deletion.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('causing', 'Reg', (90, 97))	('tumor', 'Disease', (124, 129))	('oncogene', 'Protein', (98, 106))	('Copy number alterations', 'Var', (0, 23))	('amplification', 'MPA', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('contribute', 'Reg', (45, 55))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
48875	33097743	Well-characterized examples of cancer driver events involving CNAs are CDKN2A and PTEN deletions or MYC, EGFR and ERBB2 amplifications.	('amplifications', 'Var', (120, 134))	('PTEN', 'Gene', '5728', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CDKN2A', 'Gene', (71, 77))	('MYC', 'Gene', (100, 103))	('EGFR', 'Gene', '1956', (105, 109))	('CDKN2A', 'Gene', '1029', (71, 77))	('ERBB2', 'Gene', '2064', (114, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('deletions', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('MYC', 'Gene', '4609', (100, 103))	('EGFR', 'Gene', (105, 109))	('PTEN', 'Gene', (82, 86))	('cancer', 'Disease', (31, 37))	('ERBB2', 'Gene', (114, 119))
48878	33097743	Furthermore, in a recent study based on whole genome sequencing (WGS) data from 600 tumors, we observed several non-recurrent cases of PS that arose due to intrachromosomal SVs, specifically deletions or inversions, which were associated with transcriptional activation.	('PS', 'Chemical', '-', (135, 137))	('deletions', 'Var', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('inversions', 'Var', (204, 214))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
48880	33097743	In this study, we used 9423 array-based copy number profiles made available by The Cancer Genome Atlas consortium to identify deletions and likely tandem duplications predicted to result in intrachromosomal PS events, due to either proper gene fusions or juxtaposition of strong promoters to upstream regions.	('PS', 'Chemical', '-', (207, 209))	('deletions', 'Var', (126, 135))	('tandem duplications', 'Var', (147, 166))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
48882	33097743	1a), we first sought to identify somatic tandem duplications and deletions using Genome-Wide Human SNP Array 6.0 (SNP6) data from The Cancer Genome Atlas (TCGA; Fig.	('Cancer', 'Disease', (134, 140))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Human', 'Species', '9606', (93, 98))	('deletions', 'Var', (65, 74))
48883	33097743	By comparing with WGS-based SVs from a previous study, available for a subset of samples (600 tumors), we found that 25% of the CNA-inferred SVs had a correspondence in WGS-based SVs and of these, 97% were coherently classified as deletions or duplications in the two datasets.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('deletions', 'Var', (231, 240))
48884	33097743	In the complete cohort, comprising of 9423 tumors from 32 different cancer types, we identified 110,463 predicted deletions and 84,052 tandem duplications that fulfilled our criteria.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', (68, 74))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('deletions', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
48886	33097743	The number of deletions and tandem duplications were typically comparable in a given cancer type (both plots within twofold; Fig.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('deletions', 'Var', (14, 23))	('tandem duplications', 'Var', (28, 47))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
48887	33097743	However, two cancer types, prostate (PRAD) and mesothelioma (MESO), had elevated number of deletions relative to duplications (4.2 and 5.2-fold difference, respectively).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('deletions', 'Var', (91, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('prostate', 'Disease', (27, 35))	('mesothelioma', 'Disease', (47, 59))
48888	33097743	We next identified a subset of SVs that may result in PS (Methods), involving either gene fusions or alternatively cases where the 5' promoter is juxtaposed to the upstream region of the 3' partner (Fig.	('PS', 'Chemical', '-', (54, 56))	('gene fusions', 'Var', (85, 97))	('result in', 'Reg', (44, 53))
48893	33097743	The observed frequency was lower than previously reported, and therefore we manually explored copy number profiles for the complete prostate cancer cohort, which revealed 28 additional cases with deletions potentially fusing these two genes.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('complete prostate cancer', 'Disease', (123, 147))	('deletions', 'Var', (196, 205))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('complete prostate cancer', 'Disease', 'MESH:D011471', (123, 147))
48901	33097743	We also identified the previously reported ESR1-CCDC170 fusion in breast cancer (n = 3), associated with CCDC170 elevated expression resulting from recruiting the strong promoter of ESR1 (p = 0.02; Supplementary Fig.	('ESR1', 'Gene', (43, 47))	('expression', 'MPA', (122, 132))	('CCDC170', 'Gene', '80129', (48, 55))	('elevated', 'PosReg', (113, 121))	('ESR1', 'Gene', (182, 186))	('ESR1', 'Gene', '2099', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('fusion', 'Var', (56, 62))	('CCDC170', 'Gene', (48, 55))	('CCDC170', 'Gene', (105, 112))	('breast cancer', 'Disease', (66, 79))	('CCDC170', 'Gene', '80129', (105, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('recruiting', 'PosReg', (148, 158))	('ESR1', 'Gene', '2099', (182, 186))
48903	33097743	Notable among novel significant cases was predicted fusions between SCAF8 and TIAM2 resulting from deletions bridging these two closely positioned neighbor genes (Fig.	('SCAF8', 'Gene', '22828', (68, 73))	('SCAF8', 'Gene', (68, 73))	('deletions', 'Var', (99, 108))	('TIAM2', 'Gene', '26230', (78, 83))	('TIAM2', 'Gene', (78, 83))	('fusions', 'Var', (52, 59))
48910	33097743	Analysis of RNA-Seq data from all included ovarian and endometrial tumors revealed two additional samples with SCAF8-TIAM2 fusion transcripts in the absence of DNA-level support, suggesting that this could be due to read through events (Fig.	('TIAM2', 'Gene', (117, 122))	('fusion', 'Var', (123, 129))	('TIAM2', 'Gene', '26230', (117, 122))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('SCAF8', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('SCAF8', 'Gene', '22828', (111, 116))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('ovarian and endometrial tumors', 'Disease', 'MESH:D010051', (43, 73))
48913	33097743	Additionally, we found that deletion breakpoints did not overlap with common fragile sites in the HumCFS database.	('deletion', 'Var', (28, 36))	('fragile', 'Disease', 'MESH:D005600', (77, 84))	('fragile', 'Disease', (77, 84))
48915	33097743	Novel recurrent cases were also found in ovarian (n = 6), endometrial (n = 2) and breast (n = 2) cancers involving CCDC6, a coiled-coil domain protein, fusing with ANK3 at the 3' end, which encodes the ankyrin G protein that plays a key role in cell proliferation, as result of tandem duplications (Fig.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('CCDC6', 'Gene', '8030', (115, 120))	('ovarian', 'Disease', 'MESH:D010049', (41, 48))	('CCDC6', 'Gene', (115, 120))	('ovarian', 'Disease', (41, 48))	('cancers', 'Disease', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('ANK3', 'Gene', '288', (164, 168))	('ANK3', 'Gene', (164, 168))	('ankyrin G', 'Gene', (202, 211))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ankyrin G', 'Gene', '288', (202, 211))	('tandem duplications', 'Var', (278, 297))	('endometrial', 'Disease', (58, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('245', '263'))	('breast', 'Disease', (82, 88))
48917	33097743	Here, we observed that fusion with CCDC6 was associated with strong overexpression of ANK3 in all three cancers (Fig.	('CCDC6', 'Gene', '8030', (35, 40))	('fusion', 'Var', (23, 29))	('ANK3', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('overexpression', 'PosReg', (68, 82))	('ANK3', 'Gene', '288', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('CCDC6', 'Gene', (35, 40))
48921	33097743	Another recurrent case (n = 4) was found in stomach, esophageal and lung adenocarcinoma, where SCARB1, a high-density lipoprotein (HDL) receptor, was overexpressed through fusion with NCOR2 due to tandem duplications on chromosome 12q24 (Fig.	('HDL) receptor', 'molecular_function', 'GO:0070506', ('131', '144'))	('SCARB1', 'Gene', '949', (95, 101))	('tandem duplications', 'Var', (197, 216))	('NCOR2', 'Gene', '9612', (184, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (68, 87))	('high-density lipoprotein', 'molecular_function', 'GO:0005321', ('105', '129'))	('stomach', 'Disease', (44, 51))	('fusion', 'Interaction', (172, 178))	('SCARB1', 'Gene', (95, 101))	('NCOR2', 'Gene', (184, 189))	('lung adenocarcinoma', 'Disease', (68, 87))	('esophageal', 'Disease', (53, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('220', '230'))	('overexpressed', 'PosReg', (150, 163))
48924	33097743	Overexpression of SCARB1 has been associated with cancer development and shown to be inversely correlated with survival in multiple cancer types, although no molecular mechanism was proposed.	('associated', 'Reg', (34, 44))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (50, 56))	('SCARB1', 'Gene', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('inversely', 'NegReg', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Overexpression', 'Var', (0, 14))	('SCARB1', 'Gene', '949', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
48925	33097743	Finally, we observed overexpression of LHFPL3 in four stomach tumors harboring KMT2E-LHFPL3 fusions arising due to tandem duplications on chromosome 7q22 (Supplementary Fig.	('tandem duplications', 'Var', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('stomach tumors', 'Disease', (54, 68))	('LHFPL3', 'Gene', '375612', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (92, 99))	('LHFPL3', 'Gene', (39, 45))	('stomach tumors', 'Phenotype', 'HP:0006753', (54, 68))	('LHFPL3', 'Gene', (85, 91))	('overexpression', 'PosReg', (21, 35))	('KMT2E', 'Gene', (79, 84))	('LHFPL3', 'Gene', '375612', (85, 91))	('KMT2E', 'Gene', '55904', (79, 84))	('stomach tumors', 'Disease', 'MESH:D013274', (54, 68))
48935	33097743	Promoter substitutions, whereby structural genomic changes lead to one gene gaining a promoter from another gene, is a known mechanism for transcriptional activation of oncogenes in cancer, but the phenomenon has not previously been comprehensively investigated.	('gaining a', 'PosReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('promoter', 'MPA', (86, 94))	('Promoter substitutions', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('lead', 'Reg', (59, 63))	('cancer', 'Disease', (182, 188))
48948	33097743	In summary, we leveraged CNA and expression profiles available for nearly 10,000 tumors to screen for cases where genes were transcriptionally activated due to fusion with nearby genes having strong promoters, pinpointing several events with potential importance for cancer development.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('activated', 'PosReg', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('fusion', 'Var', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
48953	33097743	WGS-based SV data for a subset of samples (600) was obtained from Alaei-Mahabadi, et al.. SVs resulting in a valid PS cases were identified using the following logic: We considered two different cases: (1) SVs predicted to produce a viable fusion between two genes, i.e.	('fusion', 'Interaction', (240, 246))	('PS', 'Chemical', '-', (115, 117))	('SVs', 'Var', (206, 209))
49015	30873708	PTX3 acted as a regulator of C3-deposition on cancer cells by interacting with the Complement inhibitor Factor H. Interestingly, PTX3-deficiency resulted in increased DNA damage, as shown by more mutations of Trp53, one of the genes targeted by 3-MCA, oxidative DNA damage and expression of DNA damage markers.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('3-MCA', 'Chemical', 'MESH:D008748', (245, 250))	('DNA', 'cellular_component', 'GO:0005574', ('262', '265'))	('C3-deposition', 'Disease', 'MESH:C565169', (29, 42))	('PTX3', 'Gene', (129, 133))	('PTX3', 'Gene', '5806', (129, 133))	('DNA damage', 'MPA', (167, 177))	('PTX3-deficiency', 'Disease', 'MESH:D007153', (129, 144))	('DNA', 'cellular_component', 'GO:0005574', ('291', '294'))	('cancer', 'Disease', (46, 52))	('PTX3', 'Gene', (0, 4))	('C3-deposition', 'Phenotype', 'HP:0012576', (29, 42))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PTX3', 'Gene', '5806', (0, 4))	('Factor H', 'Gene', '3075', (104, 112))	('mutations', 'Var', (196, 205))	('Trp53', 'Gene', (209, 214))	('PTX3-deficiency', 'Disease', (129, 144))	('Trp53', 'Gene', '7157', (209, 214))	('increased', 'PosReg', (157, 166))	('Factor H', 'Gene', (104, 112))	('C3-deposition', 'Disease', (29, 42))	('oxidative', 'MPA', (252, 261))
49016	30873708	Importantly, in selected human mesenchymal and epithelial tumors, the PTX3 promoter and regulatory regions were highly methylated and this epigenetic modification resulted in transcriptional inactivation and silencing of PTX3 expression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('PTX3', 'Gene', '5806', (70, 74))	('PTX3', 'Gene', '5806', (221, 225))	('silencing', 'NegReg', (208, 217))	('epithelial tumors', 'Disease', (47, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'MPA', (226, 236))	('epigenetic', 'Var', (139, 149))	('human', 'Species', '9606', (25, 30))	('epithelial tumors', 'Disease', 'MESH:D002277', (47, 64))	('PTX3', 'Gene', (70, 74))	('PTX3', 'Gene', (221, 225))	('transcriptional', 'MPA', (175, 190))
49017	30873708	In colorectal cancer PTX3 gene methylation and silencing was detected as an early event, already identified in adenomas and stage 1 neoplastic lesions, an observation consistent with an important role in pathogenesis.	('adenomas', 'Disease', 'MESH:D000236', (111, 119))	('neoplastic lesions', 'Disease', 'MESH:D007680', (132, 150))	('neoplastic lesions', 'Disease', (132, 150))	('adenomas', 'Disease', (111, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('silencing', 'NegReg', (47, 56))	('PTX3', 'Gene', (21, 25))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (132, 150))	('methylation', 'Var', (31, 42))	('colorectal cancer', 'Disease', (3, 20))	('PTX3', 'Gene', '5806', (21, 25))	('pathogenesis', 'biological_process', 'GO:0009405', ('204', '216'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
49023	30873708	Along the same line, in myeloproliferative neoplasms, PTX3 levels correlated with mutant JAK2 (JAK2V617F) allele burden, which is well esteblished to sustain leukocyte activation.	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (24, 52))	('correlated', 'Reg', (66, 76))	('PTX3', 'Gene', (54, 58))	('JAK2', 'Gene', '3717', (95, 99))	('JAK2V617F', 'Gene', '3717', (95, 104))	('leukocyte activation', 'biological_process', 'GO:0045321', ('158', '178'))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('JAK2V617F', 'Gene', (95, 104))	('JAK', 'molecular_function', 'GO:0004713', ('89', '92'))	('JAK2', 'Gene', '3717', (89, 93))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (24, 52))	('PTX3', 'Gene', '5806', (54, 58))	('JAK2', 'Gene', (95, 99))	('JAK2', 'Gene', (89, 93))	('mutant', 'Var', (82, 88))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('myeloproliferative neoplasms', 'Disease', (24, 52))
49048	30873708	Blocking IL-1 resulted in an increase in lean body mass, improved parameters of quality of life, decreased pain and decreased constitutional symptoms.. Reducing IL-1alpha may also reduce inflammation-mediated immunosuppression, both impacting on increased survival and immune-mediated tumor regression.	('inflammation', 'Disease', 'MESH:D007249', (187, 199))	('pain', 'Phenotype', 'HP:0012531', (107, 111))	('survival', 'CPA', (256, 264))	('reduce', 'NegReg', (180, 186))	('decreased pain', 'Disease', 'MESH:D010146', (97, 111))	('IL-1', 'molecular_function', 'GO:0005149', ('9', '13'))	('IL-1alpha', 'Gene', '3552', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('Reducing', 'Var', (152, 160))	('decreased pain', 'Phenotype', 'HP:0007328', (97, 111))	('inflammation', 'Disease', (187, 199))	('IL-1', 'Gene', '3552', (161, 165))	('decreased pain', 'Disease', (97, 111))	('IL-1', 'Gene', '3552', (9, 13))	('IL-1', 'molecular_function', 'GO:0005149', ('161', '165'))	('IL-1', 'Gene', (161, 165))	('IL-1alpha', 'Gene', (161, 170))	('constitutional symptoms', 'Phenotype', 'HP:0025142', (126, 149))	('tumor', 'Disease', (285, 290))	('impacting', 'Reg', (233, 242))	('IL-1', 'Gene', (9, 13))	('increased', 'PosReg', (246, 255))	('inflammation', 'biological_process', 'GO:0006954', ('187', '199'))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
49050	30873708	In the seminal CANTOS study with 10,061 patients with atherosclerosis and high CRP levels, anti-IL-1beta (Canakinumab) resulted in a major (>50%) reduction in the incidence and mortality from lung cancer.	('CRP', 'Gene', '1401', (79, 82))	('anti-IL-1beta', 'Var', (91, 104))	('atherosclerosis', 'Disease', 'MESH:D050197', (54, 69))	('atherosclerosis', 'Phenotype', 'HP:0002621', (54, 69))	('lung cancer', 'Disease', (192, 203))	('IL-1', 'molecular_function', 'GO:0005149', ('96', '100'))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('mortality', 'Disease', (177, 186))	('patients', 'Species', '9606', (40, 48))	('atherosclerosis', 'Disease', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('CRP', 'Gene', (79, 82))	('mortality', 'Disease', 'MESH:D003643', (177, 186))	('reduction', 'NegReg', (146, 155))
49057	30873708	Inhibition of IL-1R8 unleashed NK cell-mediated resistance against liver and lung carcinogenesis and metastasis, two NK cell rich anatomical sites.	('lung carcinogenesis', 'Disease', 'MESH:D063646', (77, 96))	('IL-1R', 'molecular_function', 'GO:0004908', ('14', '19'))	('IL-1R8', 'Gene', (14, 20))	('unleashed', 'Reg', (21, 30))	('IL-1R8', 'Gene', '59307', (14, 20))	('Inhibition', 'Var', (0, 10))	('lung carcinogenesis', 'Disease', (77, 96))
49069	30873708	Interestingly, signals which orient TAM in a protumor direction (M2-like) do not inhibit their ADCC and ADCP effector function, or actually increase it.	('TAM', 'Chemical', '-', (36, 39))	('tumor', 'Disease', (48, 53))	('ADCC', 'biological_process', 'GO:0001788', ('95', '99'))	('inhibit', 'NegReg', (81, 88))	('ADCP', 'Chemical', '-', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ADCC', 'MPA', (95, 99))	('increase', 'PosReg', (140, 148))	('signals', 'Var', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('ADCP effector function', 'MPA', (104, 126))
49100	32185202	However, our previous work reported that low levels of S1P expression are associated with the severity of malaria and are correlated with the presence of thrombocytopenia and anemia.	('thrombocytopenia', 'Disease', (154, 170))	('malaria', 'Disease', 'MESH:D008288', (106, 113))	('anemia', 'Disease', (175, 181))	('anemia', 'Disease', 'MESH:D000740', (175, 181))	('low', 'Var', (41, 44))	('expression', 'MPA', (59, 69))	('S1P', 'Gene', '13609', (55, 58))	('correlated', 'Reg', (122, 132))	('malaria', 'Disease', (106, 113))	('thrombocytopenia', 'Disease', 'MESH:D013921', (154, 170))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (154, 170))	('anemia', 'Phenotype', 'HP:0001903', (175, 181))	('S1P', 'Gene', (55, 58))	('associated', 'Reg', (74, 84))
49141	32185202	Therefore, S1PR-3 might affect the pathogenesis of PE in malaria.	('PE', 'Disease', 'MESH:D011654', (51, 53))	('malaria', 'Disease', 'MESH:D008288', (57, 64))	('pathogenesis', 'biological_process', 'GO:0009405', ('35', '47'))	('S1PR-3', 'Var', (11, 17))	('malaria', 'Disease', (57, 64))	('affect', 'Reg', (24, 30))	('PE', 'Phenotype', 'HP:0100598', (51, 53))
49147	32185202	In the pulmonary EC model of acute injury by LPS, the expression levels of S1PR-1 and S1PR-3 were significantly increased, but the expression levels of SphK-1 and SphK-2 did not change significantly after LPS induction.	('LPS', 'Chemical', 'MESH:D008070', (45, 48))	('S1PR-1', 'Gene', '1901', (75, 81))	('S1PR-3', 'Var', (86, 92))	('S1PR-1', 'Gene', (75, 81))	('LPS', 'Chemical', 'MESH:D008070', (205, 208))	('expression levels', 'MPA', (54, 71))	('increased', 'PosReg', (112, 121))	('acute injury', 'Disease', (29, 41))	('acute injury', 'Disease', 'MESH:D058186', (29, 41))	('pulmonary EC', 'Disease', (7, 19))
49186	31616158	This includes translocations of the anaplastic lymphoma kinase (ALK) gene and the ROS1 proto-oncogene 1 receptor tyrosine kinase (ROS1) gene; rearrangements in kinase-encoding genes such as epidermal growth factor receptor (EGFR), Kirsten ras (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), neurotrophic tyrosine receptor kinase (NTRK), and rearranged during transfection (RET); fusions of neuregulin 1 (NRG1) and fibroblast growth factor receptor 1/3 (FGFR1/3); human epidermal growth factor receptor 2 (HER2) insertion; and AKT serine/threonine kinase 1 (AKT1) mutation.	('Kirsten ras', 'Gene', (231, 242))	('NRG1', 'Gene', '211323', (418, 422))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (251, 296))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (36, 55))	('insertion', 'Var', (525, 534))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', (251, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('EGFR', 'molecular_function', 'GO:0005006', ('224', '228'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('190', '213'))	('mutation', 'Var', (577, 585))	('AKT1', 'Gene', (571, 575))	('epidermal growth factor receptor', 'Gene', (190, 222))	('KRAS', 'Gene', '16653', (244, 248))	('HER2', 'Gene', (519, 523))	('FGFR1/3', 'Gene', (467, 474))	('neuregulin 1', 'Gene', (404, 416))	('TRK', 'Gene', (345, 348))	('Kirsten ras', 'Gene', '16653', (231, 242))	('tyrosine', 'Chemical', 'None', (113, 121))	('BRAF', 'Gene', '109880', (298, 302))	('receptor tyrosine kinase', 'Gene', '5979', (104, 128))	('AKT serine/threonine kinase 1', 'Gene', '207', (540, 569))	('human', 'Species', '9606', (477, 482))	('epidermal growth factor receptor 2', 'Gene', '2064', (483, 517))	('fibroblast growth factor receptor 1/3', 'Gene', '14182;14184', (428, 465))	('FGFR1/3', 'Gene', '14182;14184', (467, 474))	('tyrosine', 'Chemical', 'None', (318, 326))	('TRK', 'Gene', '4914', (345, 348))	('FGFR', 'molecular_function', 'GO:0005007', ('467', '471'))	('receptor tyrosine kinase', 'Gene', (104, 128))	('NRG1', 'Gene', (418, 422))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('BRAF', 'Gene', (298, 302))	('epidermal growth factor receptor', 'Gene', '13649', (190, 222))	('epidermal growth factor receptor', 'Gene', '13649', (483, 515))	('epidermal growth factor receptor 2', 'Gene', (483, 517))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('483', '506'))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('428', '452'))	('HER2', 'Gene', '2064', (519, 523))	('AKT serine/threonine kinase 1', 'Gene', (540, 569))	('neuregulin 1', 'Gene', '211323', (404, 416))	('AKT1', 'Gene', '207', (571, 575))	('fibroblast growth factor receptor 1/3', 'Gene', (428, 465))	('KRAS', 'Gene', (244, 248))
49188	31616158	It has, therefore, become standard clinical practice to test for gene mutations and fusions in patients with NSCLC and to tailor treatment strategies accordingly.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('gene mutations', 'Var', (65, 79))	('fusions', 'Var', (84, 91))	('patients', 'Species', '9606', (95, 103))	('test', 'Reg', (56, 60))	('NSCLC', 'Disease', (109, 114))
49189	31616158	In the present review, we briefly discuss the role of ALK mutations and translocations in NSCLC, the testing methods for identifying ALK-positive (ALK+) NSCLC, and present the evidence for approved ALK-targeted therapies.	('ALK', 'Gene', (54, 57))	('mutations', 'Var', (58, 67))	('translocations', 'Var', (72, 86))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))
49193	31616158	ALK mutations have been implicated in tumorigenesis, with involvement in the initiation and progression of several cancer types, including lymphomas, neuroblastoma, and NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('lymphomas', 'Disease', (139, 148))	('NSCLC', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lymphomas', 'Disease', 'MESH:D008223', (139, 148))	('neuroblastoma', 'Disease', 'MESH:D009447', (150, 163))	('ALK', 'Gene', (0, 3))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('neuroblastoma', 'Disease', (150, 163))	('implicated', 'Reg', (24, 34))	('involvement', 'Reg', (58, 69))	('lymphomas', 'Phenotype', 'HP:0002665', (139, 148))	('mutations', 'Var', (4, 13))	('neuroblastoma', 'Phenotype', 'HP:0003006', (150, 163))
49194	31616158	ALK translocations typically cause an increase in tyrosine kinase activity, resulting in increased cell proliferation and survival via their effects on signaling pathways that include phospholipase Cgamma, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) signaling cascades, among others.	('translocations', 'Var', (4, 18))	('cell proliferation', 'CPA', (99, 117))	('AKT', 'Gene', (261, 264))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('mTOR', 'Gene', '2475', (298, 302))	('kinase activity', 'molecular_function', 'GO:0016301', ('59', '74'))	('MAPK', 'Gene', (343, 347))	('signaling pathways', 'Pathway', (152, 170))	('mammalian target of rapamycin', 'Gene', '2475', (267, 296))	('increase', 'PosReg', (38, 46))	('tyrosine', 'Chemical', 'None', (50, 58))	('tyrosine kinase activity', 'MPA', (50, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('phospholipase', 'Enzyme', (184, 197))	('MAPK', 'Gene', '5594', (343, 347))	('AKT', 'Gene', '207', (261, 264))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (206, 226))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('343', '358'))	('MAPK', 'molecular_function', 'GO:0004707', ('343', '347'))	('mammalian target of rapamycin', 'Gene', (267, 296))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('protein', 'cellular_component', 'GO:0003675', ('327', '334'))	('PI3K', 'molecular_function', 'GO:0016303', ('237', '241'))	('increased', 'PosReg', (89, 98))	('survival', 'CPA', (122, 130))	('increase in tyrosine kinase activity', 'Phenotype', 'HP:0003231', (38, 74))	('ALK', 'Gene', (0, 3))	('mTOR', 'Gene', (298, 302))
49195	31616158	Translocation events at the ALK locus generate a variety of ALK fusion proteins, such as NPM1-ALK, that are found in multiple types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('Translocation', 'Var', (0, 13))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ALK', 'Gene', (28, 31))	('NPM1', 'Gene', (89, 93))	('NPM1', 'Gene', '4869', (89, 93))	('ALK fusion proteins', 'Protein', (60, 79))
49203	31616158	Demographic characteristics associated with more frequent rearrangements include young, female, never- or light-smoker status, or the presence of tumors with an adenocarcinoma histology.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('rearrangements', 'Var', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('adenocarcinoma', 'Disease', (161, 175))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (146, 152))
49204	31616158	The reported prevalence of ALK rearrangements in Chinese patients ranges between 3.3% and 11.6%, compared with 30% of patients with EGFR mutations; however, the prevalence of ALK rearrangements in the Chinese population is similar to that reported in other Asian populations (for example, 7% in Japanese patients).	('patients', 'Species', '9606', (304, 312))	('patients', 'Species', '9606', (57, 65))	('rearrangements', 'Var', (31, 45))	('mutations', 'Var', (137, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('patients', 'Species', '9606', (118, 126))
49208	31616158	ALK-EML4 gene fusions and ALK rearrangements in NSCLC can be identified in clinical specimens using several techniques: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and next generation sequencing (NGS).	('NSCLC', 'Disease', (48, 53))	('ALK-EML4', 'Gene', (0, 8))	('transcriptase', 'molecular_function', 'GO:0003968', ('199', '212'))	('transcriptase', 'molecular_function', 'GO:0003899', ('199', '212'))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('transcriptase', 'molecular_function', 'GO:0034062', ('199', '212'))	('fusions', 'Var', (14, 21))
49221	31616158	In China, a multicenter survey of 932 patients with advanced NSCLC showed that 71.4% of patients were tested for EGFR gene mutations, 44.7% were tested for ALK gene fusions, and 13.7% were tested for ROS1 gene fusions.	('patients', 'Species', '9606', (88, 96))	('tested', 'Reg', (102, 108))	('NSCLC', 'Disease', (61, 66))	('EGFR', 'Gene', (113, 117))	('patients', 'Species', '9606', (38, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('ALK', 'Protein', (156, 159))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('mutations', 'Var', (123, 132))
49229	31616158	Ceritinib, more potent than crizotinib, is active against multiple ALK mutations that appear to result in resistance to crizotinib.	('crizotinib', 'Chemical', 'MESH:C551994', (120, 130))	('crizotinib', 'Chemical', 'MESH:C551994', (28, 38))	('mutations', 'Var', (71, 80))	('Ceritinib', 'Chemical', 'MESH:C586847', (0, 9))	('ALK', 'Gene', (67, 70))
49233	31616158	Targets for each TKI are as follows: alectinib (inhibitor of ALK tyrosine kinase and RET kinase, including the ALK L1196M mutant); ensartinib (ROS proto-oncogene 1 receptor tyrosine kinase, ROS1; MET protocol-oncogene receptor tyrosine kinase, MET; STE20 like kinase, SLK; AXL receptor tyrosine kinase, AXL; leukocyte receptor tyrosine kinase, LTK; ABL proto-oncogene 1 non-receptor tyrosine kinase, ABL1; and EPH receptor A2, EPHA2); brigatinib (inhibitor of ALK and EGFR, including ALK L1196M and EGFR T790M mutants); lorlatinib (ALK and ROS1); and repotrectinib (ALK, ROS1, and TRK).	('ROS proto-oncogene 1 receptor tyrosine kinase', 'Gene', (143, 188))	('tyrosine', 'Chemical', 'None', (173, 181))	('ensartinib', 'Chemical', 'None', (131, 141))	('EPH receptor A2', 'Gene', (410, 425))	('SLK', 'Gene', (268, 271))	('STE20 like kinase', 'Gene', '9748', (249, 266))	('ABL1', 'Gene', '25', (400, 404))	('ROS proto-oncogene 1 receptor tyrosine kinase', 'Gene', '6098', (143, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('468', '472'))	('ABL proto-oncogene 1 non-receptor tyrosine kinase', 'Gene', (349, 398))	('tyrosine', 'Chemical', 'None', (227, 235))	('receptor tyrosine kinase', 'Gene', '5979', (218, 242))	('EPHA2', 'Gene', (427, 432))	('brigatinib', 'Chemical', 'None', (435, 445))	('SLK', 'Gene', '9748', (268, 271))	('AXL', 'Gene', '558', (273, 276))	('L1196M', 'Var', (488, 494))	('LTK', 'Gene', '4058', (344, 347))	('tyrosine', 'Chemical', 'None', (65, 73))	('receptor tyrosine kinase', 'Gene', (218, 242))	('AXL', 'Gene', '558', (303, 306))	('receptor tyrosine kinase', 'Gene', '5979', (318, 342))	('tyrosine', 'Chemical', 'None', (327, 335))	('TRK', 'Gene', (581, 584))	('tyrosine', 'Chemical', 'None', (383, 391))	('LTK', 'Gene', (344, 347))	('receptor tyrosine kinase', 'Gene', '5979', (374, 398))	('T790M', 'Var', (504, 509))	('AXL', 'Gene', (273, 276))	('EPHA2', 'Gene', '1969', (427, 432))	('T790M', 'Mutation', 'p.T790M', (504, 509))	('STE20 like kinase', 'Gene', (249, 266))	('ABL proto-oncogene 1 non-receptor tyrosine kinase', 'Gene', '25', (349, 398))	('tyrosine', 'Chemical', 'None', (286, 294))	('receptor tyrosine kinase', 'Gene', (318, 342))	('alectinib', 'Chemical', 'MESH:C582670', (37, 46))	('receptor tyrosine kinase', 'Gene', '5979', (277, 301))	('receptor tyrosine kinase', 'Gene', '5979', (164, 188))	('TRK', 'Gene', '4914', (581, 584))	('AXL', 'Gene', (303, 306))	('ABL1', 'Gene', (400, 404))	('L1196M', 'Mutation', 'p.L1196M', (488, 494))	('EGFR', 'Gene', (499, 503))	('EGFR', 'molecular_function', 'GO:0005006', ('499', '503'))	('L1196M', 'Mutation', 'p.L1196M', (115, 121))	('lorlatinib', 'Chemical', 'None', (520, 530))	('EPH receptor A2', 'Gene', '1969', (410, 425))	('receptor tyrosine kinase', 'Gene', (277, 301))
49235	31616158	First-line drug regimens in cases of advanced NSCLC include platinum-doublet chemotherapy and targeted molecular therapy drugs, such as gefitinib, erlotinib, or icotinib if EGFR mutations are detected; or crizotinib if ALK fusion genes are detected.	('erlotinib', 'Chemical', 'MESH:C400278', (147, 156))	('icotinib', 'Chemical', 'MESH:C531470', (161, 169))	('NSCLC', 'Disease', (46, 51))	('platinum', 'Chemical', 'MESH:D010984', (60, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('gefitinib', 'Chemical', 'MESH:C419708', (136, 145))	('EGFR', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))	('crizotinib', 'Chemical', 'MESH:C551994', (205, 215))
49237	31616158	More recently, Chinese guidelines for the treatment and diagnosis of ALK+ and ROS1+ NSCLC were published.	('NSCLC', 'Disease', (84, 89))	('ROS1+', 'Var', (78, 83))	('ALK+', 'Disease', (69, 73))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))
49246	31616158	Alectinib (CH5424802/RO5424802) is a potent and highly selective second-generation inhibitor of ALK tyrosine kinase that acts only on ALK+ NSCLC.	('Alectinib', 'Chemical', 'MESH:C582670', (0, 9))	('CH5424802', 'Chemical', 'MESH:C582670', (11, 20))	('NSCLC', 'Disease', (139, 144))	('tyrosine', 'Chemical', 'None', (100, 108))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('CH5424802/RO5424802', 'Var', (11, 30))	('RO5424802', 'Chemical', 'MESH:C582670', (21, 30))
49253	31616158	The unique chemical structure of alectinib means it 1) targets both ALK rearrangements and RET fusion+ tumors, but not MET or ROS1 kinase activity, and 2) overcomes acquired resistance to crizotinib through its ability to target the mutations that develop with crizotinib treatment.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('crizotinib', 'Chemical', 'MESH:C551994', (188, 198))	('alectinib', 'Chemical', 'MESH:C582670', (33, 42))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('crizotinib', 'Chemical', 'MESH:C551994', (261, 271))	('kinase activity', 'molecular_function', 'GO:0016301', ('131', '146'))	('overcomes', 'NegReg', (155, 164))	('ALK', 'Disease', (68, 71))	('acquired resistance', 'MPA', (165, 184))	('mutations', 'Var', (233, 242))
49255	31616158	Together, these characteristics may contribute to its ability to overcome resistance to other ALK inhibitors caused by mutations and its increased potency over crizotinib for treating CNS metastases.	('crizotinib', 'Chemical', 'MESH:C551994', (160, 170))	('potency', 'MPA', (147, 154))	('metastases', 'Disease', (188, 198))	('mutations', 'Var', (119, 128))	('metastases', 'Disease', 'MESH:D009362', (188, 198))
49263	31616158	The global phase III ALEX study demonstrated prolonged PFS in newly diagnosed patients receiving alectinib versus those receiving crizotinib.	('crizotinib', 'Chemical', 'MESH:C551994', (130, 140))	('alectinib', 'Chemical', 'MESH:C582670', (97, 106))	('prolonged', 'PosReg', (45, 54))	('patients', 'Species', '9606', (78, 86))	('PFS', 'MPA', (55, 58))	('alectinib', 'Var', (97, 106))
49274	31616158	The percent of patients experiencing disease progression or death was higher with crizotinib versus alectinib treatment (60% vs 21%, respectively).	('patients', 'Species', '9606', (15, 23))	('death', 'Disease', 'MESH:D003643', (60, 65))	('death', 'Disease', (60, 65))	('alectinib', 'Chemical', 'MESH:C582670', (100, 109))	('crizotinib', 'Chemical', 'MESH:C551994', (82, 92))	('disease progression', 'CPA', (37, 56))	('crizotinib', 'Var', (82, 92))
49293	31616158	In the phase III ALUR study of European and Asian patients previously treated with crizotinib, it was shown that there was a greater CNS ORR in patients receiving alectinib versus those receiving chemotherapy (54.2% vs 0%, p<0.001).	('patients', 'Species', '9606', (50, 58))	('alectinib', 'Chemical', 'MESH:C582670', (163, 172))	('crizotinib', 'Chemical', 'MESH:C551994', (83, 93))	('patients', 'Species', '9606', (144, 152))	('greater', 'PosReg', (125, 132))	('alectinib', 'Var', (163, 172))	('CNS ORR', 'CPA', (133, 140))
49303	31616158	Furthermore, the phase III ALEX trial also reported fewer grade 3-5 adverse events in treatment-naive patients receiving alectinib relative to those receiving crizotinib.	('fewer', 'NegReg', (52, 57))	('grade 3-5 adverse events', 'MPA', (58, 82))	('alectinib', 'Chemical', 'MESH:C582670', (121, 130))	('patients', 'Species', '9606', (102, 110))	('alectinib', 'Var', (121, 130))	('crizotinib', 'Chemical', 'MESH:C551994', (159, 169))
49306	31616158	Similar results were also observed in the phase III ALUR trial of crizotinib-pretreated patients and in the phase III ALESIA trial in Asian patients: fewer grade >=3 adverse events and fewer adverse events leading to discontinuation occurred in patients receiving alectinib versus those receiving the other treatment.	('patients', 'Species', '9606', (245, 253))	('alectinib', 'Chemical', 'MESH:C582670', (264, 273))	('patients', 'Species', '9606', (88, 96))	('alectinib', 'Var', (264, 273))	('crizotinib', 'Chemical', 'MESH:C551994', (66, 76))	('patients', 'Species', '9606', (140, 148))	('fewer', 'NegReg', (150, 155))	('grade >=3 adverse events', 'MPA', (156, 180))
49309	31616158	Currently recommended testing methods for identifying ALK gene rearrangements in NSCLC patients include the use of Ventana IHC, which is recommended by the Chinese guidelines.	('ALK gene', 'Gene', (54, 62))	('rearrangements', 'Var', (63, 77))	('NSCLC', 'Disease', (81, 86))	('patients', 'Species', '9606', (87, 95))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
49319	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))
49320	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))
49327	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))
49348	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))
49354	31299995	CD8+ TILs density was assessed by using a mouse anti-CD8 monoclonal antibody (M7103, clone C8144B, DAKO).	('antibody', 'molecular_function', 'GO:0003823', ('68', '76'))	('C8144B', 'SUBSTITUTION', 'None', (91, 97))	('CD8', 'Gene', (53, 56))	('mouse', 'Species', '10090', (42, 47))	('CD8', 'Gene', '925', (53, 56))	('antibody', 'cellular_component', 'GO:0042571', ('68', '76'))	('CD8', 'Gene', (0, 3))	('antibody', 'cellular_component', 'GO:0019815', ('68', '76'))	('CD8', 'Gene', '925', (0, 3))	('antibody', 'cellular_component', 'GO:0019814', ('68', '76'))	('C8144B', 'Var', (91, 97))
49357	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))
49370	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))
49373	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))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('FGFR1', 'Gene', '2260', (11, 16))
49375	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', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('ALK', 'Gene', (72, 75))
49380	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))
49382	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))
49384	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))
49386	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))
49397	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))
49398	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))
49401	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))
49404	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))
49405	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))
49406	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))
49407	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))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('CDKN2A', 'Gene', '1029', (97, 103))	('amplifications', 'Var', (70, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('PIK3CA', 'Gene', (63, 69))	('lower', 'NegReg', (139, 144))	('FGFR1', 'Gene', (46, 51))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('PIK3CA', 'Gene', '5290', (63, 69))	('FGFR1', 'Gene', '2260', (46, 51))	('loss', 'NegReg', (89, 93))
49414	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))	('discriminatory', 'MPA', (50, 64))	('PD-L1', 'Gene', (26, 31))	('TMB', 'Var', (17, 20))	('PD-L1', 'Gene', '29126', (26, 31))	('CD8', 'Gene', (36, 39))	('CD8', 'Gene', '925', (36, 39))
49415	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))
49418	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))
49419	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))
49430	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))
49441	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))
49442	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))
49443	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))	('PIK3CA', 'Gene', '5290', (54, 60))	('CDKN2A', 'Gene', '1029', (88, 94))	('loss', 'Var', (80, 84))	('EGFR', 'Gene', '1956', (44, 48))	('lower', 'NegReg', (131, 136))	('EGFR', 'Gene', (44, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('amplifications', 'Var', (61, 75))	('PIK3CA', 'Gene', (54, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
49444	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))	('immune response', 'biological_process', 'GO:0006955', ('240', '255'))	('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))
49446	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))
49449	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))	('oncogenesis', 'biological_process', 'GO:0007048', ('78', '89'))	('KEAP1', 'Gene', (23, 28))	('destroy', 'NegReg', (45, 52))
49450	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))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('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))	('tumor', 'Disease', (285, 290))	('lead to', 'Reg', (143, 150))	('increased', 'PosReg', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
49453	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))
49454	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))
49466	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))
49473	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))
49479	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))	('higher', 'PosReg', (82, 88))	('PIK3CA', 'Gene', (41, 47))	('TMB', 'MPA', (89, 92))	('CD8', 'Gene', (103, 106))	('lower', 'NegReg', (97, 102))	('PD-L1', 'Gene', (178, 183))	('PIK3CA', 'Gene', '5290', (41, 47))	('PD-L1', 'Gene', '29126', (178, 183))	('TMB', 'Chemical', '-', (89, 92))	('amplification', 'Var', (48, 61))
49488	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))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('ALK', 'Gene', (75, 78))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('ALK', 'Gene', '238', (75, 78))	('patients', 'Species', '9606', (6, 14))
49489	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))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('squamous cell carcinoma', 'Disease', (20, 43))	('ALK', 'Gene', (85, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('EGFR', 'Gene', (49, 53))	('patients', 'Species', '9606', (6, 14))	('ALK', 'Gene', '238', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
49490	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))	('EGFR', 'molecular_function', 'GO:0005006', ('265', '269'))	('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))
49493	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))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('ALK', 'Gene', '238', (194, 197))	('EGFR', 'Gene', (86, 90))	('negative', 'NegReg', (12, 20))	('patients', 'Species', '9606', (180, 188))
49498	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.	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))	('EGFR', 'Gene', '1956', (268, 272))	('mutation', 'Var', (273, 281))	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('268', '272'))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('51', '74'))	('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', (166, 169))	('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))	('overall survival', 'MPA', (217, 233))
49500	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))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('NSCLC', 'Disease', (16, 21))	('EGFR', 'Gene', (149, 153))	('mutation', 'Var', (128, 136))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))
49501	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))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
49502	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', 'molecular_function', 'GO:0005006', ('287', '291'))	('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))	('EGFR', 'Gene', '1956', (287, 291))	('EGFR', 'Gene', (287, 291))	('patients', 'Species', '9606', (330, 338))	('patients', 'Species', '9606', (223, 231))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))
49503	31144459	Smoking history and regional lymph nodes involvement were identified as independent predictors of EGFR mutation in multivariate analysis.	('EGFR', 'Gene', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (98, 102))	('mutation', 'Var', (103, 111))
49506	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))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('ALK', 'Gene', '238', (76, 79))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (176, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('176', '180'))	('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))
49507	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.	('NSCLC', 'Disease', (271, 276))	('ALK', 'Gene', '238', (305, 308))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('NSCLC', 'Phenotype', 'HP:0030358', (271, 276))	('ALK', 'Gene', (305, 308))	('EGFR', 'Gene', '1956', (132, 136))	('mutation', 'Var', (137, 145))	('ALK', 'Gene', '238', (193, 196))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('patients', 'Species', '9606', (257, 265))	('EGFR', 'Gene', (287, 291))	('ALK', 'Gene', (193, 196))	('mutations', 'Var', (292, 301))	('EGFR', 'molecular_function', 'GO:0005006', ('287', '291'))	('ALK', 'Gene', '238', (150, 153))	('ALK', 'Gene', (150, 153))	('EGFR', 'Gene', (132, 136))	('NSCLC', 'Disease', 'MESH:D002289', (271, 276))	('EGFR', 'Gene', '1956', (287, 291))	('EGFR', 'Gene', (173, 177))
49512	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
49513	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))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('343', '347'))	('EGFR', 'molecular_function', 'GO:0005006', ('394', '398'))	('EGFR', 'molecular_function', 'GO:0005006', ('264', '268'))	('ALK', 'Gene', '238', (231, 234))	('EGFR', 'Gene', '1956', (343, 347))	('ALK', 'Gene', '238', (412, 415))	('ALK', 'Gene', (231, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('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))	('metastases', 'Disease', 'MESH:D009362', (439, 449))	('ALK', 'Gene', (348, 351))
49524	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))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))
49525	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))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('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))
49528	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))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('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))
49535	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))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('19del', 'Var', (96, 101))	('21L858R', 'Var', (106, 113))	('patients', 'Species', '9606', (10, 18))	('L858R', 'Mutation', 'rs121434568', (108, 113))
49536	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))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('T790M', 'Mutation', 'rs121434569', (89, 94))	('EGFR', 'Gene', '1956', (36, 40))	('L858R', 'Mutation', 'rs121434568', (79, 84))	('T790M', 'Var', (89, 94))	('EGFR', 'Gene', (36, 40))
49538	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))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('ALK', 'Gene', '238', (86, 89))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('ALK', 'Gene', (86, 89))	('patients', 'Species', '9606', (6, 14))
49539	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))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('squamous cell carcinoma', 'Disease', (20, 43))	('ALK', 'Gene', '238', (93, 96))	('EGFR', 'Gene', (49, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('patients', 'Species', '9606', (6, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('ALK', 'Gene', (93, 96))
49540	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))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('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))
49541	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))	('EGFR', 'molecular_function', 'GO:0005006', ('284', '288'))
49542	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))	('IV tumor', 'Disease', 'MESH:D009369', (184, 192))	('EGFR', 'Gene', '1956', (71, 75))	('patients', 'Species', '9606', (6, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('mutation', 'Var', (76, 84))	('EGFR', 'Gene', (71, 75))	('pleural nodules metastases', 'Disease', 'MESH:D009362', (240, 266))
49543	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))	('EGFR', 'molecular_function', 'GO:0005006', ('225', '229'))
49544	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))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
49545	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))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))
49548	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))	('patients', 'Species', '9606', (6, 14))	('ALK', 'Gene', (79, 82))
49552	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))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('ALK', 'Gene', '238', (123, 126))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (52, 60))
49553	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))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('ALK', 'Gene', '238', (207, 210))	('EGFR', 'Gene', (86, 90))	('negative', 'NegReg', (12, 20))
49554	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))	('squamous carcinoma', 'Disease', 'MESH:D002294', (149, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (41, 55))	('ALK', 'Gene', '238', (209, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('ALK', 'Gene', (209, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('EGFR', 'Gene', (175, 179))	('squamous carcinoma', 'Disease', (149, 167))	('ALK', 'Gene', '238', (119, 122))	('ALK', 'Gene', (119, 122))	('EGFR', 'Gene', '1956', (114, 118))	('adenocarcinoma', 'Disease', (41, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('175', '179'))	('mutation', 'Var', (180, 188))	('EGFR', 'Gene', '1956', (175, 179))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (149, 167))
49556	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))
49560	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))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('mutation', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('mutation', 'Var', (153, 161))
49561	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', 'molecular_function', 'GO:0005006', ('127', '131'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('244', '248'))	('brain metastases', 'Disease', 'MESH:D009362', (252, 268))	('brain metastases', 'Disease', (252, 268))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
49564	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.	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('NSCLC', 'Disease', (224, 229))	('EGFR', 'Gene', '1956', (211, 215))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('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))
49567	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))	('patients', 'Species', '9606', (208, 216))	('ALK', 'Gene', '238', (261, 264))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('EGFR', 'molecular_function', 'GO:0005006', ('233', '237'))	('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))
49572	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))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('NSCLC', 'Disease', (130, 135))	('ALK', 'Gene', (163, 166))
49586	31273306	Taken together, these results indicate that aberrant expression of KS is predictive of pancreatic cancer progression and metastasis and may serve as a novel prognostic biomarker for pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('metastasis', 'CPA', (121, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('pancreatic cancer', 'Disease', (87, 104))	('progression', 'CPA', (105, 116))	('pancreatic cancer', 'Disease', (182, 199))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('KS', 'Chemical', 'MESH:D007632', (67, 69))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('aberrant expression', 'Var', (44, 63))
49591	31273306	In tissues, KS chains can be either N- or O-linked to the proteoglycan core protein.	('O-linked', 'Var', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('KS chains', 'Protein', (12, 21))	('KS', 'Chemical', 'MESH:D007632', (12, 14))	('core', 'cellular_component', 'GO:0019013', ('71', '75'))	('proteoglycan', 'molecular_function', 'GO:0005203', ('58', '70'))
49597	31273306	Dysregulation of KS biosynthesis has been associated with numerous diseased conditions, including macular degeneration and keratoconus, amyotrophic lateral sclerosis, Alzheimer's diseases, and mucopolysaccharidosis IV.	('KS', 'Chemical', 'MESH:D007632', (17, 19))	('biosynthesis', 'biological_process', 'GO:0009058', ('20', '32'))	('macular degeneration', 'Phenotype', 'HP:0000608', (98, 118))	('amyotrophic lateral sclerosis', 'Disease', (136, 165))	('Dysregulation', 'Var', (0, 13))	('keratoconus', 'Disease', (123, 134))	('associated', 'Reg', (42, 52))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (136, 165))	('keratoconus', 'Phenotype', 'HP:0000563', (123, 134))	('mucopolysaccharidosis IV', 'Disease', (193, 217))	('mucopolysaccharidosis IV', 'Disease', 'MESH:D009085', (193, 217))	('macular degeneration', 'Disease', (98, 118))	("Alzheimer's diseases", 'Disease', (167, 187))	("Alzheimer's diseases", 'Disease', 'MESH:D000544', (167, 187))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (136, 165))
49598	31273306	In addition, several studies have reported that aberrant expression of KS is highly associated with malignant conditions such as Burkitt's lymphoma, astrocytic tumors, glioblastoma, and in human embryonic cancer cells.	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('embryonic cancer', 'Disease', 'MESH:D009373', (195, 211))	('aberrant expression', 'Var', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('associated', 'Reg', (84, 94))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (129, 147))	('embryonic cancer', 'Disease', (195, 211))	('human', 'Species', '9606', (189, 194))	('astrocytic tumors', 'Disease', (149, 166))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (129, 147))	('KS', 'Chemical', 'MESH:D007632', (71, 73))	("Burkitt's lymphoma", 'Disease', (129, 147))	('astrocytic tumors', 'Disease', 'MESH:D001254', (149, 166))	('glioblastoma', 'Disease', 'MESH:D005909', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glioblastoma', 'Disease', (168, 180))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (168, 180))	('embryonic cancer', 'Phenotype', 'HP:0002898', (195, 211))
49611	31273306	In addition to this, we also observed the correlation of aberrant expression of KS with increase risk and reduced overall patients' survival.	('aberrant expression', 'Var', (57, 76))	('patients', 'Species', '9606', (122, 130))	('KS', 'Chemical', 'MESH:D007632', (80, 82))	('reduced', 'NegReg', (106, 113))
49623	31273306	In general, positive KS expression was observed in 21 (60%) of 35 pancreatic tumor specimens and has significantly higher probability to be in stage III/IV compared to patients with KS negative staining (95 vs. 57.1, p value = 0.01).	('pancreatic tumor', 'Phenotype', 'HP:0002894', (66, 82))	('KS', 'Chemical', 'MESH:D007632', (182, 184))	('pancreatic tumor', 'Disease', 'MESH:D010190', (66, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (168, 176))	('pancreatic tumor', 'Disease', (66, 82))	('positive KS expression', 'Var', (12, 34))	('KS', 'Chemical', 'MESH:D007632', (21, 23))
49626	31273306	Kaplan-Meier analysis showed that positive KS level is associated with a shorter median survival of 5.9 months compared to 12.5 months with negative KS expression and is significantly predictive of overall survival in patients (Fig.	('median survival', 'MPA', (81, 96))	('patients', 'Species', '9606', (218, 226))	('KS', 'Chemical', 'MESH:D007632', (149, 151))	('positive', 'Var', (34, 42))	('shorter', 'NegReg', (73, 80))	('overall', 'MPA', (198, 205))	('predictive', 'Reg', (184, 194))	('KS', 'Chemical', 'MESH:D007632', (43, 45))
49641	31273306	Dysregulation of glycosyltransferases expression that are involved in KS biosynthesis mediates aberrant KS expression in numerous pathophysiological conditions including cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('Dysregulation', 'Var', (0, 13))	('KS', 'Chemical', 'MESH:D007632', (70, 72))	('KS', 'Chemical', 'MESH:D007632', (104, 106))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('biosynthesis', 'biological_process', 'GO:0009058', ('73', '85'))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('glycosyltransferases', 'Enzyme', (17, 37))	('aberrant', 'Var', (95, 103))
49657	31273306	Aberrant expression of KS results in numerous pathophysiological conditions including cancers.	('Aberrant expression', 'Var', (0, 19))	('results in', 'Reg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('KS', 'Chemical', 'MESH:D007632', (23, 25))
49661	31273306	We showed for the first time the correlation of aberrant KS expression with pancreatic cancer progression and metastasis and with worse overall patient survival status.	('metastasis', 'CPA', (110, 120))	('pancreatic cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patient', 'Species', '9606', (144, 151))	('aberrant', 'Var', (48, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('KS', 'Chemical', 'MESH:D007632', (57, 59))	('KS expression', 'Protein', (57, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))
49670	31273306	These features are mainly caused by genetic and epigenetic dysregulation of glycosyltransferase genes and the tumor microenvironment, which results in increased cell proliferation, cell cycle progression, EMT, angiogenesis, and immune evasion.	('increased', 'PosReg', (151, 160))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('EMT', 'CPA', (205, 208))	('epigenetic dysregulation', 'Var', (48, 72))	('caused', 'Reg', (26, 32))	('EMT', 'biological_process', 'GO:0001837', ('205', '208'))	('cell cycle progression', 'CPA', (181, 203))	('cell proliferation', 'CPA', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('immune evasion', 'CPA', (228, 242))	('genetic', 'Var', (36, 43))	('immune evasion', 'biological_process', 'GO:0042783', ('228', '242'))	('cell cycle', 'biological_process', 'GO:0007049', ('181', '191'))	('immune evasion', 'biological_process', 'GO:0051842', ('228', '242'))	('glycosyltransferase genes', 'Gene', (76, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('210', '222'))	('tumor', 'Disease', (110, 115))	('angiogenesis', 'CPA', (210, 222))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
49673	31273306	Previously, we have reported that aberrant O-glycophenotype directly induces oncogenic features with enhanced cell growth and invasion in pancreatic cancer cells, and is critical during tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('pancreatic cancer', 'Disease', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('aberrant', 'Var', (34, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('tumor', 'Disease', (186, 191))	('induces', 'Reg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('O-glycophenotype', 'Protein', (43, 59))	('enhanced', 'PosReg', (101, 109))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('oncogenic', 'Disease', (77, 86))	('cell growth', 'CPA', (110, 121))
49674	31273306	Interestingly, studies have shown that O-glycopeptide epitopes with truncated O-glycan and a short peptide sequence have cancer-specific antigens properties and can be targeted by drug-loaded antibodies and T cell-engaging immunotherapies.	('truncated', 'Var', (68, 77))	('O-glycan', 'Chemical', '-', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('O-glycopeptide', 'Protein', (39, 53))	('O-glycan', 'Protein', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
49691	31273306	95% of pancreatic cancers carry activating mutations in KRAS, and up to 70% have mutated p53 tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p53', 'Gene', '7157', (89, 92))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (7, 25))	('KRAS', 'Gene', (56, 60))	('tumor', 'Disease', (93, 98))	('KRAS', 'Gene', '3845', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutated', 'Var', (81, 88))	('p53', 'Gene', (89, 92))	('pancreatic cancers', 'Disease', 'MESH:D010190', (7, 25))	('pancreatic cancers', 'Disease', (7, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (7, 24))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('activating', 'PosReg', (32, 42))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
49694	31273306	In this study, we demonstrated that a higher-level expression of B3GNT5 mRNA in KRAS and p53 mutated highly metastatic FG, T3M-4, and HPAF pancreatic cancer cell lines (Fig.	('KRAS', 'Gene', (80, 84))	('mutated', 'Var', (93, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('HPAF pancreatic cancer', 'Disease', 'MESH:D010190', (134, 156))	('KRAS', 'Gene', '3845', (80, 84))	('p53', 'Gene', (89, 92))	('highly metastatic FG', 'CPA', (101, 121))	('B3GNT5', 'Gene', (65, 71))	('HPAF pancreatic cancer', 'Disease', (134, 156))	('p53', 'Gene', '7157', (89, 92))	('B3GNT5', 'Gene', '84002', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
49695	31273306	Further, B3GNT5 mRNA expression was also increased in human primary pancreatic tumors which carry activating KRAS mutations in approximately 93% of patient cohort (Fig.	('human', 'Species', '9606', (54, 59))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (68, 85))	('B3GNT5', 'Gene', '84002', (9, 15))	('increased', 'PosReg', (41, 50))	('mutations', 'Var', (114, 123))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (68, 84))	('KRAS', 'Gene', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('KRAS', 'Gene', '3845', (109, 113))	('pancreatic tumors', 'Disease', 'MESH:D010190', (68, 85))	('patient', 'Species', '9606', (148, 155))	('pancreatic tumors', 'Disease', (68, 85))	('B3GNT5', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('activating', 'PosReg', (98, 108))
49696	31273306	Interestingly, gain of function mutation in B3GNT2 has been reported to be associated with increased tumorigenic potential in cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gain of function', 'PosReg', (15, 31))	('B3GNT2', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('B3GNT2', 'Gene', '10678', (44, 50))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('increased', 'PosReg', (91, 100))	('mutation', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
49697	31273306	Moreover, transfer of a sulfate residue to position 6 of GlcNAc residues in KS by CHST2/6/7 has been reported to activate p38 MAPK-PI3K cell survival signaling pathway axis and reduced radiation induced apoptosis in Burkitt's Lymphoma cells.	('KS', 'Chemical', 'MESH:D007632', (76, 78))	('reduced', 'NegReg', (177, 184))	('CHST2/6/7', 'Gene', (82, 91))	('signaling pathway', 'biological_process', 'GO:0007165', ('150', '167'))	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('GlcNAc', 'Chemical', 'MESH:D000117', (57, 63))	('radiation induced apoptosis', 'CPA', (185, 212))	('p38', 'Gene', (122, 125))	('activate', 'PosReg', (113, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('CHST2/6/7', 'Gene', '9435;4166;56548', (82, 91))	("Burkitt's Lymphoma", 'Disease', 'MESH:D002051', (216, 234))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('p38', 'Gene', '1432', (122, 125))	('transfer', 'Var', (10, 18))	('sulfate', 'Chemical', 'MESH:D013431', (24, 31))	("Burkitt's Lymphoma", 'Disease', (216, 234))	('Lymphoma', 'Phenotype', 'HP:0002665', (226, 234))
49698	31273306	Therefore, it is predicted that mutations might contribute to the differential expression of KS specific glycosyltransferase genes and aberrant sulfation of KS, thereby leading to pancreatic cancer growth and metastasis.	('leading to', 'Reg', (169, 179))	('expression', 'MPA', (79, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('pancreatic cancer', 'Disease', (180, 197))	('growth', 'CPA', (198, 204))	('KS', 'Chemical', 'MESH:D007632', (93, 95))	('sulfation', 'biological_process', 'GO:0051923', ('144', '153'))	('mutations', 'Var', (32, 41))	('contribute', 'Reg', (48, 58))	('sulfation', 'MPA', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('aberrant', 'Var', (135, 143))	('metastasis', 'CPA', (209, 219))	('KS', 'Chemical', 'MESH:D007632', (157, 159))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))
49702	31273306	Overall, the results of this study support the concept that aberrant expression of KS contributes to aggressive nature of pancreatic tumors and their early metastases (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic tumors', 'Disease', (122, 139))	('aberrant expression', 'Var', (60, 79))	('metastases', 'Disease', (156, 166))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (122, 139))	('KS', 'Chemical', 'MESH:D007632', (83, 85))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (122, 138))	('contributes', 'Reg', (86, 97))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('pancreatic tumors', 'Disease', 'MESH:D010190', (122, 139))	('aggressive nature', 'CPA', (101, 118))
49732	31273306	Analysis and interpretation of data: P.D.L., P.P.P., N.R., B.S., F.Y., F.Q.	('B.S.', 'Var', (59, 63))	('N.R.', 'Disease', (53, 57))	('F.Y.', 'Var', (65, 69))	('P.P.P', 'Disease', 'MESH:C000656865', (45, 50))	('P.D.L.', 'Var', (37, 43))	('P.P.P', 'Disease', (45, 50))
49733	31273306	Critical revision of the manuscript for important intellectual content: P.D.L., P.P.P., N.R., B.S., P.M.G., F.Y., F.Q.	('P.D.L.', 'Var', (72, 78))	('B.S.', 'Var', (94, 98))	('F.Y.', 'Var', (108, 112))	('P.P.P', 'Disease', 'MESH:C000656865', (80, 85))	('P.M.G.', 'Var', (100, 106))	('P.P.P', 'Disease', (80, 85))	('N.R.', 'Var', (88, 92))
49850	30485330	We identified that NORC1 is mutated in more than 3% of breast tumors and lung adenocarcinomas and linked this fact with detrimental outcome in some subtypes, particularly in those that are hormone receptor negative.	('mutated', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('hormone receptor', 'Gene', (189, 205))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('hormone receptor', 'Gene', '3164', (189, 205))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (73, 93))	('NORC1', 'Gene', (19, 24))	('breast tumors', 'Phenotype', 'HP:0100013', (55, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('breast tumors and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (55, 93))
49851	30485330	In addition to these findings, as mutations in this gene are deleterious, we confirmed that high levels of this gene were linked with good prognosis in the same tumor subtypes.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('linked', 'Reg', (122, 128))	('tumor', 'Disease', (161, 166))	('mutations', 'Var', (34, 43))
49852	30485330	Findings in the same direction were identified in lung adenocarcinomas, with mutations associated with detrimental prognosis and high expression with better outcome.	('lung adenocarcinomas', 'Disease', (50, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (50, 70))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (50, 70))	('associated', 'Reg', (87, 97))	('mutations', 'Var', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))
49853	30485330	In conclusion, hereby we describe the presence and prognostic role of mutations in the NCOR1 gene in hormone receptor negative breast and lung adenocarcinomas, and we also confirm that NCOR1 is a tumor suppressor gene.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (196, 201))	('NCOR1', 'Gene', '9611', (185, 190))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (138, 158))	('tumor suppressor', 'biological_process', 'GO:0051726', ('196', '212'))	('NCOR1', 'Gene', '9611', (87, 92))	('hormone receptor', 'Gene', (101, 117))	('hormone receptor', 'Gene', '3164', (101, 117))	('NCOR1', 'Gene', (185, 190))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('196', '212'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (138, 157))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('NCOR1', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('breast and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (127, 158))
49854	30485330	In this context, modifications of the transcription process have been associated with human disorders, such as neurological or inflammatory diseases or cancer, among others.	('modifications', 'Var', (17, 30))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('neurological', 'Disease', (111, 123))	('transcription', 'biological_process', 'GO:0006351', ('38', '51'))	('human', 'Species', '9606', (86, 91))	('associated', 'Reg', (70, 80))	('inflammatory diseases', 'Disease', 'MESH:D007249', (127, 148))	('neurological', 'Disease', 'MESH:D009461', (111, 123))	('inflammatory diseases', 'Disease', (127, 148))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
49855	30485330	Notably, epigenetic modifications on histones can impact on the transcription of different genes, and its deregulation has been involved in the initiation and progression of tumors.	('deregulation', 'PosReg', (106, 118))	('tumors', 'Disease', (174, 180))	('impact', 'Reg', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('histones', 'Protein', (37, 45))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('involved', 'Reg', (128, 136))	('epigenetic modifications', 'Var', (9, 33))	('transcription', 'MPA', (64, 77))
49861	30485330	Mutations or deletions of this gene have been described in several solid tumors, such as colorectal cancer, bladder cancer or hepatocarcinomas.	('solid tumors', 'Disease', (67, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('hepatocarcinomas', 'Disease', 'None', (126, 142))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('described', 'Reg', (46, 55))	('deletions', 'Var', (13, 22))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Mutations', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('hepatocarcinomas', 'Disease', (126, 142))
49864	30485330	We identified that NCOR1 is mutated in more than 3% of breast tumors and lung adenocarcinomas and linked with detrimental outcome in some subtypes.	('mutated', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('NCOR1', 'Gene', (19, 24))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (73, 93))	('linked with', 'Reg', (98, 109))	('breast tumors', 'Phenotype', 'HP:0100013', (55, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('NCOR1', 'Gene', '9611', (19, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('breast tumors and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (55, 93))
49865	30485330	In addition to these findings, as mutations at this gene are deleterious, we confirmed that high levels of this gene were linked with good prognosis in those tumor types.	('tumor', 'Disease', (158, 163))	('high', 'Var', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('linked', 'Reg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (34, 43))
49869	30485330	The frequency of mutation was independently confirmed for all the four different breast cancer subtypes using TCGA database (n = 818).	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
49871	30485330	This tool was also used to evaluate genes present in the mutated NCOR1 signature.	('NCOR1', 'Gene', '9611', (65, 70))	('mutated', 'Var', (57, 64))	('NCOR1', 'Gene', (65, 70))
49872	30485330	The genotype-2-Outcome online tool (http://www.g-2-o.com) was used to evaluate the relationship between the presence of mutated NCOR1 and patient clinical outcome through the development of a NCOR1 expression signature associated with all NCOR1 mutations.	('associated', 'Reg', (219, 229))	('NCOR1', 'Gene', (128, 133))	('mutations', 'Var', (245, 254))	('NCOR1', 'Gene', '9611', (192, 197))	('NCOR1', 'Gene', (239, 244))	('patient', 'Species', '9606', (138, 145))	('NCOR1', 'Gene', (192, 197))	('NCOR1', 'Gene', '9611', (239, 244))	('NCOR1', 'Gene', '9611', (128, 133))	('mutated', 'Var', (120, 127))
49873	30485330	This includes not only patients with NCOR1 mutation, but all patients who have a gene expression signature similar to those with an NCOR1 mutation.	('NCOR1', 'Gene', (37, 42))	('NCOR1', 'Gene', (132, 137))	('mutation', 'Var', (43, 51))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (61, 69))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))	('NCOR1', 'Gene', '9611', (37, 42))	('NCOR1', 'Gene', '9611', (132, 137))
49875	30485330	In the analysis, the expression of genes related to NCOR1 mutation was computed for each sample.	('mutation', 'Var', (58, 66))	('NCOR1', 'Gene', '9611', (52, 57))	('NCOR1', 'Gene', (52, 57))
49882	30485330	The information contained at cBioportal (http://www.cbioportal.org) was used to identify NCOR1 mutations.	('NCOR1', 'Gene', '9611', (89, 94))	('NCOR1', 'Gene', (89, 94))	('mutations', 'Var', (95, 104))
49883	30485330	The effect of each mutation on NCOR1 activity was investigated in SIFT (http://sift.bii.a-star.edu.sg/) and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) databases.	('SIFT', 'Disease', (66, 70))	('NCOR1', 'Gene', (31, 36))	('mutation', 'Var', (19, 27))	('SIFT', 'Disease', 'None', (66, 70))	('NCOR1', 'Gene', '9611', (31, 36))	('pph', 'molecular_function', 'GO:0033978', ('152', '155'))	('pph', 'molecular_function', 'GO:0004238', ('152', '155'))
49890	30485330	With this approach, we found 9 mutated genes associated with worse patient outcome (Fig 1A and S2 Table).	('patient', 'Species', '9606', (67, 74))	('mutated', 'Var', (31, 38))	('associated', 'Reg', (45, 55))
49892	30485330	However, others have been less studied, like TAF1, KTM2D, RUNX1, EP300 or NCOR1 and NCOR2.	('RUNX1', 'Gene', '861', (58, 63))	('NCOR2', 'Gene', '9612', (84, 89))	('EP300', 'Gene', (65, 70))	('NCOR1', 'Gene', (74, 79))	('EP300', 'Gene', '2033', (65, 70))	('TAF1', 'Gene', (45, 49))	('NCOR2', 'Gene', (84, 89))	('NCOR1', 'Gene', '9611', (74, 79))	('RUNX1', 'Gene', (58, 63))	('TAF1', 'Gene', '6872', (45, 49))	('KTM2D', 'Var', (51, 56))
49895	30485330	As shown, NCOR1 was mutated in 3.76% of all breast tumors, and in 3.65% of basal-like, 2% of Luminal A, 2.45% of Luminal B, and 3.33% of HER2 positive (Fig 1C).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('breast tumors', 'Phenotype', 'HP:0100013', (44, 57))	('NCOR1', 'Gene', '9611', (10, 15))	('HER2', 'Gene', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('breast tumors', 'Disease', (44, 57))	('breast tumors', 'Disease', 'MESH:D001943', (44, 57))	('HER2', 'Gene', '2064', (137, 141))	('NCOR1', 'Gene', (10, 15))	('mutated', 'Var', (20, 27))
49897	30485330	Mutations at NCOR1 were associated with detrimental outcome in all breast tumors (HR:0.63, CI: 0.56-0.7; log rank p = 0), luminal B (HR:0.65, CI: 0.54-0.79; log rank p = 1.2e-05), basal (HR:0.58, CI: 0.45-0.76; log rank p = 3.3e-05) and HER2 positive tumors (HR:0.62, CI: 0.43-0.90; log rank p = 0.012) (Fig 2A, 2B, 2C and 2D, respectively).	('NCOR1', 'Gene', '9611', (13, 18))	('detrimental', 'NegReg', (40, 51))	('breast tumors', 'Disease', 'MESH:D001943', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast tumors', 'Disease', (67, 80))	('Mutations', 'Var', (0, 9))	('NCOR1', 'Gene', (13, 18))	('HER2 positive tumors', 'Disease', 'MESH:D009369', (237, 257))	('HER2 positive tumors', 'Disease', (237, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('breast tumors', 'Phenotype', 'HP:0100013', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
49901	30485330	As mutations of this gene have an impact on patient outcome, we aimed to analyze the biological role of these mutations on the expression of the protein and its function.	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('patient', 'Species', '9606', (44, 51))	('mutations', 'Var', (3, 12))	('impact', 'Reg', (34, 40))
49902	30485330	To do so, we used the cancer genomics database cBioportal to identify NCOR1 mutations in each METABRIC patient (Fig 3B).	('NCOR1', 'Gene', (70, 75))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('NCOR1', 'Gene', '9611', (70, 75))	('patient', 'Species', '9606', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
49903	30485330	The functional impact of all these different mutations, evaluated with two different databases (SIFT and PolyPhen-2), is displayed in Fig 3D.	('mutations', 'Var', (45, 54))	('SIFT', 'Disease', 'None', (96, 100))	('SIFT', 'Disease', (96, 100))
49904	30485330	As shown, most NCOR1 mutations are deleterious or damaging, therefore affecting the functional role of the protein.	('mutations', 'Var', (21, 30))	('NCOR1', 'Gene', (15, 20))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('affecting', 'Reg', (70, 79))	('functional role of the protein', 'MPA', (84, 114))	('NCOR1', 'Gene', '9611', (15, 20))
49905	30485330	If lack of activity of NCOR1 due to mutations is associated with detrimental outcome, elevated levels of the gene would be linked with good prognosis.	('lack of', 'NegReg', (3, 10))	('activity', 'MPA', (11, 19))	('NCOR1', 'Gene', (23, 28))	('mutations', 'Var', (36, 45))	('NCOR1', 'Gene', '9611', (23, 28))
49907	30485330	As can be seen in Fig 4, high expression of NCOR1 is associated with better relapse free survival in all breast cancer subtypes, including the luminal A subtype: all breast tumors (HR: 0.7, CI: 0.62-0.78; log rank p = 9e-11); luminal B (HR: 0.81, CI: 0.67-0.99; log rank p = 0.04); basal (HR: 0.73, CI: 0.57-0.94; log rank p = 0.016); HER2 (HR:0.72, CI: 0.49-1.05; log rank p = 0.085) and luminal A (HR:0.69, CI: 0.58-0.82; log rank p = 2e-05) (Fig 4A-4E).	('NCOR1', 'Gene', '9611', (44, 49))	('breast tumors', 'Disease', (166, 179))	('relapse free survival', 'CPA', (76, 97))	('high expression', 'Var', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('NCOR1', 'Gene', (44, 49))	('breast tumors', 'Phenotype', 'HP:0100013', (166, 179))	('better', 'PosReg', (69, 75))	('HER2', 'Gene', (335, 339))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('HER2', 'Gene', '2064', (335, 339))	('breast cancer', 'Disease', (105, 118))	('breast tumors', 'Disease', 'MESH:D001943', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
49910	30485330	To explore the option that NCOR1 also have a role in other cancer types, we explored if mutations at this gene were linked with detrimental prognosis in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('detrimental prognosis in lung cancer', 'Disease', (128, 164))	('mutations', 'Var', (88, 97))	('NCOR1', 'Gene', '9611', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (158, 164))	('detrimental prognosis in lung cancer', 'Disease', 'MESH:D008175', (128, 164))	('linked', 'Reg', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('NCOR1', 'Gene', (27, 32))
49912	30485330	Of note, mutations in LUAD was reported in 3.91% of tumors (Fig 1C).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('LUAD', 'Gene', (22, 26))	('reported', 'Reg', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('LUAD', 'Phenotype', 'HP:0030078', (22, 26))
49913	30485330	Similarly, to breast cancer, we observed that high expression of the NCOR1 gene was associated with better overall survival and relapse free survival (HR: 0.38, CI: 0.3-0.48; log rank p<1e-16; HR: 0.26, CI: 0.16-0.41; log rank p = 3.9e-10; respectively) (Fig 5C and 5D), suggesting that this gene could behave as a tumor suppressor also in this tumor subtype.	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('relapse free survival', 'CPA', (128, 149))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('overall survival', 'CPA', (107, 123))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('NCOR1', 'Gene', '9611', (69, 74))	('better', 'PosReg', (100, 106))	('tumor', 'Disease', (345, 350))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('breast cancer', 'Disease', (14, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('315', '331'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('315', '331'))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('high expression', 'Var', (46, 61))	('NCOR1', 'Gene', (69, 74))	('tumor', 'Disease', (315, 320))
49915	30485330	Deregulation of genes within transcription regulation has been involved in human pathologies, including tumor initiation and progression.	('tumor initiation', 'Disease', 'MESH:D009369', (104, 120))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Deregulation', 'Var', (0, 12))	('involved', 'Reg', (63, 71))	('tumor initiation', 'Disease', (104, 120))	('human', 'Species', '9606', (75, 80))	('transcription', 'biological_process', 'GO:0006351', ('29', '42'))	('transcription regulation', 'Gene', (29, 53))
49922	30485330	However, the role of NCOR1 mutations, particularly in tumors that do not express the estrogen receptor has not been explored in the mentioned studies.	('mutations', 'Var', (27, 36))	('estrogen receptor', 'Gene', (85, 102))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('estrogen receptor', 'Gene', '2099', (85, 102))	('NCOR1', 'Gene', '9611', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('NCOR1', 'Gene', (21, 26))	('tumors', 'Disease', (54, 60))
49923	30485330	Mutations in NCOR1 have been also described in other solid tumors, like colorectal cancer or bladder cancer.	('solid tumors', 'Disease', (53, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('NCOR1', 'Gene', '9611', (13, 18))	('bladder cancer', 'Disease', (93, 107))	('solid tumors', 'Disease', 'MESH:D009369', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('NCOR1', 'Gene', (13, 18))	('colorectal cancer', 'Disease', (72, 89))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('described', 'Reg', (34, 43))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))
49924	30485330	In most occasions, these mutations were associated with a loss of function of the protein impairing their tumor suppressor capabilities.	('mutations', 'Var', (25, 34))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('impairing', 'NegReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('loss of function', 'NegReg', (58, 74))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('protein', 'Protein', (82, 89))	('tumor', 'Disease', (106, 111))
49925	30485330	In our article, we found that NCOR1 mutations in breast cancer are mainly missense and truncating, and produce a deleterious or damaging effect, leading to a nonfunctional protein.	('leading to', 'Reg', (145, 155))	('truncating', 'MPA', (87, 97))	('NCOR1', 'Gene', '9611', (30, 35))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (36, 45))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('NCOR1', 'Gene', (30, 35))	('nonfunctional protein', 'MPA', (158, 179))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('missense', 'Var', (74, 82))
49926	30485330	The lack of function of this protein is therefore associated with the poor prognosis observed in those patients harboring the mutation.	('patients', 'Species', '9606', (103, 111))	('lack of function', 'NegReg', (4, 20))	('mutation', 'Var', (126, 134))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
49931	30485330	Finally, it should be mentioned that the low number of mutations in luminal A tumors limits their evaluation in relation with prognosis.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (55, 64))	('A tumors', 'Disease', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('A tumors', 'Disease', 'MESH:D009369', (76, 84))
49933	30485330	In conclusion, in the present work we describe the presence and prognostic role of mutations at NCOR1 gene in hormone receptor negative breast and lung adenocarcinomas and we also confirm that NCOR1 is a tumor suppressor gene.	('mutations', 'Var', (83, 92))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (147, 167))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('hormone receptor', 'Gene', '3164', (110, 126))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('hormone receptor', 'Gene', (110, 126))	('NCOR1', 'Gene', (193, 198))	('tumor', 'Disease', (204, 209))	('NCOR1', 'Gene', '9611', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor suppressor', 'biological_process', 'GO:0051726', ('204', '220'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('204', '220'))	('breast and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (136, 167))	('NCOR1', 'Gene', (96, 101))	('NCOR1', 'Gene', '9611', (193, 198))
50062	29259016	Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1.	('ERK1/2', 'Gene', (141, 147))	('BRAF', 'Gene', (36, 40))	('ERK1/2', 'Gene', '26417;26413', (141, 147))	('RAS', 'Chemical', 'MESH:D011883', (28, 31))	('ERK1', 'molecular_function', 'GO:0004707', ('141', '145'))	('RAS', 'Chemical', 'MESH:D011883', (87, 90))	('oncogenic RAS', 'Var', (18, 31))	('localization', 'biological_process', 'GO:0051179', ('63', '75'))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('perinuclear re-localization', 'MPA', (48, 75))	('RAS pathway', 'Pathway', (87, 98))
50072	29259016	Oncogenic mutations stabilize the active GTP-bound form of RAS, resulting in continuous GF-independent signaling, primarily through the RAF-MEK-ERK (MAPK) pathway.	('RAF', 'Gene', '387609', (136, 139))	('GTP', 'Chemical', 'MESH:D006160', (41, 44))	('ERK', 'molecular_function', 'GO:0004707', ('144', '147'))	('RAS', 'Chemical', 'MESH:D011883', (59, 62))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('mutations', 'Var', (10, 19))	('RAF', 'Gene', (136, 139))	('GF-independent signaling', 'MPA', (88, 112))
50073	29259016	The prevalence of RAS mutations in cancer has prompted extensive efforts to define the properties that distinguish mutant RAS signaling from that elicited by GFs.	('RAS', 'Chemical', 'MESH:D011883', (122, 125))	('RAS', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutant', 'Var', (115, 121))	('RAS', 'Chemical', 'MESH:D011883', (18, 21))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
50076	29259016	Although normal and pathological RAS signaling have been studied extensively, a full understanding of the features that underlie "oncogenic drive" by mutant RAS is still lacking.	('RAS', 'Gene', (157, 160))	('RAS', 'Chemical', 'MESH:D011883', (33, 36))	('RAS', 'Chemical', 'MESH:D011883', (157, 160))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('mutant', 'Var', (150, 156))
50077	29259016	For example, cancer cells do not always exhibit elevated MAPK pathway output despite the presence of mutations such as KRAS that are expected to activate the RAF-MEK-ERK cascade (The Cancer Genome Atlas Research Network, 4,5).	('RAF', 'Gene', '387609', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (101, 110))	('ERK cascade', 'biological_process', 'GO:0070371', ('166', '177'))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('ERK', 'molecular_function', 'GO:0004707', ('166', '169'))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('KRAS', 'Gene', (119, 123))	('MAPK pathway', 'Pathway', (57, 69))	('activate', 'PosReg', (145, 153))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RAF', 'Gene', (158, 161))
50079	29259016	In addition to its oncogenic activity in cancer cells, expression of mutant RAS in normal primary cells can provoke oncogene-induced senescence (OIS), a permanent form of cell cycle arrest that provides an intrinsic barrier to tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('provoke', 'PosReg', (108, 115))	('tumor', 'Disease', (227, 232))	('mutant', 'Var', (69, 75))	('expression', 'Species', '29278', (55, 65))	('senescence', 'biological_process', 'GO:0010149', ('133', '143'))	('oncogene-induced senescence', 'Disease', (116, 143))	('OIS', 'biological_process', 'GO:0090402', ('145', '148'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (171, 188))	('RAS', 'Gene', (76, 79))	('RAS', 'Chemical', 'MESH:D011883', (76, 79))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('171', '188'))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
50082	29259016	Cebpb-/- MEFs or CEBPB-depleted human fibroblasts do not undergo OIS and display impaired expression of senescence-associated secretory phenotype (SASP) genes, which are typically up-regulated in senescent cells.	('OIS', 'biological_process', 'GO:0090402', ('65', '68'))	('MEFs', 'CellLine', 'CVCL:9115', (9, 13))	('senescence', 'biological_process', 'GO:0010149', ('104', '114'))	('Cebpb-/- MEFs', 'Var', (0, 13))	('up-regulated', 'PosReg', (180, 192))	('expression', 'Species', '29278', (90, 100))	('impaired', 'NegReg', (81, 89))	('expression', 'MPA', (90, 100))	('human', 'Species', '9606', (32, 37))
50083	29259016	Oncogenic RAS induces post-translational activation of C/EBPbeta, which otherwise is maintained in an auto-inhibited, low activity state.	('Oncogenic RAS', 'Var', (0, 13))	('post-translational activation', 'MPA', (22, 51))	('RAS', 'Chemical', 'MESH:D011883', (10, 13))	('C/EBPbeta', 'Gene', (55, 64))
50085	29259016	C/EBPbeta de-repression is critically dependent on the RAF-MEK-ERK cascade, and several RAS-induced modifications mediate increased DNA binding, transcriptional activity and homodimerization.	('C/EBPbeta', 'Gene', (0, 9))	('transcriptional', 'MPA', (145, 160))	('modifications', 'Var', (100, 113))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('de-repression', 'NegReg', (10, 23))	('homodimerization', 'Interaction', (174, 190))	('RAF', 'Gene', (55, 58))	('DNA binding', 'Interaction', (132, 143))	('RAF', 'Gene', '387609', (55, 58))	('DNA binding', 'molecular_function', 'GO:0003677', ('132', '143'))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('increased', 'PosReg', (122, 131))	('ERK cascade', 'biological_process', 'GO:0070371', ('63', '74'))	('RAS', 'Chemical', 'MESH:D011883', (88, 91))
50087	29259016	In addition, phosphorylation on C/EBPbeta Ser273 in the leucine zipper by the ERK-activated kinase, p90RSK, potentiates DNA binding and homodimerization and is critical for its cytostatic activity.	('p90RSK', 'Gene', (100, 106))	('potentiates', 'PosReg', (108, 119))	('homodimerization', 'MPA', (136, 152))	('Ser273 in the leucine', 'Mutation', 'p.S273L', (42, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('ERK', 'molecular_function', 'GO:0004707', ('78', '81'))	('Ser273', 'Var', (42, 48))	('phosphorylation', 'Var', (13, 28))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('DNA binding', 'molecular_function', 'GO:0003677', ('120', '131'))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('DNA binding', 'Interaction', (120, 131))	('p90RSK', 'Gene', '20111', (100, 106))
50095	29259016	We show that perinuclear signaling complexes (PSCs), which are localized structures containing multiple RAS pathway components, are induced persistently or transiently by mutant and physiological RAS signaling, respectively.	('RAS', 'Chemical', 'MESH:D011883', (196, 199))	('RAS', 'Chemical', 'MESH:D011883', (104, 107))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('mutant', 'Var', (171, 177))	('perinuclear signaling complexes', 'MPA', (13, 44))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('induced', 'Reg', (132, 139))
50096	29259016	Disruption of PSCs blocked RAS-C/EBPbeta signaling.	('PSCs', 'Gene', (14, 18))	('blocked', 'NegReg', (19, 26))	('RAS', 'Chemical', 'MESH:D011883', (27, 30))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('RAS-C/EBPbeta signaling', 'MPA', (27, 50))	('Disruption', 'Var', (0, 10))
50115	29259016	Anti-mouse (W4028) and anti-rabbit (W4018) HRP conjugated secondary antibodies were from Promega.	('HRP', 'Protein', (43, 46))	('W4018', 'Var', (36, 41))	('W4028', 'Var', (12, 17))	('mouse', 'Species', '10090', (5, 10))	('rabbit', 'Species', '9986', (28, 34))
50119	29259016	Inhibitors, including dynasore hydrochloride (Santa Cruz), TBB (Sigma), CX-4945 (Activate Scientific), U0126 (Promega) and SCH772984 (MedChem Express), were reconstituted following the manufacturer's recommendations and used at the indicated doses.	('CX-4945', 'Var', (72, 79))	('dynasore hydrochloride', 'Chemical', '-', (22, 44))	('TBB', 'Gene', (59, 62))	('SCH772984', 'Var', (123, 132))	('U0126', 'Chemical', 'MESH:C113580', (103, 108))	('CX-4945', 'Chemical', 'MESH:C555142', (72, 79))	('U0126', 'Var', (103, 108))	('SCH772984', 'Chemical', 'MESH:C587178', (123, 132))	('TBB', 'Chemical', 'MESH:C103118', (59, 62))
50120	29259016	ON-Target Plus Smart Pool siRNA against mouse CK2alpha (L-058353-00 and L-051582-00), and KSR-1 (L-045873-00) and a non-silencing control siRNA (D-001810-10) were purchased from Dharmacon (Thermo Scientific).	('KSR-1', 'Gene', (90, 95))	('CK2alpha', 'Gene', '1459', (46, 54))	('CK2alpha', 'Gene', (46, 54))	('L-058353-00', 'Var', (56, 67))	('L-045873-00', 'Var', (97, 108))	('mouse', 'Species', '10090', (40, 45))	('L-051582-00', 'Var', (72, 83))	('KSR-1', 'Gene', '16706', (90, 95))
50121	29259016	Primers used in RT-qPCR analysis were from Qiagen: Il-6 (QT00098875), Il1a (QT00113505), Cxcl1 (QT00115647), Cxcl2 (QT00113253), Ccr1 (QT00156058) and Pp1a (QT00247709).	('Ccr', 'molecular_function', 'GO:0043880', ('129', '132'))	('QT00247709', 'Var', (157, 167))	('Cxcl1', 'Gene', '14825', (89, 94))	('Il-6', 'Gene', '16193', (51, 55))	('QT00156058', 'Var', (135, 145))	('Ccr1', 'Gene', (129, 133))	('QT00113505', 'Var', (76, 86))	('QT00115647', 'Var', (96, 106))	('Pp1a', 'Gene', '19045', (151, 155))	('Cxcl2', 'Gene', (109, 114))	('Cxcl2', 'Gene', '20310', (109, 114))	('Cxcl1', 'Gene', (89, 94))	('QT00113253', 'Var', (116, 126))	('Ccr1', 'Gene', '12768', (129, 133))	('Pp1a', 'Gene', (151, 155))	('Il1a', 'Gene', (70, 74))	('Il-6', 'Gene', (51, 55))	('Il1a', 'Gene', '16175', (70, 74))	('Il1', 'molecular_function', 'GO:0005149', ('70', '73'))	('QT00098875', 'Var', (57, 67))	('Il-6', 'molecular_function', 'GO:0005138', ('51', '55'))
50123	29259016	Lentiviral expression vectors for GFP-tagged mouse KSR1 and mCherry-tagged mouse CK2alpha were purchased from Genecopia (Rockville, MD).	('GFP-tagged', 'Var', (34, 44))	('mouse', 'Species', '10090', (45, 50))	('CK2alpha', 'Gene', '1459', (81, 89))	('KSR1', 'Gene', (51, 55))	('CK2alpha', 'Gene', (81, 89))	('mouse', 'Species', '10090', (75, 80))	('expression vectors', 'Species', '29278', (11, 29))
50126	29259016	Mouse C/EBPbeta mutant plasmids (S223A and S223D) were generated using a Stratagene site-directed mutagenesis kit per the manufacturer's instructions.	('rat', 'Species', '10116', (75, 78))	('S223A', 'Var', (33, 38))	('S223D', 'Var', (43, 48))	('S223A', 'Mutation', 'p.S223A', (33, 38))	('Mouse', 'Species', '10090', (0, 5))	('rat', 'Species', '10116', (59, 62))	('mutagenesis', 'biological_process', 'GO:0006280', ('98', '109'))	('S223D', 'Mutation', 'p.S223D', (43, 48))
50127	29259016	Retroviral packaging plasmid, VSVG, was a gift from S. Hughes, and lentiviral packaging/envelope plasmids pMD2.G (#12259), pMDLg/pRRE (#12251), and pRSV/Rev (#12253) were purchased from AddGene.	('#12251', 'Var', (135, 141))	('envelope', 'cellular_component', 'GO:0009274', ('88', '96'))	('#12259', 'Var', (114, 120))	('pRSV', 'Species', '12205', (148, 152))	('envelope', 'cellular_component', 'GO:0031975', ('88', '96'))	('#12253', 'Var', (158, 164))
50169	29259016	A375 melanoma cells (homozygous BRAFV600E) were transfected with 100 nM BRAFV600E siRNA (sense: 5'-GCUACAGAGAAAUCUCGAUUU; antisense: 5'-AUCGAGAUUUCUCUGUAGCUU).	('BRAFV600E', 'Var', (72, 81))	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (32, 41))
50182	29259016	Further analysis of these data showed that Ser223 in rat C/EBPbeta (Ser222 in mouse) was also consistently phosphorylated when the protein was co-expressed with HRASG12V (Fig.	('HRAS', 'Gene', (161, 165))	('Ser223', 'Var', (43, 49))	('Ser', 'cellular_component', 'GO:0005790', ('43', '46'))	('rat', 'Species', '10116', (53, 56))	('Ser222', 'Chemical', '-', (68, 74))	('Ser223', 'Chemical', '-', (43, 49))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('mouse', 'Species', '10090', (78, 83))	('HRAS', 'Gene', '15461', (161, 165))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))
50183	29259016	Ser223/222 is located within the extended basic region, indicting a possible role in DNA binding.	('Ser223', 'Chemical', '-', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('Ser223/222', 'Var', (0, 10))	('DNA binding', 'molecular_function', 'GO:0003677', ('85', '96'))	('DNA binding', 'Interaction', (85, 96))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
50184	29259016	Using EMSA to assess DNA binding of WT and mutant C/EBPbeta proteins expressed from constructs lacking the 3'UTR (C/EBPbetaDeltaUTR) in 293T cells, we found that a phosphorylation-defective variant (S223A) was refractory to activation by HRASG12V while a phosphomimetic mutant (S223D) displayed elevated basal binding (Fig.	('S223A', 'Mutation', 'p.S223A', (199, 204))	('binding', 'molecular_function', 'GO:0005488', ('310', '317'))	('DNA binding', 'molecular_function', 'GO:0003677', ('21', '32'))	('S223D', 'Mutation', 'p.S223D', (278, 283))	('HRAS', 'Gene', '15461', (238, 242))	('elevated', 'PosReg', (295, 303))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('phosphorylation', 'biological_process', 'GO:0016310', ('164', '179'))	('S223A', 'Var', (199, 204))	('basal binding', 'MPA', (304, 317))	('HRAS', 'Gene', (238, 242))	('293T', 'CellLine', 'CVCL:0063', (136, 140))	('S223D', 'Var', (278, 283))
50185	29259016	Transactivation assays using a C/EBP-driven reporter (2X C/EBP-luc) showed that RAS-stimulated C/EBPbeta transcriptional activity was impaired in the S223A mutant and increased for S223D (Fig.	('EBP', 'Gene', (33, 36))	('EBP', 'Gene', '13595', (59, 62))	('EBP', 'Gene', '13595', (97, 100))	('EBP', 'Gene', (59, 62))	('impaired', 'NegReg', (134, 142))	('S223A', 'Var', (150, 155))	('increased', 'PosReg', (167, 176))	('EBP', 'Gene', (97, 100))	('EBP', 'Gene', '13595', (33, 36))	('S223D', 'Var', (181, 186))	('RAS', 'Chemical', 'MESH:D011883', (80, 83))	('transcriptional activity', 'MPA', (105, 129))	('S223D', 'Mutation', 'p.S223D', (181, 186))	('S223A', 'Mutation', 'p.S223A', (150, 155))
50186	29259016	Furthermore, stable expression of WT C/EBPbeta in HRASG12V-expressing Cebpb-/- MEFs caused proliferative arrest, whereas the S223A mutant displayed impaired cytostatic activity in colony formation assays (Fig.	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('S223A', 'Var', (125, 130))	('impaired', 'NegReg', (148, 156))	('colony formation assays', 'CPA', (180, 203))	('HRAS', 'Gene', '15461', (50, 54))	('S223A', 'Mutation', 'p.S223A', (125, 130))	('cytostatic', 'MPA', (157, 167))	('proliferative arrest', 'CPA', (91, 111))	('rat', 'Species', '10116', (98, 101))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))	('HRAS', 'Gene', (50, 54))	('Cebpb-/-', 'Gene', (70, 78))	('expression', 'Species', '29278', (20, 30))
50194	29259016	RAS-induced phosphorylation on Ser223 was also blocked by TBB (Fig.	('TBB', 'Gene', (58, 61))	('Ser223', 'Chemical', '-', (31, 37))	('RAS', 'Chemical', 'MESH:D011883', (0, 3))	('blocked', 'NegReg', (47, 54))	('Ser', 'cellular_component', 'GO:0005790', ('31', '34'))	('TBB', 'Chemical', 'MESH:C103118', (58, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('12', '27'))	('phosphorylation', 'MPA', (12, 27))	('Ser223', 'Var', (31, 37))
50196	29259016	Finally, co-IP assays showed that HA-tagged C/EBPbeta interacted with endogenous CK2alpha in 293T cells and this association was enhanced by co-expression of oncogenic RAS (Fig.	('enhanced', 'PosReg', (129, 137))	('C/EBPbeta', 'Gene', (44, 53))	('association', 'Interaction', (113, 124))	('expression', 'Species', '29278', (144, 154))	('oncogenic', 'Var', (158, 167))	('RAS', 'Chemical', 'MESH:D011883', (168, 171))	('CK2alpha', 'Gene', '1459', (81, 89))	('293T', 'CellLine', 'CVCL:0063', (93, 97))	('CK2alpha', 'Gene', (81, 89))	('interacted', 'Interaction', (54, 64))
50199	29259016	We previously showed that C/EBPbeta expressed from the C/EBPbetaDeltaUTR construct potently activates transcription of SASP genes in NIH3T3RAS cells (betaDeltaUTR-3T3RAS cells).	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('transcription', 'MPA', (102, 115))	('activates', 'PosReg', (92, 101))	('NIH3T3RAS', 'CellLine', 'CVCL:0594', (133, 142))	('SASP genes', 'Gene', (119, 129))	('T3RAS', 'CellLine', 'CVCL:M810', (164, 169))	('T3RAS', 'CellLine', 'CVCL:M810', (137, 142))	('C/EBPbetaDeltaUTR', 'Var', (55, 72))
50200	29259016	1J, siRNA depletion of CK2alpha (catalytic subunit) in these cells reduced the levels of IL-6, IL-1alpha, Cxcl1, Cxcl2, and Ccr1 mRNAs by 40-60%.	('IL-1alpha', 'Gene', '16175', (95, 104))	('IL-6', 'molecular_function', 'GO:0005138', ('89', '93'))	('Ccr1', 'Gene', '12768', (124, 128))	('CK2alpha', 'Gene', '1459', (23, 31))	('Cxcl1', 'Gene', (106, 111))	('CK2alpha', 'Gene', (23, 31))	('IL-1', 'molecular_function', 'GO:0005149', ('95', '99'))	('depletion', 'Var', (10, 19))	('Ccr', 'molecular_function', 'GO:0043880', ('124', '127'))	('reduced', 'NegReg', (67, 74))	('Cxcl2', 'Gene', '20310', (113, 118))	('Cxcl2', 'Gene', (113, 118))	('IL-6', 'Gene', (89, 93))	('IL-6', 'Gene', '16193', (89, 93))	('Cxcl1', 'Gene', '14825', (106, 111))	('Ccr1', 'Gene', (124, 128))	('IL-1alpha', 'Gene', (95, 104))
50202	29259016	1 show that CK2-mediated phosphorylation on Ser222 is critical for induction of C/EBPbeta DNA-binding and cytostatic activity and its ability to activate SASP genes.	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('Ser222', 'Chemical', '-', (44, 50))	('Ser222', 'Var', (44, 50))	('C/EBPbeta DNA-binding', 'Protein', (80, 101))	('Ser', 'cellular_component', 'GO:0005790', ('44', '47'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('90', '101'))	('SASP genes', 'Gene', (154, 164))	('activate', 'PosReg', (145, 153))
50204	29259016	2A, the Cebpb 3'UTR suppressed RAS-induced phosphorylation of Ser222 in 293T cells; ERK-mediated phosphorylation on T188 was also inhibited, supporting our previous findings.	('Ser', 'cellular_component', 'GO:0005790', ('62', '65'))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('inhibited', 'NegReg', (130, 139))	('suppressed', 'NegReg', (20, 30))	('RAS', 'Chemical', 'MESH:D011883', (31, 34))	('293T', 'CellLine', 'CVCL:0063', (72, 76))	('Ser222', 'Chemical', '-', (62, 68))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('Cebpb', 'Var', (8, 13))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('RAS-induced phosphorylation of Ser222', 'MPA', (31, 68))
50207	29259016	However, expression of HRASG12V caused perinuclear re-localization of CK2alpha, with only faint staining remaining in the nucleus.	('CK2alpha', 'Gene', '1459', (70, 78))	('expression', 'Var', (9, 19))	('CK2alpha', 'Gene', (70, 78))	('localization', 'biological_process', 'GO:0051179', ('54', '66'))	('perinuclear re-localization', 'MPA', (39, 66))	('expression', 'Species', '29278', (9, 19))	('nucleus', 'cellular_component', 'GO:0005634', ('122', '129'))	('HRAS', 'Gene', '15461', (23, 27))	('HRAS', 'Gene', (23, 27))
50217	29259016	Expression of SASP genes was also strongly reduced in the mutant cells (Fig.	('mutant', 'Var', (58, 64))	('Expression', 'MPA', (0, 10))	('Expression', 'Species', '29278', (0, 10))	('reduced', 'NegReg', (43, 50))	('SASP genes', 'Gene', (14, 24))
50218	29259016	IF imaging revealed that KSR1 in MEFs was broadly distributed in the cytoplasm but became localized in a perinuclear ring upon expression of oncogenic RAS (Fig.	('expression', 'Species', '29278', (127, 137))	('cytoplasm', 'cellular_component', 'GO:0005737', ('69', '78'))	('RAS', 'Chemical', 'MESH:D011883', (151, 154))	('KSR1', 'Gene', (25, 29))	('oncogenic', 'Var', (141, 150))	('MEFs', 'CellLine', 'CVCL:9115', (33, 37))
50221	29259016	3D (lanes 3 and 4), C/EBPbetaDeltaUTR co-immunoprecipitated with KSR1 and this interaction was increased in cells expressing HRASG12V.	('HRAS', 'Gene', '15461', (125, 129))	('increased', 'PosReg', (95, 104))	('C/EBPbetaDeltaUTR', 'Var', (20, 37))	('HRAS', 'Gene', (125, 129))
50225	29259016	p-ERK levels were also reduced in the RAS-expressing mutant cells, consistent with the known function of KSR1 in facilitating signaling through the RAS-ERK cascade.	('ERK', 'molecular_function', 'GO:0004707', ('152', '155'))	('ERK', 'molecular_function', 'GO:0004707', ('2', '5'))	('p-ERK levels', 'MPA', (0, 12))	('ERK cascade', 'biological_process', 'GO:0070371', ('152', '163'))	('RAS', 'Chemical', 'MESH:D011883', (38, 41))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('RAS', 'Chemical', 'MESH:D011883', (148, 151))	('mutant', 'Var', (53, 59))	('reduced', 'NegReg', (23, 30))	('facilitating signaling', 'MPA', (113, 135))
50226	29259016	Conversely, p-ERK was modestly increased in control KSR1-/- MEFs relative to WT cells, an effect that can be attributed to loss of KSR1-mediated, ERK-dependent negative feedback on RAF and MEK activity.	('p-ERK', 'MPA', (12, 17))	('ERK', 'molecular_function', 'GO:0004707', ('146', '149'))	('MEFs', 'CellLine', 'CVCL:9115', (60, 64))	('MEK activity', 'molecular_function', 'GO:0004708', ('189', '201'))	('RAF', 'Gene', (181, 184))	('increased', 'PosReg', (31, 40))	('RAF', 'Gene', '387609', (181, 184))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('loss', 'NegReg', (123, 127))	('negative', 'NegReg', (160, 168))	('KSR1-/- MEFs', 'Var', (52, 64))
50230	29259016	In addition, endogenous KSR1 and an ectopic GFP-KSR1 chimeric protein both re-localized to the perinuclear cytoplasm in NIH3T3RAS cells compared to non-transformed NIH3T3 controls (Supplementary Fig.	('NIH3T3', 'CellLine', 'CVCL:0594', (164, 170))	('KSR1', 'Gene', (24, 28))	('NIH3T3RAS', 'CellLine', 'CVCL:0594', (120, 129))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('re-localized', 'PosReg', (75, 87))	('GFP-KSR1', 'Gene', (44, 52))	('NIH3T3RAS', 'Var', (120, 129))	('cytoplasm', 'cellular_component', 'GO:0005737', ('107', '116'))	('NIH3T3', 'CellLine', 'CVCL:0594', (120, 126))	('GFP-KSR1', 'Gene', '16706', (44, 52))
50232	29259016	KSR1 depletion disrupted perinuclear localization of CK2alpha and p-ERK in NIH3T3RAS cells (Supplementary Fig.	('disrupted', 'NegReg', (15, 24))	('localization', 'biological_process', 'GO:0051179', ('37', '49'))	('depletion', 'Var', (5, 14))	('perinuclear localization', 'MPA', (25, 49))	('KSR1', 'Gene', (0, 4))	('CK2alpha', 'Gene', '1459', (53, 61))	('CK2alpha', 'Gene', (53, 61))	('NIH3T3RAS', 'CellLine', 'CVCL:0594', (75, 84))	('ERK', 'molecular_function', 'GO:0004707', ('68', '71'))	('p-ERK', 'Protein', (66, 71))
50234	29259016	These data show that KSR1 plays a key role in the perinuclear trafficking of these effector kinases in response to oncogenic RAS, irrespective of whether the cells undergo senescence (MEFs) or transformation (NIH3T3 cells).	('response', 'MPA', (103, 111))	('NIH3T3', 'CellLine', 'CVCL:0594', (209, 215))	('KSR1', 'Gene', (21, 25))	('senescence', 'biological_process', 'GO:0010149', ('172', '182'))	('perinuclear trafficking', 'MPA', (50, 73))	('MEFs', 'CellLine', 'CVCL:9115', (184, 188))	('oncogenic', 'Var', (115, 124))	('RAS', 'Chemical', 'MESH:D011883', (125, 128))
50238	29259016	Depletion of KSR1 in these cells caused CK2alpha to become almost exclusively nuclear, while p-ERK levels were decreased dramatically.	('KSR1', 'Gene', (13, 17))	('CK2alpha', 'Gene', '1459', (40, 48))	('CK2alpha', 'Gene', (40, 48))	('Depletion', 'Var', (0, 9))	('p-ERK levels', 'MPA', (93, 105))	('ERK', 'molecular_function', 'GO:0004707', ('95', '98'))
50239	29259016	Human A375 melanoma cells, which carry a homozygous BRAFV600E mutation, likewise displayed intense perinuclear staining for p-ERK, CK2alpha and KSR1 (Fig.	('Human', 'Species', '9606', (0, 5))	('CK2alpha', 'Gene', (131, 139))	('BRAFV600E', 'Var', (52, 61))	('KSR1', 'Protein', (144, 148))	('BRAFV600E', 'Mutation', 'rs113488022', (52, 61))	('A375', 'CellLine', 'CVCL:0132', (6, 10))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('CK2alpha', 'Gene', '1459', (131, 139))	('p-ERK', 'Protein', (124, 129))	('ERK', 'molecular_function', 'GO:0004707', ('126', '129'))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
50240	29259016	Moreover, the BRAFV600E oncoprotein itself was present in the nuclear-proximal region in A375 cells and its depletion greatly decreased p-ERK levels and disrupted the perinuclear trafficking of CK2alpha and KSR1.	('p-ERK levels', 'MPA', (136, 148))	('decreased', 'NegReg', (126, 135))	('CK2alpha', 'Gene', '1459', (194, 202))	('disrupted', 'NegReg', (153, 162))	('depletion', 'MPA', (108, 117))	('CK2alpha', 'Gene', (194, 202))	('A375', 'CellLine', 'CVCL:0132', (89, 93))	('ERK', 'molecular_function', 'GO:0004707', ('138', '141'))	('KSR1', 'Gene', (207, 211))	('perinuclear trafficking', 'MPA', (167, 190))	('BRAFV600E', 'Var', (14, 23))	('BRAFV600E', 'Mutation', 'rs113488022', (14, 23))
50241	29259016	Our results show that perinuclear signaling complexes (PSCs) containing p-ERK, CK2alpha and KSR1 are present in HRAS-, KRAS- and BRAF-transformed cells and occur independently of serum growth factors.	('p-ERK', 'Var', (72, 77))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('HRAS', 'Gene', (112, 116))	('ERK', 'molecular_function', 'GO:0004707', ('74', '77'))	('CK2alpha', 'Gene', '1459', (79, 87))	('HRAS', 'Gene', '15461', (112, 116))	('CK2alpha', 'Gene', (79, 87))	('KSR1', 'Gene', (92, 96))
50247	29259016	Treatment of NIH3T3RAS cells with the MEK1/2 inhibitor, U0126, strongly reduced p-ERK levels, as expected (Supplementary Fig.	('ERK', 'molecular_function', 'GO:0004707', ('82', '85'))	('reduced', 'NegReg', (72, 79))	('U0126', 'Chemical', 'MESH:C113580', (56, 61))	('MEK1', 'molecular_function', 'GO:0004708', ('38', '42'))	('MEK1/2', 'Gene', '26395;26396', (38, 44))	('p-ERK levels', 'MPA', (80, 92))	('U0126', 'Var', (56, 61))	('NIH3T3RAS', 'CellLine', 'CVCL:0594', (13, 22))	('MEK1/2', 'Gene', (38, 44))
50249	29259016	Moreover, while TBB did not noticeably affect p-ERK levels as determined by IF staining, it produced a marked dispersal of p-ERK, CK2alpha and KSR1 from the perinuclear compartment.	('dispersal', 'MPA', (110, 119))	('TBB', 'Var', (16, 19))	('TBB', 'Chemical', 'MESH:C103118', (16, 19))	('ERK', 'molecular_function', 'GO:0004707', ('125', '128'))	('CK2alpha', 'Gene', '1459', (130, 138))	('CK2alpha', 'Gene', (130, 138))	('ERK', 'molecular_function', 'GO:0004707', ('48', '51'))	('p-ERK', 'Protein', (123, 128))
50256	29259016	Treatment with U0126 blocked ERK activation, as expected, but did not appreciably affect CK2alpha binding to KSR1.	('binding', 'Interaction', (98, 105))	('U0126', 'Var', (15, 20))	('U0126', 'Chemical', 'MESH:C113580', (15, 20))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('CK2alpha', 'Gene', '1459', (89, 97))	('ERK', 'molecular_function', 'GO:0004707', ('29', '32'))	('blocked', 'NegReg', (21, 28))	('CK2alpha', 'Gene', (89, 97))	('ERK', 'Protein', (29, 32))	('activation', 'MPA', (33, 43))
50257	29259016	Conversely, TBB did not reduce levels of p-ERK or its interaction with KSR1, but reversed the RAS-induced increase in KSR1-CK2alpha binding.	('TBB', 'Var', (12, 15))	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('TBB', 'Chemical', 'MESH:C103118', (12, 15))	('CK2alpha', 'Gene', '1459', (123, 131))	('CK2alpha', 'Gene', (123, 131))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('RAS', 'Chemical', 'MESH:D011883', (94, 97))	('binding', 'Interaction', (132, 139))	('increase', 'PosReg', (106, 114))
50260	29259016	The perinuclear staining of p-ERK, CK2alpha and KSR1 was often punctate, indicating that these proteins might be associated with endosomal vesicles.	('ERK', 'molecular_function', 'GO:0004707', ('30', '33'))	('KSR1', 'Gene', (48, 52))	('CK2alpha', 'Gene', '1459', (35, 43))	('CK2alpha', 'Gene', (35, 43))	('p-ERK', 'Var', (28, 33))
50265	29259016	In accordance with these results, dynasore also caused a significant decrease in RAS-induced activation of C/EBPbeta-dependent SASP genes in MEFs (Supplementary Fig.	('C/EBPbeta-dependent SASP genes', 'Gene', (107, 137))	('activation', 'PosReg', (93, 103))	('dynasore', 'Var', (34, 42))	('decrease', 'NegReg', (69, 77))	('MEFs', 'CellLine', 'CVCL:9115', (141, 145))	('RAS', 'Chemical', 'MESH:D011883', (81, 84))
50268	29259016	Consistent with this prediction, perinuclear sorting of all three proteins in NIH3T3RAS cells was abrogated by dynasore (Fig.	('abrogated', 'NegReg', (98, 107))	('NIH3T3RAS', 'CellLine', 'CVCL:0594', (78, 87))	('NIH3T3RAS', 'Var', (78, 87))	('perinuclear sorting', 'MPA', (33, 52))
50269	29259016	Thus, endocytic trafficking plays a critical role in the subcellular compartmentalization of RAS pathway proteins and activation of C/EBPbeta by oncogenic RAS.	('oncogenic RAS', 'Var', (145, 158))	('activation', 'PosReg', (118, 128))	('RAS', 'Chemical', 'MESH:D011883', (155, 158))	('RAS', 'Chemical', 'MESH:D011883', (93, 96))	('C/EBPbeta', 'Gene', (132, 141))
50285	29259016	Notably, the tumor cells displayed clearly visible perinuclear rings containing p-ERK, CK2alpha, KSR1 and BRAF.	('tumor', 'Disease', (13, 18))	('ERK', 'molecular_function', 'GO:0004707', ('82', '85'))	('p-ERK', 'Var', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('KSR1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CK2alpha', 'Gene', '1459', (87, 95))	('CK2alpha', 'Gene', (87, 95))
50288	29259016	We also analyzed lung tumors from mice carrying a conditional BrafV600E allele which, upon activation by Cre recombinase (instillation of Ad.Cre virus), develop mainly benign adenomas with certain features of senescence (Fig.	('senescence', 'biological_process', 'GO:0010149', ('209', '219'))	('mice', 'Species', '10090', (34, 38))	('lung tumors', 'Phenotype', 'HP:0100526', (17, 28))	('lung tumors', 'Disease', (17, 28))	('develop', 'PosReg', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('BrafV600E', 'Mutation', 'rs113488022', (62, 71))	('benign adenomas', 'Disease', (168, 183))	('BrafV600E', 'Var', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('benign adenomas', 'Disease', 'MESH:D000236', (168, 183))	('lung tumors', 'Disease', 'MESH:D008175', (17, 28))
50297	29259016	p-Thr188 was also induced but did not appear until 6 hr, and phosphorylation on both sites declined at 12 hr.	('declined', 'NegReg', (91, 99))	('p-Thr188', 'Var', (0, 8))	('phosphorylation on both', 'MPA', (61, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('Thr188', 'Chemical', '-', (2, 8))
50298	29259016	These results are consistent with our findings that Ser222 is critical for activation of DNA binding (Fig.	('DNA binding', 'molecular_function', 'GO:0003677', ('89', '100'))	('Ser', 'cellular_component', 'GO:0005790', ('52', '55'))	('activation of DNA binding', 'biological_process', 'GO:0043388', ('75', '100'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('Ser222', 'Chemical', '-', (52, 58))	('Ser222', 'Var', (52, 58))	('DNA binding', 'Interaction', (89, 100))
50310	29259016	Similarly, perinuclear translocation of CK2alpha at 4-6 hr was abrogated by KSR1 knockdown.	('abrogated', 'NegReg', (63, 72))	('CK2alpha', 'Gene', '1459', (40, 48))	('CK2alpha', 'Gene', (40, 48))	('knockdown', 'Var', (81, 90))	('KSR1', 'Gene', (76, 80))	('perinuclear translocation', 'MPA', (11, 36))
50311	29259016	These findings, together with the results from tumor cells, demonstrate a critical role for KSR1 in PSC formation by mutant or physiological RAS signaling.	('rat', 'Species', '10116', (67, 70))	('mutant', 'Var', (117, 123))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('RAS', 'Chemical', 'MESH:D011883', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('PSC', 'Disease', (100, 103))	('tumor', 'Disease', (47, 52))	('KSR1', 'Gene', (92, 96))
50313	29259016	Therefore, we asked whether KSR1 depletion affects GF-induced phosphorylation on the Elk-1 ERK site (Ser383).	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('depletion', 'Var', (33, 42))	('Elk-1', 'Gene', (85, 90))	('Ser383', 'Chemical', '-', (101, 107))	('Elk-1', 'Gene', '13712', (85, 90))	('KSR1', 'Gene', (28, 32))	('GF-induced phosphorylation', 'MPA', (51, 77))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
50315	29259016	These results indicate that phosphorylation of Elk-1 on Ser383 does not involve p-ERK localized to PSCs, consistent with the impaired activation of Elk-1 that has been observed in senescent cells, which display cytoplasmic p-ERK (also see Fig.	('Elk-1', 'Gene', (47, 52))	('Ser', 'cellular_component', 'GO:0005790', ('56', '59'))	('ERK', 'molecular_function', 'GO:0004707', ('82', '85'))	('ERK', 'molecular_function', 'GO:0004707', ('225', '228'))	('Ser383', 'Chemical', '-', (56, 62))	('Elk-1', 'Gene', '13712', (47, 52))	('Ser383', 'Var', (56, 62))	('Elk-1', 'Gene', (148, 153))	('Elk-1', 'Gene', '13712', (148, 153))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))
50319	29259016	In addition to their subcellular location, PSCs are defined by 1) their persistence in tumor cells deprived of growth factors, 2) their induction by driver oncogenes such as KRASG12D and BRAFV600E, 3) their dependence on the signaling scaffold, KSR1, 4) the requirement for MEK-ERK and CK2 activity, and 5) their dependence on endocytosis and association with perinuclear endosomes.	('KRASG12D', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ERK', 'molecular_function', 'GO:0004707', ('278', '281'))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('tumor', 'Disease', (87, 92))	('BRAFV600E', 'Var', (187, 196))	('BRAFV600E', 'Mutation', 'rs113488022', (187, 196))	('endocytosis', 'biological_process', 'GO:0006897', ('327', '338'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
50321	29259016	The striking spatial similarities between GF-induced PSCs present at 4-6 hr and those in tumor cells suggest that dysregulated RAS pathway signaling persistently activates the delayed phase of GF signaling to drive oncogenesis.	('GF signaling', 'MPA', (193, 205))	('activates', 'PosReg', (162, 171))	('oncogenesis', 'CPA', (215, 226))	('oncogenesis', 'biological_process', 'GO:0007048', ('215', '226'))	('dysregulated', 'Var', (114, 126))	('RAS', 'Chemical', 'MESH:D011883', (127, 130))	('signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('RAS', 'Protein', (127, 130))	('drive', 'PosReg', (209, 214))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('delayed phase', 'MPA', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
50324	29259016	Depletion of KSR1 in tumor cells severely curtailed ERK activation, as expected, but also affected p-ERK localization.	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('KSR1', 'Gene', (13, 17))	('tumor', 'Disease', (21, 26))	('localization', 'biological_process', 'GO:0051179', ('105', '117'))	('ERK', 'Protein', (52, 55))	('activation', 'MPA', (56, 66))	('Depletion', 'Var', (0, 9))	('affected', 'Reg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('curtailed', 'NegReg', (42, 51))	('ERK', 'molecular_function', 'GO:0004707', ('101', '104'))	('p-ERK localization', 'MPA', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
50325	29259016	Conversely, KSR1 ablation in serum-starved, non-transformed cells modestly increased basal p-ERK levels and its absence did not impair GF-induced activation of ERK, its ability to enter the nucleus or activation of a known nuclear target, Elk-1.	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('KSR1', 'Gene', (12, 16))	('Elk-1', 'Gene', '13712', (239, 244))	('Elk-1', 'Gene', (239, 244))	('increased', 'PosReg', (75, 84))	('ablation', 'Var', (17, 25))	('ERK', 'Protein', (160, 163))	('impair', 'NegReg', (128, 134))	('nucleus', 'cellular_component', 'GO:0005634', ('190', '197'))	('ERK', 'molecular_function', 'GO:0004707', ('93', '96'))	('p-ERK levels', 'MPA', (91, 103))
50331	29259016	PSCs are also induced by mutant RAS in primary MEFs undergoing OIS.	('mutant', 'Var', (25, 31))	('MEFs', 'CellLine', 'CVCL:9115', (47, 51))	('OIS', 'biological_process', 'GO:0090402', ('63', '66'))	('PSCs', 'Disease', (0, 4))	('RAS', 'Chemical', 'MESH:D011883', (32, 35))	('induced by', 'Reg', (14, 24))	('RAS', 'Protein', (32, 35))
50332	29259016	When C/EBPbeta is expressed without its 3'UTR in tumor cells or when UPA is absent, as in MEFs, its activation can still be blocked by disruption of PSCs (e.g., by mutation/depletion of KSR1 or inhibition of endocytosis).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('endocytosis', 'MPA', (208, 219))	('mutation/depletion', 'Var', (164, 182))	('UPA', 'molecular_function', 'GO:0008243', ('69', '72'))	('tumor', 'Disease', (49, 54))	('inhibition of endocytosis', 'biological_process', 'GO:0045806', ('194', '219'))	('KSR1', 'Gene', (186, 190))	('activation', 'PosReg', (100, 110))	('MEFs', 'CellLine', 'CVCL:9115', (90, 94))	('disruption', 'Var', (135, 145))
50335	29259016	Our results indicate that CK2 functions as a RAS effector kinase, as its ability to phosphorylate C/EBPbeta is greatly increased by oncogenic or physiological RAS signaling (Fig.	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('CK2', 'Gene', (26, 29))	('RAS', 'Chemical', 'MESH:D011883', (159, 162))	('RAS', 'Chemical', 'MESH:D011883', (45, 48))	('ability', 'MPA', (73, 80))	('oncogenic', 'Var', (132, 141))	('increased', 'PosReg', (119, 128))
50338	29259016	The timing of their re-localization corresponds to phosphorylation on the C/EBPbeta CK2 and ERK sites (Ser222 and Thr188) (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('Ser', 'cellular_component', 'GO:0005790', ('103', '106'))	('Thr188', 'Chemical', '-', (114, 120))	('phosphorylation', 'MPA', (51, 66))	('ERK', 'Gene', (92, 95))	('ERK', 'molecular_function', 'GO:0004707', ('92', '95'))	('localization', 'biological_process', 'GO:0051179', ('23', '35'))	('Ser222', 'Chemical', '-', (103, 109))	('Ser222', 'Var', (103, 109))
50351	29259016	The presence of PSCs across a wide range of tumors suggests their formation can be induced by a variety of driver mutations, not just those affecting core RAS pathway components.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('PSCs', 'Disease', (16, 20))	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('core', 'cellular_component', 'GO:0019013', ('150', '154'))	('mutations', 'Var', (114, 123))	('RAS', 'Chemical', 'MESH:D011883', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('induced', 'Reg', (83, 90))
50352	29259016	Thus, future characterizations of rare or non-canonical tumor-associated mutations should include determining whether the mutant proteins promote PSC formation and/or are components of these signaling complexes.	('PSC', 'Disease', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('promote', 'PosReg', (138, 145))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('proteins', 'Protein', (129, 137))	('mutant', 'Var', (122, 128))	('mutations', 'Var', (73, 82))
50359	28548957	Consequently, a serine 186 to alanine (SA) mutant of TTP was resistant to radiation-induced degradation.	('SA', 'Chemical', '-', (39, 41))	('serine 186 to', 'Var', (16, 29))	('degradation', 'biological_process', 'GO:0009056', ('92', '103'))	('serine 186 to alanine', 'Mutation', 'p.S186A', (16, 37))	('TTP', 'Gene', (53, 56))
50360	28548957	Similarly, either a p38 kinase inhibitor (SB203580), or siRNA-mediated beta-TrCP knockdown, or overexpression of dominant negative Cullin1 mutants protected TTP from radiation-induced degradation.	('Cullin1', 'Gene', '26965', (131, 138))	('Cullin1', 'Gene', (131, 138))	('SB203580', 'Chemical', 'MESH:C093642', (42, 50))	('protected', 'PosReg', (147, 156))	('degradation', 'biological_process', 'GO:0009056', ('184', '195'))	('TTP', 'MPA', (157, 160))	('mutants', 'Var', (139, 146))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('24', '40'))
50367	28548957	As long-term delivery of siRNA or antisense oligonucleotides remains a challenge, identification of novel targets that can be accessed using a small molecule would be important to limit RILT.	('RILT', 'Disease', (186, 190))	('oligonucleotides', 'Chemical', 'MESH:D009841', (44, 60))	('antisense', 'Var', (34, 43))
50375	28548957	Specific phosphorylation of TTP at serine 186 by p38 MAPK inactivates its mRNA-destabilizing ability.	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('TTP', 'Gene', (28, 31))	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('serine', 'Chemical', 'MESH:D012694', (35, 41))	('p38', 'Var', (49, 52))	('inactivates', 'NegReg', (58, 69))	('mRNA-destabilizing ability', 'MPA', (74, 100))	('phosphorylation', 'MPA', (9, 24))
50407	28548957	As Cullin plays an important role in beta-TrCP mediated substrate polyubiquitination and degradation, we tested two different Cullin-1 mutants (K720R and 1-327 deletion), which are known to inhibit beta-TrCP activity.	('inhibit', 'NegReg', (190, 197))	('tested', 'Reg', (105, 111))	('K720R', 'Mutation', 'p.K720R', (144, 149))	('K720R', 'Var', (144, 149))	('Cullin-1', 'Gene', '26965', (126, 134))	('degradation', 'biological_process', 'GO:0009056', ('89', '100'))	('beta-TrCP', 'Enzyme', (198, 207))	('activity', 'MPA', (208, 216))	('Cullin-1', 'Gene', (126, 134))	('degradation', 'MPA', (89, 100))	('1-327 deletion', 'Var', (154, 168))
50408	28548957	In Figure 3F, we demonstrate that radiation-induced TTP downregulation can be inhibited by overexpressing either of the two Cullin-1 mutants.	('TTP', 'MPA', (52, 55))	('Cullin-1', 'Gene', '26965', (124, 132))	('overexpressing', 'PosReg', (91, 105))	('Cullin-1', 'Gene', (124, 132))	('mutants', 'Var', (133, 140))
50409	28548957	As shown in Figure 4A (left panel), serine (S) to alanine (A) substitution (SA) at degron I had a minimal effect on radiation-induced TTP downregulation.	('SA', 'Chemical', '-', (76, 78))	('alanine', 'Chemical', 'MESH:D000409', (50, 57))	('serine', 'Var', (36, 42))	('TTP', 'MPA', (134, 137))	('serine', 'Chemical', 'MESH:D012694', (36, 42))	('downregulation', 'NegReg', (138, 152))
50412	28548957	In our previous study (Figure 2E) we reported that overexpression of S186A mutant TTP can block radiation-induced TNF-alpha release by irradiated lung macrophages (MH-S), suggesting the functional significance of this phosphorylation.	('TNF-alpha', 'Gene', '21926', (114, 123))	('block', 'NegReg', (90, 95))	('S186A', 'Mutation', 'p.S186A', (69, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('218', '233'))	('TNF-alpha', 'Gene', (114, 123))	('S186A', 'Var', (69, 74))	('overexpression', 'PosReg', (51, 65))	('TTP', 'Gene', (82, 85))
50413	28548957	Previous studies have reported that p38-mediated serine 186 phosphorylation promotes functional inactivation of TTP, which is essential for increased stabilization of various cytokine transcripts including TNF-alpha.	('p38-mediated', 'Var', (36, 48))	('TNF-alpha', 'Gene', '21926', (206, 215))	('functional inactivation', 'MPA', (85, 108))	('TNF-alpha', 'Gene', (206, 215))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('serine', 'Chemical', 'MESH:D012694', (49, 55))	('TTP', 'Gene', (112, 115))
50414	28548957	As we showed previously that radiation induces p38-mediated TTP phosphorylation at S186 both in vitro and in vivo, and as now we have found that S186A mutant TTP is resistant to radiation-induced ubiquitination and degradation, we hypothesized that, in the context of radiation the S186 phosphorylation and beta-TrCP mediated ubiquitination and degradation are interconnected.	('degradation', 'biological_process', 'GO:0009056', ('215', '226'))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('phosphorylation', 'biological_process', 'GO:0016310', ('287', '302'))	('degradation', 'MPA', (345, 356))	('p38-mediated TTP phosphorylation', 'MPA', (47, 79))	('S186A', 'Mutation', 'p.S186A', (145, 150))	('degradation', 'biological_process', 'GO:0009056', ('345', '356'))	('S186A', 'Var', (145, 150))
50416	28548957	Taken together, these data show that radiation induces Ser186 phosphorylation of TTP to prime it for beta-TrCP recognition followed by polyubiquitination and proteasomal degradation.	('degradation', 'biological_process', 'GO:0009056', ('170', '181'))	('beta-TrCP recognition', 'MPA', (101, 122))	('phosphorylation', 'MPA', (62, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))	('polyubiquitination', 'MPA', (135, 153))	('Ser', 'cellular_component', 'GO:0005790', ('55', '58'))	('TTP', 'Gene', (81, 84))	('Ser186', 'Chemical', '-', (55, 61))	('prime', 'PosReg', (88, 93))	('proteasomal degradation', 'MPA', (158, 181))	('Ser186', 'Var', (55, 61))
50421	28548957	As shown in Figure 5B, an improved survival of macrophages was noted when they were irradiated in the presence of SB203580, with a radiation enhancement ratio (ER) of 0.86.	('SB203580', 'Chemical', 'MESH:C093642', (114, 122))	('improved', 'PosReg', (26, 34))	('survival', 'CPA', (35, 43))	('SB203580', 'Var', (114, 122))
50425	28548957	Here, we report that upon genetic ablation of Ttp, mouse lungs were more susceptible to radiation-induced inflammation (pneumonitis), which is correlated with increased TNF-alpha levels.	('pneumonitis', 'Disease', 'MESH:D011014', (120, 131))	('TNF-alpha', 'Gene', '21926', (169, 178))	('Ttp', 'Gene', '22695', (46, 49))	('increased', 'PosReg', (159, 168))	('mouse', 'Species', '10090', (51, 56))	('TNF-alpha', 'Gene', (169, 178))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('Ttp', 'Gene', (46, 49))	('inflammation', 'biological_process', 'GO:0006954', ('106', '118'))	('pneumonitis', 'Disease', (120, 131))	('inflammation', 'Disease', (106, 118))	('genetic ablation', 'Var', (26, 42))
50428	28548957	Such concerted phosphorylation and degradation-mediated inactivation of TTP releases its anti-inflammatory effects, allowing the secretion of TNF-alpha by irradiated lung macrophages.	('anti-inflammatory effects', 'MPA', (89, 114))	('secretion', 'biological_process', 'GO:0046903', ('129', '138'))	('TTP', 'Gene', (72, 75))	('inactivation', 'Var', (56, 68))	('TNF-alpha', 'Gene', (142, 151))	('secretion of', 'MPA', (129, 141))	('allowing', 'PosReg', (116, 124))	('TNF-alpha', 'Gene', '21926', (142, 151))	('degradation', 'biological_process', 'GO:0009056', ('35', '46'))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))
50430	28548957	In this manuscript, we report for the first time that Ttp knockout mice are also prone to radiation-induced lung inflammation.	('lung inflammation', 'Disease', 'MESH:D011014', (108, 125))	('inflammation', 'biological_process', 'GO:0006954', ('113', '125'))	('Ttp', 'Gene', '22695', (54, 57))	('prone', 'Reg', (81, 86))	('lung inflammation', 'Disease', (108, 125))	('knockout', 'Var', (58, 66))	('Ttp', 'Gene', (54, 57))	('mice', 'Species', '10090', (67, 71))
50434	28548957	Our in vivo findings raised the possibility that Ttp plays an important role in blocking early phenotypes of radiation-induced lung pneumonitis in the C57BL/6 as compared to the C3H-HeN strain.	('lung pneumonitis', 'Disease', 'MESH:D011014', (127, 143))	('C57BL/6', 'Var', (151, 158))	('Ttp', 'Gene', (49, 52))	('lung pneumonitis', 'Disease', (127, 143))	('Ttp', 'Gene', '22695', (49, 52))
50435	28548957	Our data (Figure 1D, 1E) further support such a hypothesis, where we noted faster decay of Ttp protein particularly in C3H mice.	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('decay', 'MPA', (82, 87))	('Ttp', 'Gene', '22695', (91, 94))	('C3H', 'Var', (119, 122))	('faster', 'PosReg', (75, 81))	('Ttp', 'Gene', (91, 94))	('mice', 'Species', '10090', (123, 127))
50442	28548957	Interestingly, a previous study has shown that LPS treatment can mitigate radiation-induced lung injury in knockout mice of either TNF-alpha or its receptors in the C57BL/6J background.	('TNF-alpha', 'Gene', '21926', (131, 140))	('mice', 'Species', '10090', (116, 120))	('LPS', 'Var', (47, 50))	('mitigate', 'NegReg', (65, 73))	('TNF-alpha', 'Gene', (131, 140))	('lung injury', 'Disease', 'MESH:D055370', (92, 103))	('lung injury', 'Disease', (92, 103))
50443	28548957	Thus, one could speculate that LPS-induced compensatory upregulation of functionally inactive (phosphorylated) Ttp can still inhibit radiation-induced lung inflammation, although this needs to be tested.	('inhibit', 'NegReg', (125, 132))	('upregulation', 'PosReg', (56, 68))	('lung inflammation', 'Disease', (151, 168))	('Ttp', 'Gene', '22695', (111, 114))	('Ttp', 'Gene', (111, 114))	('LPS-induced', 'Var', (31, 42))	('lung inflammation', 'Disease', 'MESH:D011014', (151, 168))	('inflammation', 'biological_process', 'GO:0006954', ('156', '168'))
50462	28548957	To generate serine-to-alanine mutants (SA) of TTP [S34A, S34/35/39A (3SA) and S186A] wild-type construct was subjected to site-directed mutagenesis using the QuikChange II site-directed mutagenesis kit (Agilent Technologies, Santa Clara, CA).	('SA', 'Chemical', '-', (70, 72))	('S186A', 'Mutation', 'p.S186A', (78, 83))	('S186A', 'Var', (78, 83))	('mutagenesis', 'biological_process', 'GO:0006280', ('136', '147'))	('S34A', 'Mutation', 'p.S34A', (51, 55))	('SA', 'Chemical', '-', (39, 41))	('serine-to-alanine', 'MPA', (12, 29))	('TTP', 'Gene', (46, 49))	('alanine', 'Chemical', 'MESH:D000409', (22, 29))	('serine', 'Chemical', 'MESH:D012694', (12, 18))	('mutagenesis', 'biological_process', 'GO:0006280', ('186', '197'))
50477	28548957	In brief, U2OS cells overexpressing FLAG-tagged wild-type TTP protein were either sham-irradiated or exposed to 4 Gy.	('TTP', 'Gene', (58, 61))	('FLAG-tagged', 'Var', (36, 47))	('U2OS', 'CellLine', 'CVCL:0042', (10, 14))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
50497	27794582	Interestingly, exogenous PUFA may be associated with prevention of some cancers.	('PUFA', 'Protein', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prevention', 'NegReg', (53, 63))	('exogenous', 'Var', (15, 24))	('PUFA', 'Chemical', 'MESH:D005231', (25, 29))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
50539	27794582	It was suggested that the FAS expression is of functional importance in human esophageal tumorigenesis, and that inhibiting FAS might be applied to treat esophageal cancer.	('FAS', 'Gene', '2194', (124, 127))	('FAS', 'Gene', (124, 127))	('esophageal cancer', 'Disease', (154, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('human', 'Species', '9606', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('FAS', 'Gene', '2194', (26, 29))	('FAS', 'Gene', (26, 29))	('inhibiting', 'Var', (113, 123))	('tumor', 'Disease', (89, 94))
50574	27794582	It was recently found that cisplatin in adult C57Bl/6J male mice caused a decrease in the lipogenic enzymes FAS and SCD1 in liver, white adipose tissue (WAT), and muscle; concurrently, cisplatin increased lipolysis in WAT and beta-oxidation in liver and WAT.	('WAT', 'Disease', (254, 257))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('FAS', 'Gene', '2194', (108, 111))	('lipolysis', 'MPA', (205, 214))	('increased', 'PosReg', (195, 204))	('mice', 'Species', '10090', (60, 64))	('FAS', 'Gene', (108, 111))	('SCD1', 'Enzyme', (116, 120))	('decrease', 'NegReg', (74, 82))	('WAT', 'Disease', 'None', (218, 221))	('beta-oxidation', 'MPA', (226, 240))	('WAT', 'Disease', (218, 221))	('lipolysis', 'biological_process', 'GO:0016042', ('205', '214'))	('WAT', 'Disease', 'None', (153, 156))	('cisplatin', 'Var', (185, 194))	('WAT', 'Disease', (153, 156))	('WAT', 'Disease', 'None', (254, 257))	('cisplatin', 'Var', (27, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))
50590	27604143	NSD2 knock down combined with MEK or BRD4 inhibitors causes co-operative inhibitory responses on cell growth.	('causes', 'Reg', (53, 59))	('BRD4', 'Gene', (37, 41))	('NSD2', 'Gene', (0, 4))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('co-operative', 'MPA', (60, 72))	('inhibitory responses on cell growth', 'MPA', (73, 108))	('knock down', 'Var', (5, 15))	('BRD4', 'Gene', '23476', (37, 41))	('MEK', 'Gene', (30, 33))	('MEK', 'Gene', '5609', (30, 33))
50594	27604143	Deletions in NSD2 cause the Wolf-Hirschhorn syndrome (WHS) characterized by delayed growth and intellectual disability while NSD2 overexpression has been linked to cancer (reviewed in Morishita and Di Luccio).	('NSD2', 'Gene', (13, 17))	('WHS', 'Disease', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('intellectual disability', 'Phenotype', 'HP:0001249', (95, 118))	('cause', 'Reg', (18, 23))	('Wolf-Hirschhorn syndrome', 'Disease', (28, 52))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Wolf-Hirschhorn syndrome', 'Disease', 'MESH:D054877', (28, 52))	('delayed growth', 'Phenotype', 'HP:0001510', (76, 90))	('Deletions', 'Var', (0, 9))	('WHS', 'Disease', 'MESH:D054877', (54, 57))
50595	27604143	NSD2 shows gain of function in blood cancers due to fusions to the IgH locus via t(4;14) translocations that cause its overexpression in multiple myeloma or recurrent E1099K mutations that enhance its methyltransferase activity in lymphomas.	('NSD2', 'Gene', (0, 4))	('blood cancers', 'Disease', 'MESH:D009369', (31, 44))	('blood cancers', 'Disease', (31, 44))	('lymphomas', 'Disease', (231, 240))	('IgH', 'Gene', (67, 70))	('methyltransferase activity', 'MPA', (201, 227))	('lymphoma', 'Phenotype', 'HP:0002665', (231, 239))	('gain', 'PosReg', (11, 15))	('enhance', 'PosReg', (189, 196))	('multiple myeloma', 'Phenotype', 'HP:0006775', (137, 153))	('E1099K', 'Mutation', 'rs772470710', (167, 173))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('201', '227'))	('fusions', 'Var', (52, 59))	('E1099K', 'Var', (167, 173))	('lymphomas', 'Disease', 'MESH:D008223', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lymphomas', 'Phenotype', 'HP:0002665', (231, 240))	('IgH', 'Gene', '3492', (67, 70))	('multiple myeloma', 'Disease', 'MESH:D009101', (137, 153))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('blood cancers', 'Phenotype', 'HP:0001909', (31, 44))	('overexpression', 'PosReg', (119, 133))	('blood cancer', 'Phenotype', 'HP:0001909', (31, 43))	('multiple myeloma', 'Disease', (137, 153))
50598	27604143	Additionally, NSD2 has been demonstrated to support the proliferation and/or survival of several cancer cell lines including myeloma cell lines with t(4;14) translocations, leukemia cell lines carrying the E1099K mutation, prostate cancer and osteo and fibrosarcoma cell lines.	('E1099K', 'Var', (206, 212))	('cancer', 'Disease', (232, 238))	('proliferation', 'CPA', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('myeloma', 'Disease', (125, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (223, 238))	('cancer', 'Disease', (97, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (223, 238))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (253, 265))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', (223, 238))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('survival', 'CPA', (77, 85))	('osteo and fibrosarcoma', 'Disease', 'MESH:D005354', (243, 265))	('leukemia', 'Disease', (173, 181))	('leukemia', 'Disease', 'MESH:D007938', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('E1099K', 'Mutation', 'rs772470710', (206, 212))	('support', 'PosReg', (44, 51))	('myeloma', 'Disease', 'MESH:D009101', (125, 132))
50613	27604143	We next evaluated potential consequences of NSD2 knock down in the lung cancer cell line H1299 that expresses high levels of NSD2.	('knock down', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('H1299', 'CellLine', 'CVCL:0060', (89, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('lung cancer', 'Disease', (67, 78))	('NSD2', 'Gene', (44, 48))
50622	27604143	Both cell lines, KMS11, a multiple myeloma line which harbors the t(4;14) translocation, and RCH-ACV, a lymphoblastic leukemia line with the E1099K activating mutation, were sensitive to NSD2 depletion mediated by sh3 and sh5 (Supplementary Fig.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (104, 126))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (104, 126))	('sh3', 'Gene', '100125849', (214, 217))	('E1099K', 'Var', (141, 147))	('E1099K', 'Mutation', 'rs772470710', (141, 147))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('multiple myeloma', 'Phenotype', 'HP:0006775', (26, 42))	('multiple myeloma', 'Disease', 'MESH:D009101', (26, 42))	('lymphoblastic leukemia', 'Disease', (104, 126))	('multiple myeloma', 'Disease', (26, 42))	('sh3', 'Gene', (214, 217))
50631	27604143	To verify whether the knock down of NSD2 in the lung cancer cell line H1299 causes similar changes in histone methylation we conducted mass spectrometry analysis to monitor the status of histone H3 K36 methylation in combination with K27 methylation that can be readily detected on the same peptide (Fig.	('changes', 'Reg', (91, 98))	('H1299', 'CellLine', 'CVCL:0060', (70, 75))	('histone H3 K36 methylation', 'biological_process', 'GO:0010452', ('187', '213'))	('histone methylation', 'biological_process', 'GO:0016571', ('102', '121'))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('methylation', 'biological_process', 'GO:0032259', ('238', '249'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('knock down', 'Var', (22, 32))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('NSD2', 'Gene', (36, 40))
50632	27604143	Among the peptides that contain methylation on H3K36, the most abundant species corresponded to dimethylated K36 combined with non-modified K27.	('dimethylated', 'Var', (96, 108))	('methylation', 'Var', (32, 43))	('peptides', 'Chemical', 'MESH:D010455', (10, 18))	('H3K36', 'Protein', (47, 52))	('K36', 'Protein', (109, 112))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))
50634	27604143	Unlike reported in myeloma cell lines with t (4;14) translocations, we did not detect global changes in H3K27me3 after NSD2 depletion by western blot (Fig.	('depletion', 'Var', (124, 133))	('myeloma', 'Disease', (19, 26))	('myeloma', 'Disease', 'MESH:D009101', (19, 26))	('H3K27me3', 'Protein', (104, 112))
50637	27604143	Figure 2d,e show that the knock down of the type II isoform causes a decrease in proliferation, suggesting that the methyltransferase activity is important to support the growth of H1299 cells.	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('116', '142'))	('H1299', 'CellLine', 'CVCL:0060', (181, 186))	('decrease', 'NegReg', (69, 77))	('knock down', 'Var', (26, 36))	('proliferation', 'CPA', (81, 94))
50644	27604143	Moreover, depletion of NSD2 in other lung cancer cell lines with RAS activating mutations and high levels of NSD2 (Fig.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('RAS', 'Gene', (65, 68))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('depletion', 'MPA', (10, 19))
50648	27604143	Importantly, overexpression of the catalytic mutant (E1099K) with enhanced methyltransferase activity further increased the number of foci (Fig.	('activity', 'MPA', (93, 101))	('increased', 'PosReg', (110, 119))	('methyltransferase', 'Enzyme', (75, 92))	('E1099K', 'Var', (53, 59))	('enhanced', 'PosReg', (66, 74))	('E1099K', 'Mutation', 'rs772470710', (53, 59))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('75', '101'))
50654	27604143	To understand how PD0325901, JQ1 and NSD2 depletion cooperate to prevent the growth of lung cancer cells we analyzed by RNA-seq the changes in gene expression caused by the individual treatments and in combination (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('RNA', 'cellular_component', 'GO:0005562', ('120', '123'))	('PD0325901', 'Var', (18, 27))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gene expression', 'biological_process', 'GO:0010467', ('143', '158'))	('PD0325901', 'Chemical', 'MESH:C506614', (18, 27))
50655	27604143	PD0325901 caused the downregulation of the largest number of genes and showed a larger overlap with JQ1 than with doxycycline treatment (Fig.	('doxycycline', 'Chemical', 'MESH:D004318', (114, 125))	('PD0325901', 'Var', (0, 9))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))	('downregulation', 'NegReg', (21, 35))
50657	27604143	Only the treatment with PD0325901 caused a significant downregulation of MYC expression that was lost after combination with the other treatments.	('MYC', 'Gene', (73, 76))	('PD0325901', 'Var', (24, 33))	('PD0325901', 'Chemical', 'MESH:C506614', (24, 33))	('downregulation', 'NegReg', (55, 69))	('MYC', 'Gene', '4609', (73, 76))
50659	27604143	Clusters 1 to 3 contain genes downregulated by NSD2 knock down but only genes in cluster 3 are also downregulated by JQ1 and PD0325901 treatment.	('PD0325901', 'Chemical', 'MESH:C506614', (125, 134))	('NSD2', 'Gene', (47, 51))	('downregulated', 'NegReg', (30, 43))	('knock down', 'Var', (52, 62))	('downregulated', 'NegReg', (100, 113))	('PD0325901', 'Var', (125, 134))
50660	27604143	Cluster 4 contains the largest number of genes which are targeted by JQ1 and PD0325901 but not NSD2.	('PD0325901', 'Var', (77, 86))	('PD0325901', 'Chemical', 'MESH:C506614', (77, 86))	('JQ1', 'Gene', (69, 72))
50661	27604143	JQ1 and PD0325901 show the largest overlap on the RAS signature, while NSD2 depletion seems to affect a different subset of RAS-target genes.	('RAS signature', 'MPA', (50, 63))	('affect', 'Reg', (95, 101))	('PD0325901', 'Var', (8, 17))	('PD0325901', 'Chemical', 'MESH:C506614', (8, 17))
50662	27604143	Importantly, phospho-ERK was unaffected by NSD2 depletion or by JQ1 treatment (Supplementary Fig.	('NSD2', 'Gene', (43, 47))	('ERK', 'molecular_function', 'GO:0004707', ('21', '24'))	('ERK', 'Gene', '5594', (21, 24))	('depletion', 'Var', (48, 57))	('ERK', 'Gene', (21, 24))
50664	27604143	JQ1 causes downregulation of oncogenes regulated by super-enhancers, affecting the proliferation of cancer cells.	('cancer', 'Disease', (100, 106))	('oncogenes', 'Protein', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('affecting', 'Reg', (69, 78))	('JQ1', 'Var', (0, 3))	('downregulation', 'NegReg', (11, 25))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
50665	27604143	In order to address this question, we identified super-enhancers in H1299 and in normal lung according to H3K27ac density signal (Supplementary Fig.	('H3K27ac', 'Var', (106, 113))	('H1299', 'Var', (68, 73))	('H1299', 'CellLine', 'CVCL:0060', (68, 73))
50666	27604143	Comparison of the density of H3K27ac at super-enhancer regions between both samples shows that some super-enhancers are present in both H1299 and normal lung, but others are heavily H3K27 acetylated only in H1299 and are likely to be specifically acquired during oncogenic transformation (Supplementary Fig.	('H1299', 'Var', (207, 212))	('H1299', 'Var', (136, 141))	('H1299', 'CellLine', 'CVCL:0060', (207, 212))	('H1299', 'CellLine', 'CVCL:0060', (136, 141))	('H3K27', 'Var', (182, 187))
50671	27604143	Genes downregulated by JQ1 contributing the most to the cancer-acquired super-enhancer signature (leading-edge genes) were also significantly downregulated by PD0325901 but not by doxycycline (Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (159, 168))	('doxycycline', 'Chemical', 'MESH:D004318', (180, 191))	('JQ1', 'Gene', (23, 26))	('downregulated', 'NegReg', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('downregulated', 'NegReg', (142, 155))	('PD0325901', 'Var', (159, 168))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
50672	27604143	In accordance PD0325901 treatment contributed to downregulate genes associated with cancer-acquired super-enhancers (Fig.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('PD0325901', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('downregulate', 'NegReg', (49, 61))	('PD0325901', 'Chemical', 'MESH:C506614', (14, 23))
50673	27604143	4e) and less significantly to those shared between both samples (Supplementary Table 2) and genes downregulated by PD0325901 contributing the most to the cancer-acquired super-enhancer signature were significantly downregulated by JQ1 (Fig.	('downregulated', 'NegReg', (98, 111))	('PD0325901', 'Chemical', 'MESH:C506614', (115, 124))	('JQ1', 'Var', (231, 234))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('downregulated', 'NegReg', (214, 227))	('PD0325901', 'Gene', (115, 124))
50675	27604143	Although previous reports described interactions between BRD4 and NSD2, there was a lack or enrichment of the cancer-acquired super-enhancer signature in genes changing expression after the NSD2 knock down (Supplementary Table 2), and genes contributing the most to the cancer-acquired super-enhancer signature in H1299 cells treated with JQ1 were not significantly changing after NSD2 knock down (Fig.	('cancer', 'Disease', (110, 116))	('H1299', 'CellLine', 'CVCL:0060', (314, 319))	('BRD4', 'Gene', (57, 61))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('expression', 'MPA', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('BRD4', 'Gene', '23476', (57, 61))	('interactions', 'Interaction', (36, 48))	('knock down', 'Var', (195, 205))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
50678	27604143	The general profile of H3K36me2 in vehicle treated H1299 cells recapitulated basic features previously described for this mark, including positive correlation with marks of active transcription and negative correlation with the repressive H3K27me3 mark (Supplementary Fig.	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('H3K36me2', 'Var', (23, 31))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('positive', 'PosReg', (138, 146))	('negative', 'NegReg', (198, 206))
50684	27604143	Subtraction of signals clearly shows that in doxycycline treated cells H3K36me2 is decreased at intergenic regions while signal is retained at coding regions and proximal promoters, coincident with the presence of H3K36me3 and H3K27ac, respectively.	('H3K36me3', 'Var', (214, 222))	('H3K36me2', 'Var', (71, 79))	('decreased', 'NegReg', (83, 92))	('H3K27ac', 'Var', (227, 234))	('doxycycline', 'Chemical', 'MESH:D004318', (45, 56))
50687	27604143	In order to identify most likely NSD2 target genes, we selected top H3K36me2 islands that loose this signal after NSD2 knock down (Supplementary Table 4) and located the genes whose promoters (-/+ 5Kb around the TSS) are embedded in these islands to build a H3K36me2 signature for GSEA.	('loose', 'NegReg', (90, 95))	('-/+ 5Kb', 'Var', (193, 200))	('GSEA', 'Chemical', '-', (281, 285))	('knock down', 'Var', (119, 129))	('NSD2', 'Gene', (114, 118))
50690	27604143	Consistently, the expression of genes in the leading edge of the H3K36me2 signature was not significantly downregulated by JQ1 or PD0325901 but remained downregulated in combined treatments with doxycycline (Fig.	('PD0325901', 'Var', (130, 139))	('H3K36me2', 'Gene', (65, 73))	('JQ1', 'Var', (123, 126))	('PD0325901', 'Chemical', 'MESH:C506614', (130, 139))	('expression', 'MPA', (18, 28))	('doxycycline', 'Chemical', 'MESH:D004318', (195, 206))	('downregulated', 'NegReg', (153, 166))
50695	27604143	The importance of NSD2 translocations in blood tumors has been previously demonstrated.	('blood tumors', 'Disease', 'MESH:D009383', (41, 53))	('translocations', 'Var', (23, 37))	('blood tumors', 'Phenotype', 'HP:0004377', (41, 53))	('NSD2', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('blood tumors', 'Disease', (41, 53))
50698	27604143	We show that NSD2 is involved in the proliferation of several lung cancer RAS-mutant cell lines, whereas it seems of lesser importance in cells that do not have RAS mutations.	('NSD2', 'Gene', (13, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('involved', 'Reg', (21, 29))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('RAS-mutant', 'Gene', (74, 84))	('RAS-mutant', 'Var', (74, 84))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
50702	27604143	Genes downregulated by both JQ1 and PD0325901 (cluster 4) are enriched in super-enhancers (p < 6.32 x 10-11 and p < 7.4 x 10-12, respectively) while a significant number of genes downregulated by doxycycline (clusters 1 and 2) are located in top H3K36me2 regions (p < 4.11 x 10-08).	('PD0325901', 'Var', (36, 45))	('downregulated', 'NegReg', (6, 19))	('downregulated', 'NegReg', (179, 192))	('JQ1', 'Var', (28, 31))	('PD0325901', 'Chemical', 'MESH:C506614', (36, 45))	('doxycycline', 'Chemical', 'MESH:D004318', (196, 207))
50703	27604143	Therefore, a subset of RAS target genes are marked with super-enhancers and downregulated by JQ1 or PD0325901 and a different subset have high levels of H3K36me2 and are downregulated after the NSD2 knock down.	('PD0325901', 'Chemical', 'MESH:C506614', (100, 109))	('JQ1', 'Var', (93, 96))	('H3K36me2', 'Protein', (153, 161))	('downregulated', 'NegReg', (76, 89))	('PD0325901', 'Var', (100, 109))	('super-enhancers', 'PosReg', (56, 71))	('downregulated', 'NegReg', (170, 183))	('NSD2', 'Gene', (194, 198))	('knock down', 'Var', (199, 209))
50707	27604143	Ultimately, our results suggest that the RAS pathway through MEK activation controls functional enhancers in cancer cells and that overexpression of NSD2 causes the spread of the H3K36me2 mark from these enhancers into neighboring areas that have low levels of H3K27me3 further activating the expression of genes embedded in these regions (Fig.	('MEK', 'Gene', (61, 64))	('MEK', 'Gene', '5609', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('activating', 'PosReg', (278, 288))	('cancer', 'Disease', (109, 115))	('H3K36me2', 'Var', (179, 187))	('expression', 'MPA', (293, 303))	('NSD2', 'Gene', (149, 153))
50711	27604143	Events of long range epigenetic activation that affect the expression of genes located on genomic clusters have been previously described in prostate cancer.	('affect', 'Reg', (48, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (141, 156))	('epigenetic activation', 'Var', (21, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('described', 'Reg', (128, 137))	('expression', 'MPA', (59, 69))	('prostate cancer', 'Disease', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
50712	27604143	Long domains of dysregulated gene expression that correlate with alterations in H3K4me3 levels have been described in Down's syndrome and aberrant spreading of H3K27ac mark into long domains caused by BRD4-NUT fusions has been recently reported in NUT midline carcinoma.	('alterations', 'Reg', (65, 76))	("'s syndrome", 'Disease', 'MESH:D010300', (122, 133))	('midline', 'cellular_component', 'GO:0031430', ('252', '259'))	('H3K27ac', 'Var', (160, 167))	('NUT midline carcinoma', 'Disease', (248, 269))	('BRD4', 'Gene', '23476', (201, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	("'s syndrome", 'Disease', (122, 133))	('BRD4', 'Gene', (201, 205))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (248, 269))	('H3K4me3', 'MPA', (80, 87))
50713	27604143	Here we show that cancer-associated alterations in the expression the histone methyltransferase NSD2 can contribute to the formation of aberrant epigenetic domains that alter the expression of clusters of genes.	('alter', 'Reg', (169, 174))	('expression', 'MPA', (179, 189))	('alterations', 'Var', (36, 47))	('NSD2', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('clusters of genes', 'MPA', (193, 210))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
50714	27604143	Overall, long range epigenetic remodeling seems to be playing an important role in tumor progression, and perhaps other diseases, thus the dissection of the mechanisms contributing to this process appears crucial to understand the molecular basis of oncogenic transformation.	('tumor', 'Disease', (83, 88))	('epigenetic', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))
50722	27604143	Antibodies were obtained from the following sources: NSD2 39879, H3K36me2 61019 and H3K36me2 39255 from Active Motif, NSD3 11345-1-AP from Proteintech, phospho ERK 4370 and H3K36me2 2901 from Cell Signaling, total ERK from BD Biosciences (anti-ERK1 554100 and anti-ERK2 610103), H3K36me2 ab9049 from Abcam, H3 07-690 and H3K27me3 07-449 from Merck Millipore and ACTB A5441 from Sigma Aldrich.	('ERK', 'Gene', (244, 247))	('ERK', 'molecular_function', 'GO:0004707', ('214', '217'))	('ERK1', 'Gene', (244, 248))	('NSD3', 'Gene', '54904', (118, 122))	('H3K27me3 07-449', 'Var', (321, 336))	('ERK', 'Gene', (265, 268))	('ERK', 'Gene', '5594', (160, 163))	('ERK2', 'Gene', '5594', (265, 269))	('H3K36me2 39255', 'Var', (84, 98))	('ERK1', 'Gene', '5595', (244, 248))	('H3K36me2 ab9049', 'Var', (279, 294))	('ERK2', 'Gene', (265, 269))	('ERK1', 'molecular_function', 'GO:0004707', ('244', '248'))	('ERK', 'Gene', '5594', (214, 217))	('ERK2', 'molecular_function', 'GO:0004707', ('265', '269'))	('ERK', 'Gene', (160, 163))	('Signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('ERK', 'Gene', '5594', (244, 247))	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('NSD3', 'Gene', (118, 122))	('ERK', 'Gene', (214, 217))	('ERK', 'Gene', '5594', (265, 268))
50764	27604143	Three biological ChIP replicates for H3K36me2 were mapped to the human genome build hg19 using Bowtie and pooled, resulting in about 140 x 106 uniquely mapped reads for each treatment.	('hg19', 'Gene', (84, 88))	('H3K36me2', 'Var', (37, 45))	('human', 'Species', '9606', (65, 70))
50768	27604143	Briefly, genes included in above signatures were compiled to elaborate a Ras signature gene set that was used to select genes that were significantly downregulated by doxycycline, JQ1 or PD0325901 treatments (205 genes at FDR < 0.05).	('PD0325901', 'Chemical', 'MESH:C506614', (187, 196))	('doxycycline', 'Chemical', 'MESH:D004318', (167, 178))	('downregulated', 'NegReg', (150, 163))	('PD0325901', 'Var', (187, 196))
50769	27604143	SICER was used to identify H3K27ac intervals in H1299 and normal lung and super-enhancers were identified using ROSE.	('H3K27ac', 'Protein', (27, 34))	('H1299', 'Var', (48, 53))	('H1299', 'CellLine', 'CVCL:0060', (48, 53))
50772	27604143	Regions with a ratio of H3K27ac signal in H1299 vs. normal lung higher than 10 fold were considered cancer-acquired super-enhancers while regions with a ratio between 2 and 0.5 were considered shared super-enhancers.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('H1299', 'CellLine', 'CVCL:0060', (42, 47))	('H1299', 'Var', (42, 47))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('H3K27ac', 'Protein', (24, 31))
50777	27604143	ChIP-seq for H3K27ac (DRX015250), RNA Pol II (DRX015243), H3K4me1 (DRX015247), H3K27me3 (DRX015249) and H3K36me3 (DRX015248) in H1299 were previously published and raw data was downloaded from the DNA Data Bank of Japan.	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('H1299', 'CellLine', 'CVCL:0060', (128, 133))	('DRX015243', 'Var', (46, 55))	('H3K27me3 (DRX015249', 'Var', (79, 98))	('DRX015249', 'Var', (89, 98))	('H3K4me1', 'Protein', (58, 65))	('DRX015250', 'Var', (22, 31))	('H3K36me3 (DRX015248', 'Var', (104, 123))	('DRX015247', 'Var', (67, 76))
50780	27604143	NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation.	('transcription', 'biological_process', 'GO:0006351', ('41', '54'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('NSD2', 'Gene', (0, 4))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('epigenetic', 'Var', (95, 105))	('oncogenic RAS-driven transcription', 'MPA', (20, 54))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('contributes', 'Reg', (5, 16))
50784	27517038	Recent data also suggest the prophylactic use of low molecular weight Heparins (LMWHs) and Warfarin to be effective in reducing VTEs related to long-term central venous catheter use.	('LMWH', 'Chemical', 'MESH:D006495', (80, 84))	('low molecular', 'Var', (49, 62))	('Heparins', 'Chemical', 'MESH:D006493', (70, 78))	('Warfarin', 'Chemical', 'MESH:D014859', (91, 99))	('VTE', 'Disease', 'MESH:D054556', (128, 131))	('VTE', 'Disease', (128, 131))	('reducing', 'NegReg', (119, 127))
50825	27517038	Chemotherapy is associated with a two- to sixfold increase in the risk of VTE compared to the general population and in patients starting new chemotherapy regimens, accounts for 9% of deaths.	('patients', 'Species', '9606', (120, 128))	('death', 'Disease', (184, 189))	('Chemotherapy', 'Var', (0, 12))	('death', 'Disease', 'MESH:D003643', (184, 189))	('VTE', 'Disease', 'MESH:D054556', (74, 77))	('VTE', 'Disease', (74, 77))
50828	27517038	Additional predictors for Thalidomide associated VTE include its combined use with Doxorubicin (OR = 4.3), newly diagnosed disease (OR = 2.5), and Chromosome 11 abnormalities (OR = 1.8).	('Thalidomide', 'Var', (26, 37))	('VTE', 'Disease', 'MESH:D054556', (49, 52))	('Chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))	('VTE', 'Disease', (49, 52))	('Chromosome', 'Var', (147, 157))	('Thalidomide', 'Chemical', 'MESH:D013792', (26, 37))	('Doxorubicin', 'Chemical', 'MESH:D004317', (83, 94))
50849	27517038	This is important as a number of predisposing genetic factors, such as Factor V Leiden and Prothrombin gene mutations are known to confer an increased risk of VTE in cancer patients when compared to those without the mutations.	('cancer', 'Disease', (166, 172))	('Prothrombin', 'Gene', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (173, 181))	('VTE', 'Disease', 'MESH:D054556', (159, 162))	('VTE', 'Disease', (159, 162))	('Factor V Leiden', 'Gene', '2153', (71, 86))	('Prothrombin', 'Gene', '2147', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Factor V Leiden', 'Gene', (71, 86))
50870	27517038	In the more recent PROTECHT study, Nadroparin use was found to be associated with a statistically significant 50% relative risk reduction in thromboembolic events among cancer patients in the ambulatory setting receiving chemotherapy for advanced cancers of the breast, lung, gastrointestinal tract, head/neck region, ovary, and pancreas.	('thromboembolic event', 'Phenotype', 'HP:0001907', (141, 161))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('ovary', 'Disease', (318, 323))	('thromboembolic events', 'Disease', 'MESH:D013923', (141, 162))	('cancers of the breast', 'Phenotype', 'HP:0100013', (247, 268))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('neck', 'cellular_component', 'GO:0044326', ('305', '309'))	('thromboembolic events', 'Phenotype', 'HP:0001907', (141, 162))	('pancreas', 'Disease', (329, 337))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('thromboembolic events', 'Disease', (141, 162))	('Nadroparin use', 'Var', (35, 49))	('Nadroparin', 'Chemical', 'MESH:D017762', (35, 45))	('patients', 'Species', '9606', (176, 184))	('gastrointestinal tract', 'Disease', (276, 298))	('reduction', 'NegReg', (128, 137))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (276, 298))	('head/neck', 'Disease', (300, 309))
50871	27517038	Fifteen (2.0%) of 769 patients treated with Nadroparin and 15 (3.9%) of 381 patients treated with placebo had a thromboembolic event (single-sided P = 0.02).	('patients', 'Species', '9606', (76, 84))	('thromboembolic event', 'Phenotype', 'HP:0001907', (112, 132))	('thromboembolic', 'Disease', (112, 126))	('patients', 'Species', '9606', (22, 30))	('Nadroparin', 'Chemical', 'MESH:D017762', (44, 54))	('thromboembolic', 'Disease', 'MESH:D013923', (112, 126))	('Nadroparin', 'Var', (44, 54))
50877	27517038	VTE occurred in 20 of 1,608 patients (1.2%) receiving Semuloparin, compared with 55 of 1,604 patients (3.4%) on placebo (HR: 0.36; 95% CI, 0.21-0.60).	('VTE', 'Disease', 'MESH:D054556', (0, 3))	('Semuloparin', 'Chemical', 'MESH:C569346', (54, 65))	('VTE', 'Disease', (0, 3))	('Semuloparin', 'Var', (54, 65))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (93, 101))
50891	27517038	is required for at least 5-7 days until the international normalized ratio (INR) is between 2 and 3 for at least 24 h. Studies have shown that in patients with advanced cancers, LMWHs significantly reduce the incidence of recurrent VTE (by as much as 50% in some studies) when compared to oral VKA, without any difference in bleeding complications.	('reduce', 'NegReg', (198, 204))	('bleeding complications', 'Disease', (325, 347))	('cancers', 'Disease', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('bleeding complications', 'Disease', 'MESH:D006470', (325, 347))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('VTE', 'Disease', 'MESH:D054556', (232, 235))	('VTE', 'Disease', (232, 235))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('patients', 'Species', '9606', (146, 154))	('LMWH', 'Chemical', 'MESH:D006495', (178, 182))	('LMWHs', 'Var', (178, 183))
50893	27517038	According to international guidelines, LMWHs are preferable to full dose Warfarin for initial treatment of cancer-related VTE, particularly in the first 3-6 months.	('VTE', 'Disease', 'MESH:D054556', (122, 125))	('VTE', 'Disease', (122, 125))	('Warfarin', 'Chemical', 'MESH:D014859', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('LMWH', 'Chemical', 'MESH:D006495', (39, 43))	('LMWHs', 'Var', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
50931	27517038	Rivaroxaban was associated with a reduction in the risk of venous thrombosis compared to 10 days of treatment with Enoxaparin.	('Enoxaparin', 'Chemical', 'MESH:D017984', (115, 125))	('Rivaroxaban', 'Chemical', 'MESH:D000069552', (0, 11))	('venous thrombosis', 'Disease', (59, 76))	('venous thrombosis', 'Disease', 'MESH:D020246', (59, 76))	('reduction', 'NegReg', (34, 43))	('Rivaroxaban', 'Var', (0, 11))	('venous thrombosis', 'Phenotype', 'HP:0004936', (59, 76))
50955	34012400	The association between dysregulated store-operated calcium entry (SOCE), a key intracellular Ca2+ signaling pathway and gastroesophageal cancers are emerging.	('intracellular', 'cellular_component', 'GO:0005622', ('80', '93'))	('dysregulated', 'Var', (24, 36))	('store-operated calcium entry', 'biological_process', 'GO:0002115', ('37', '65'))	('calcium', 'Chemical', 'MESH:D002118', (52, 59))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (121, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('SOCE', 'biological_process', 'GO:0002115', ('67', '71'))	('gastroesophageal cancers', 'Disease', (121, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('signaling pathway', 'biological_process', 'GO:0007165', ('99', '116'))
50979	34012400	Different from mutant forms in lung cancer and breast cancer, EGFR often presents high copy number and its expression is correlate with advanced stage, poorly differentiated histology, vascular invasion, and poor survival rate in GC and EC.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('breast cancer', 'Disease', (47, 60))	('EGFR', 'Gene', '1956', (62, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('expression', 'MPA', (107, 117))	('EGFR', 'Gene', (62, 66))	('high copy number', 'Var', (82, 98))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('advanced stage', 'CPA', (136, 150))	('poorly differentiated histology', 'CPA', (152, 183))	('vascular invasion', 'CPA', (185, 202))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
51022	34012400	While genetic mutations in Orai1 or STIM1 were found in immune disorders, skeletal muscle myopathy and heart hypertrophy, changes in expression and/or channel complex components are more commonly reported in various types of malignant, including GE cancers.	('muscle myopathy', 'Disease', (83, 98))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('Orai1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('heart hypertrophy', 'Disease', 'MESH:D006332', (103, 120))	('GE cancers', 'Disease', 'MESH:D009369', (246, 256))	('mutations', 'Var', (14, 23))	('Orai1', 'Gene', '84876', (27, 32))	('STIM1', 'Gene', (36, 41))	('found', 'Reg', (47, 52))	('immune disorders', 'Disease', 'MESH:D007154', (56, 72))	('heart hypertrophy', 'Disease', (103, 120))	('GE cancers', 'Disease', (246, 256))	('STIM1', 'Gene', '6786', (36, 41))	('muscle myopathy', 'Disease', 'MESH:D009135', (83, 98))	('reported', 'Reg', (196, 204))	('expression', 'MPA', (133, 143))	('heart hypertrophy', 'Phenotype', 'HP:0001639', (103, 120))	('immune disorders', 'Disease', (56, 72))	('changes', 'Reg', (122, 129))	('genetic mutations', 'Var', (6, 23))	('myopathy', 'Phenotype', 'HP:0003198', (90, 98))
51024	34012400	The high expression of Orai1 is associated with poor disease-free and overall survival rates.	('Orai1', 'Gene', (23, 28))	('Orai1', 'Gene', '84876', (23, 28))	('overall survival rates', 'CPA', (70, 92))	('high', 'Var', (4, 8))	('disease-free', 'CPA', (53, 65))	('poor', 'NegReg', (48, 52))
51025	34012400	Both gene manipulation and pharmacologic studies demonstrated that elevated Orai1 results in hyperactivity of intracellular Ca2+ oscillations and, thus, controls rampant cell proliferation in ESCC cells.	('hyperactivity', 'Phenotype', 'HP:0000752', (93, 106))	('Orai1', 'Gene', '84876', (76, 81))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (110, 141))	('intracellular', 'cellular_component', 'GO:0005622', ('110', '123'))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('elevated', 'Var', (67, 75))	('hyperactivity', 'Disease', 'MESH:D006948', (93, 106))	('hyperactivity', 'Disease', (93, 106))	('intracellular Ca2+ oscillations', 'MPA', (110, 141))	('controls', 'Reg', (153, 161))	('Orai1', 'Gene', (76, 81))
51028	34012400	STIM1 can promote gastric cancer progression and silencing STIM1 inhibits cell proliferation via arrest of the cell cycle at the G0/G1 phase and increases cell apoptosis in vitro.	('gastric cancer', 'Disease', (18, 32))	('silencing', 'Var', (49, 58))	('STIM1', 'Gene', '6786', (0, 5))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('promote', 'PosReg', (10, 17))	('cell proliferation', 'CPA', (74, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('increases', 'PosReg', (145, 154))	('STIM1', 'Gene', (59, 64))	('cell cycle', 'biological_process', 'GO:0007049', ('111', '121'))	('STIM1', 'Gene', '6786', (59, 64))	('G1 phase', 'biological_process', 'GO:0051318', ('132', '140'))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('inhibits', 'NegReg', (65, 73))	('STIM1', 'Gene', (0, 5))	('arrest', 'Disease', (97, 103))	('cell apoptosis', 'CPA', (155, 169))
51038	34012400	Due to the important role of TRPC6-mediated Ca2+ signaling, it is not surprising to see that the inhibition of TRPC6 leads to cell cycle arrest via Cdk1 in ESCC cells and decreased tumor formation in a mouse xenograft ESCC model.	('inhibition', 'Var', (97, 107))	('arrest', 'Disease', (137, 143))	('decreased', 'NegReg', (171, 180))	('tumor', 'Disease', (181, 186))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('Cdk1', 'Gene', '12534', (148, 152))	('Cdk1', 'Gene', (148, 152))	('TRPC6', 'Gene', (111, 116))	('mouse', 'Species', '10090', (202, 207))	('Cdk', 'molecular_function', 'GO:0004693', ('148', '151'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('126', '143'))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))
51039	34012400	In GC epithelial cells, the TRPC6 has been shown to be upregulated on protein and mRNA level and was responsible for regulation of the cell cycle, as the inhibition of TRPC6 resulted in cell cycle arrest in the G2/M phase and inhibited cell growth.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('inhibition', 'Var', (154, 164))	('M phase', 'biological_process', 'GO:0000279', ('214', '221'))	('cell growth', 'biological_process', 'GO:0016049', ('236', '247'))	('cell growth', 'CPA', (236, 247))	('inhibited', 'NegReg', (226, 235))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('cell cycle', 'biological_process', 'GO:0007049', ('135', '145'))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('upregulated', 'PosReg', (55, 66))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('186', '203'))	('arrest', 'Disease', (197, 203))	('TRPC6', 'Gene', (28, 33))	('regulation', 'biological_process', 'GO:0065007', ('117', '127'))	('TRPC6', 'Gene', (168, 173))
51042	34012400	The authors showed that TRPC1/3/6 complex mediates Ca2+ influx and actives downstream the Ras/Raf1/ERK signaling pathway and the inhibition of TRPC1/3/6 impedes TGF-beta1-induced EMT.	('EMT', 'biological_process', 'GO:0001837', ('179', '182'))	('Ca2+ influx', 'MPA', (51, 62))	('Raf1', 'Gene', (94, 98))	('ERK', 'molecular_function', 'GO:0004707', ('99', '102'))	('inhibition', 'Var', (129, 139))	('TRPC1', 'Gene', '7220', (143, 148))	('signaling pathway', 'biological_process', 'GO:0007165', ('103', '120'))	('TRPC1', 'Gene', '7220', (24, 29))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('TRPC1', 'Gene', (143, 148))	('actives', 'PosReg', (67, 74))	('TRPC1', 'Gene', (24, 29))	('Raf1', 'Gene', '5894', (94, 98))	('TGF-beta1', 'Gene', '7040', (161, 170))	('impedes', 'NegReg', (153, 160))	('TGF-beta1', 'Gene', (161, 170))
51043	34012400	Using a newly developed potent TRPC6 antagonist, a separate study also showed that inhibition of this Ca2+ channel suppresses proliferation of several GC cell lines as well as GC tumor growth in a xenograft model.	('suppresses', 'NegReg', (115, 125))	('proliferation', 'CPA', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('inhibition', 'Var', (83, 93))	('tumor', 'Disease', (179, 184))
51046	34012400	The earliest SOCE blocker to be used is SKF-96365, which was shown to inhibit cancer cell migration and tumor metastasis in breast and cervical cancers.	('SKF-96365', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('SOCE', 'biological_process', 'GO:0002115', ('13', '17'))	('cancer', 'Disease', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('tumor metastasis in breast and cervical cancers', 'Disease', 'MESH:D001943', (104, 151))	('SKF-96365', 'Chemical', 'MESH:C063159', (40, 49))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('inhibit', 'NegReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
51052	34012400	RO2959, a novel, potent and selective SOCE inhibitor, inhibits gene expression, cytokine production, and proliferation in T cells.	('RO2959', 'Var', (0, 6))	('gene expression', 'biological_process', 'GO:0010467', ('63', '78'))	('SOCE', 'biological_process', 'GO:0002115', ('38', '42'))	('cytokine production', 'biological_process', 'GO:0001816', ('80', '99'))	('cytokine production', 'MPA', (80, 99))	('proliferation', 'CPA', (105, 118))	('gene expression', 'MPA', (63, 78))	('inhibits', 'NegReg', (54, 62))	('RO2959', 'Chemical', '-', (0, 6))
51053	34012400	SB01990, SPB06836, KM06293 and RH01882 are a cluster of SOCE inhibitors targeting and altering the Ca2+ selectivity filter of Orai1.	('SPB', 'cellular_component', 'GO:0005816', ('9', '12'))	('RH01882', 'Gene', (31, 38))	('Orai1', 'Gene', (126, 131))	('SPB06836', 'Var', (9, 17))	('altering', 'Reg', (86, 94))	('RH01882', 'Chemical', '-', (31, 38))	('Ca2+ selectivity filter', 'MPA', (99, 122))	('SB01990', 'Var', (0, 7))	('Orai1', 'Gene', '84876', (126, 131))	('SOCE', 'biological_process', 'GO:0002115', ('56', '60'))	('SB01990', 'Chemical', '-', (0, 7))	('KM06293', 'Var', (19, 26))
51054	34012400	GSK-5503A and GSK-7975A are Orai1-and Orai3-mediated SOCE inhibitors that slowly affect SOCE currents with no effect on STIM1-Orai1 coupling.	('Orai3', 'Gene', '93129', (38, 43))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('GSK-5503A', 'Var', (0, 9))	('GSK-7975A', 'Var', (14, 23))	('Orai1', 'Gene', (126, 131))	('SOCE', 'biological_process', 'GO:0002115', ('88', '92'))	('SOCE', 'biological_process', 'GO:0002115', ('53', '57'))	('STIM1', 'Gene', (120, 125))	('affect', 'Reg', (81, 87))	('Orai3', 'Gene', (38, 43))	('Orai1', 'Gene', (28, 33))	('Orai1', 'Gene', '84876', (126, 131))	('STIM1', 'Gene', '6786', (120, 125))	('Orai1', 'Gene', '84876', (28, 33))	('GSK', 'molecular_function', 'GO:0050321', ('14', '17'))	('SOCE currents', 'MPA', (88, 101))
51056	34012400	BTP2 or YM-58483 is a potent inhibitor for both CRAC and TRPC-mediated SOCE.	('TRPC-mediated', 'Protein', (57, 70))	('YM-58483', 'Chemical', 'MESH:C476308', (8, 16))	('CRAC', 'CPA', (48, 52))	('SOCE', 'biological_process', 'GO:0002115', ('71', '75'))	('YM-58483', 'Var', (8, 16))	('BTP', 'Chemical', '-', (0, 3))
51057	34012400	A report showed that BTP-2 can depolarize the cell membrane via TRPM4 activation and, thus contribute to the inhibition of SOCE and cytokine release.	('BTP-2', 'Var', (21, 26))	('depolarize', 'NegReg', (31, 41))	('TRPM4', 'Gene', (64, 69))	('SOCE', 'biological_process', 'GO:0002115', ('123', '127'))	('inhibition', 'NegReg', (109, 119))	('BTP', 'Chemical', '-', (21, 24))	('activation', 'PosReg', (70, 80))	('TRPM4', 'Gene', '54795', (64, 69))	('cell membrane', 'cellular_component', 'GO:0005886', ('46', '59'))
51059	34012400	CM2489, CM3457 and CM4620 are three more selective SOCE inhibitors, which have been shown to prevent Ca2+ entry, and, thus, are used either to treat moderate-to-severe plaque psoriasis, or to reduce acute pancreatitis severity, or to inhibit lymphocytes and T cell-derived cytokine production (Table 1).	('SOCE', 'biological_process', 'GO:0002115', ('51', '55'))	('plaque psoriasis', 'Disease', 'MESH:D011565', (168, 184))	('SOCE', 'Gene', (51, 55))	('cytokine production', 'biological_process', 'GO:0001816', ('273', '292'))	('CM2489', 'Var', (0, 6))	('pancreatitis', 'Phenotype', 'HP:0001733', (205, 217))	('pancreatitis', 'Disease', 'MESH:D010195', (205, 217))	('CM3457', 'Var', (8, 14))	('reduce', 'NegReg', (192, 198))	('CM4620', 'Var', (19, 25))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (199, 217))	('pancreatitis', 'Disease', (205, 217))	('Ca2+ entry', 'MPA', (101, 111))	('plaque psoriasis', 'Disease', (168, 184))	('inhibit', 'NegReg', (234, 241))	('CM2489', 'Chemical', '-', (0, 6))	('prevent', 'NegReg', (93, 100))	('psoriasis', 'Phenotype', 'HP:0003765', (175, 184))
51060	34012400	The Pyrazole analogs, including Pyr2, 3, 6 and 10, show different selectivity on TRPC3 and Orai1-mediated SOCE.	('Pyr2', 'Var', (32, 36))	('Orai1', 'Gene', (91, 96))	('SOCE', 'biological_process', 'GO:0002115', ('106', '110'))	('TRPC3', 'Gene', '7222', (81, 86))	('Pyrazole', 'Chemical', 'MESH:C031280', (4, 12))	('Orai1', 'Gene', '84876', (91, 96))	('Pyr2', 'Chemical', '-', (32, 36))	('TRPC3', 'Gene', (81, 86))
51061	34012400	Pyr10 is potent and selective for TRPC3-mediated SOCE.	('TRPC3', 'Gene', (34, 39))	('SOCE', 'biological_process', 'GO:0002115', ('49', '53'))	('TRPC3', 'Gene', '7222', (34, 39))	('Pyr10', 'Var', (0, 5))	('Pyr10', 'Chemical', '-', (0, 5))
51062	34012400	Pyr6 is potent to Orai1-mediated SOCE, while Pyr3 equally inhibits both channels.	('Orai1', 'Gene', (18, 23))	('Orai1', 'Gene', '84876', (18, 23))	('SOCE', 'biological_process', 'GO:0002115', ('33', '37'))	('Pyr6', 'Var', (0, 4))
51064	34012400	CM2489 and CM 4620 from CalciMedica are used to block the production and release of pro-inflammatory cytokines from immune cells, and they are used in clinical trials for the treatment of plaque psoriasis and pancreatitis.	('block', 'NegReg', (48, 53))	('CM2489', 'Var', (0, 6))	('pancreatitis', 'Disease', (209, 221))	('plaque psoriasis', 'Disease', (188, 204))	('production', 'MPA', (58, 68))	('plaque psoriasis', 'Disease', 'MESH:D011565', (188, 204))	('release of pro-inflammatory cytokines from immune', 'MPA', (73, 122))	('pancreatitis', 'Phenotype', 'HP:0001733', (209, 221))	('psoriasis', 'Phenotype', 'HP:0003765', (195, 204))	('pancreatitis', 'Disease', 'MESH:D010195', (209, 221))	('CM2489', 'Chemical', '-', (0, 6))
51066	34012400	With improved selectivity and reduced toxicity, modified forms of these SOCE channel inhibitors may still hold promise for further cancer therapeutic drug development.	('cancer', 'Disease', (131, 137))	('SOCE', 'biological_process', 'GO:0002115', ('72', '76'))	('SOCE channel', 'Gene', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('toxicity', 'Disease', 'MESH:D064420', (38, 46))	('toxicity', 'Disease', (38, 46))	('modified', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
51067	34012400	RP4010 from Rhizen Pharmaceuticals is another selective SOCE channel inhibitor.	('RP4010', 'Chemical', '-', (0, 6))	('SOCE', 'biological_process', 'GO:0002115', ('56', '60'))	('SOCE', 'Pathway', (56, 60))	('RP4010', 'Var', (0, 6))
51071	34012400	Compared with other reported SOCE channel inhibitors, RP4010 is more potent in blocking SOCE in ESCC cells.	('blocking', 'NegReg', (79, 87))	('RP4010', 'Chemical', '-', (54, 60))	('SOCE', 'biological_process', 'GO:0002115', ('88', '92'))	('SOCE', 'Gene', (88, 92))	('SOCE', 'biological_process', 'GO:0002115', ('29', '33'))	('RP4010', 'Var', (54, 60))
51073	34012400	Our studies showed that treatment of RP4010 resulted in reduction of intracellular Ca2+ oscillations, and caused cell cycle arrest at G0/G1 phase in several cultured human ESCC cell lines.	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (69, 100))	('RP4010', 'Chemical', '-', (37, 43))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('113', '130'))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('human', 'Species', '9606', (166, 171))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (113, 130))	('arrest', 'Disease', (124, 130))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('G1 phase', 'biological_process', 'GO:0051318', ('137', '145'))	('RP4010', 'Var', (37, 43))	('reduction', 'NegReg', (56, 65))	('intracellular Ca2+ oscillations', 'MPA', (69, 100))
51077	34012400	Drug resistance is responsible for relapses of cancers and remains to be a big challenge in most cancer treatment.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('responsible', 'Reg', (19, 30))	('cancer', 'Disease', (47, 53))	('Drug resistance', 'Var', (0, 15))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', (47, 54))	('Drug resistance', 'biological_process', 'GO:0009315', ('0', '15'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Drug resistance', 'biological_process', 'GO:0042493', ('0', '15'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
51087	34012400	While some cell surface markers, such as CD44, CD24, and CD133, have been identified as common CSC markers for almost all cancer types, CSC in GC and EC cancers present their specific markers as well.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cell surface', 'cellular_component', 'GO:0009986', ('11', '23'))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (122, 128))	('CD24', 'Gene', (47, 51))	('CD44', 'Var', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('EC cancers', 'Disease', 'MESH:D009369', (150, 160))	('EC cancers', 'Disease', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CD133', 'Gene', (57, 62))	('CD133', 'Gene', '8842', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('CSC', 'Disease', (136, 139))
51098	34012400	With RyR1 knockdown, the CSCs diminish in the severe combined immunodeficiency (SCID) mice model.	('knockdown', 'Var', (10, 19))	('immunodeficiency', 'Phenotype', 'HP:0002721', (62, 78))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (53, 78))	('immunodeficiency', 'Disease', (62, 78))	('immunodeficiency', 'Disease', 'MESH:D007153', (62, 78))	('mice', 'Species', '10090', (86, 90))	('diminish', 'NegReg', (30, 38))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (46, 78))	('CSCs', 'MPA', (25, 29))	('RyR1', 'Gene', (5, 9))	('RyR', 'cellular_component', 'GO:1990425', ('5', '8'))	('SCID', 'Disease', (80, 84))	('SCID', 'Disease', 'MESH:D053632', (80, 84))
51105	34012400	Furthermore, the treatment of SKF-96365 can reduce CSC cell proliferation and decrease stemness in glioblastoma.	('reduce', 'NegReg', (44, 50))	('decrease stemness in glioblastoma', 'Disease', 'MESH:D005909', (78, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('SKF-96365', 'Var', (30, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('decrease stemness in glioblastoma', 'Disease', (78, 111))	('CSC cell proliferation', 'CPA', (51, 73))	('SKF-96365', 'Chemical', 'MESH:C063159', (30, 39))
51111	34012400	Metformin, a widely used diabetes drug, has been administrated in combination with chemotherapy in several clinical trials to treat multiple cancers, including colon cancer (NCT01440127), ovarian, fallopian tube, and primary peritoneal cancer (NCT01579812).	('diabetes', 'Disease', (25, 33))	('NCT01440127', 'Var', (174, 185))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('fallopian tube', 'Disease', (197, 211))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('primary peritoneal cancer', 'Phenotype', 'HP:0030406', (217, 242))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('ovarian', 'Disease', 'MESH:D010049', (188, 195))	('cancers', 'Disease', (141, 148))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (166, 172))	('colon cancer', 'Disease', 'MESH:D015179', (160, 172))	('diabetes', 'Disease', 'MESH:D003920', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('colon cancer', 'Disease', (160, 172))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('ovarian', 'Disease', (188, 195))
51119	34012400	We speculate that combined inhibitors for both SOCE and EGFR pathways could achieve better anti-cancer effects than single agent alone for GE cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGFR', 'Gene', '1956', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inhibitors', 'Var', (27, 37))	('SOCE', 'biological_process', 'GO:0002115', ('47', '51'))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('SOCE', 'Pathway', (47, 51))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (142, 148))
51145	33398925	According to the 1995 Lung Cancer Study Group (LCSG) trial, limited resection was associated with a five-year overall survival of 42% compared with 63% in the lobectomy group (one-sided P-value = 0.088).	('Lung Cancer', 'Disease', (22, 33))	('limited resection', 'Var', (60, 77))	('Lung Cancer', 'Phenotype', 'HP:0100526', (22, 33))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Lung Cancer', 'Disease', 'MESH:D008175', (22, 33))
51209	33291708	Muscle loss has significant effects on patient health and quality of life.	('Muscle loss', 'Phenotype', 'HP:0003202', (0, 11))	('loss', 'NegReg', (7, 11))	('Muscle', 'Var', (0, 6))	('patient', 'Species', '9606', (39, 46))
51223	33291708	Other attributes of cancer-associated muscle wasting include enhanced autophagy, inhibition of myoblast differentiation and derangements in the renin-angiotensin system which all contribute to muscle degradation (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('autophagy', 'biological_process', 'GO:0006914', ('70', '79'))	('enhanced', 'PosReg', (61, 69))	('autophagy', 'CPA', (70, 79))	('degradation', 'biological_process', 'GO:0009056', ('200', '211'))	('muscle wasting', 'Disease', (38, 52))	('myoblast differentiation', 'CPA', (95, 119))	('inhibition', 'NegReg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('muscle degradation', 'MPA', (193, 211))	('derangements in the renin-angiotensin system', 'Phenotype', 'HP:0000847', (124, 168))	('muscle wasting', 'Phenotype', 'HP:0003202', (38, 52))	('inhibition of myoblast differentiation', 'biological_process', 'GO:0045662', ('81', '119'))	('cancer', 'Disease', (20, 26))	('renin-angiotensin system', 'MPA', (144, 168))	('autophagy', 'biological_process', 'GO:0016236', ('70', '79'))	('derangements', 'Var', (124, 136))	('muscle wasting', 'Disease', 'MESH:D009133', (38, 52))
51240	33291708	In gastric cancer patients, a polymorphism of IL-8 was associated with cachexia.	('cachexia', 'Phenotype', 'HP:0004326', (71, 79))	('IL-8', 'Gene', (46, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('associated', 'Reg', (55, 65))	('cachexia', 'Disease', (71, 79))	('cachexia', 'Disease', 'MESH:D002100', (71, 79))	('patients', 'Species', '9606', (18, 26))	('gastric cancer', 'Disease', (3, 17))	('polymorphism', 'Var', (30, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('IL-8', 'molecular_function', 'GO:0005153', ('46', '50'))
51245	33291708	TWEAK induces muscle wasting in mice.	('muscle wasting', 'Disease', 'MESH:D009133', (14, 28))	('muscle wasting', 'Disease', (14, 28))	('mice', 'Species', '10090', (32, 36))	('TWEAK', 'Var', (0, 5))	('muscle wasting', 'Phenotype', 'HP:0003202', (14, 28))
51280	33291708	TWEAK also impairs oxidative metabolism in muscle, likely by decreasing PGC1alpha expression and activation of NF-kappaB.	('PGC1alpha', 'Gene', (72, 81))	('activation', 'PosReg', (97, 107))	('decreasing', 'NegReg', (61, 71))	('expression', 'MPA', (82, 92))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('19', '39'))	('PGC1alpha', 'Gene', '10891', (72, 81))	('NF-kappaB', 'Gene', '4790', (111, 120))	('impairs', 'NegReg', (11, 18))	('TWEAK', 'Var', (0, 5))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('97', '120'))	('NF-kappaB', 'Gene', (111, 120))	('oxidative metabolism in', 'MPA', (19, 42))
51281	33291708	Alterations in skeletal muscle mitochondria have been documented in the context of cancer.	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('skeletal muscle mitochondria', 'MPA', (15, 43))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('rat', 'Species', '10116', (4, 7))	('mitochondria', 'cellular_component', 'GO:0005739', ('31', '43'))	('cancer', 'Disease', (83, 89))
51300	33291708	Antagonism of ActRIIB reverses skeletal muscle loss and heart atrophy in multiple cancer cachexia models by inhibiting proteolysis and stimulating muscle stem cell growth.	('heart atrophy in multiple cancer cachexia', 'Disease', 'MESH:D006338', (56, 97))	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('heart atrophy in multiple cancer cachexia', 'Disease', (56, 97))	('skeletal muscle loss', 'Disease', (31, 51))	('cachexia', 'Phenotype', 'HP:0004326', (89, 97))	('Antagonism', 'Var', (0, 10))	('skeletal muscle loss', 'Disease', 'MESH:D005207', (31, 51))	('ActRIIB', 'Gene', (14, 21))	('muscle stem cell growth', 'CPA', (147, 170))	('proteolysis', 'MPA', (119, 130))	('muscle loss', 'Phenotype', 'HP:0003202', (40, 51))	('inhibiting', 'NegReg', (108, 118))	('proteolysis', 'biological_process', 'GO:0006508', ('119', '130'))	('reverses', 'NegReg', (22, 30))	('stimulating', 'PosReg', (135, 146))
51362	33291708	In mice bearing Fn14-expressing tumors, antibodies against Fn14 markedly reduce tumor-induced weight loss and extended lifespan.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Fn14', 'Gene', (59, 63))	('weight loss', 'Disease', 'MESH:D015431', (94, 105))	('antibodies', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mice', 'Species', '10090', (3, 7))	('lifespan', 'CPA', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('reduce', 'NegReg', (73, 79))	('weight loss', 'Disease', (94, 105))	('tumor', 'Disease', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('weight loss', 'Phenotype', 'HP:0001824', (94, 105))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (32, 37))	('extended', 'PosReg', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
51365	33291708	Inhibition of Hsp 70/90 expression abrogates tumor-induced muscle catabolism.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Hsp 70/90', 'Gene', '15511;111042', (14, 23))	('tumor', 'Disease', (45, 50))	('catabolism', 'biological_process', 'GO:0009056', ('66', '76'))	('Hsp 70/90', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('abrogates', 'NegReg', (35, 44))
51366	33291708	Additionally, in an orthotopic pancreatic carcinoma mouse model, zinc transporter 4 (ZIP4) was shown to induce the secretion of HSP 70/90 to induce p38 mitogen-activated protein kinase (MAPK)-mediated muscle wasting.	('pancreatic', 'Disease', (31, 41))	('HSP 70/90', 'Gene', (128, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('186', '190'))	('ZIP4', 'Gene', '22785', (85, 89))	('secretion', 'biological_process', 'GO:0046903', ('115', '124'))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('p38', 'Var', (148, 151))	('mitogen-activated protein kinase', 'Gene', '5609', (152, 184))	('induce', 'PosReg', (104, 110))	('ZIP4', 'Gene', (85, 89))	('muscle wasting', 'Disease', (201, 215))	('HSP 70/90', 'Gene', '15511;111042', (128, 137))	('zinc transporter 4', 'Gene', (65, 83))	('muscle wasting', 'Phenotype', 'HP:0003202', (201, 215))	('mouse', 'Species', '10090', (52, 57))	('induce', 'PosReg', (141, 147))	('muscle wasting', 'Disease', 'MESH:D009133', (201, 215))	('secretion', 'MPA', (115, 124))	('pancreatic', 'Disease', 'MESH:D010195', (31, 41))	('zinc transporter 4', 'Gene', '22785', (65, 83))	('mitogen-activated protein kinase', 'Gene', (152, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
51384	33291708	In vivo, CXCL1 impairs muscle regeneration.	('CXCL1', 'Var', (9, 14))	('impairs', 'NegReg', (15, 22))	('muscle regeneration', 'CPA', (23, 42))	('rat', 'Species', '10116', (36, 39))	('regeneration', 'biological_process', 'GO:0031099', ('30', '42'))
51399	33291708	In the murine C26 colon carcinoma model, LIF emerged as an important tumor-derived factor that induced atrophy in myotubules.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('atrophy', 'Disease', (103, 110))	('myotubules', 'MPA', (114, 124))	('tumor', 'Disease', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('colon carcinoma', 'Disease', (18, 33))	('murine', 'Species', '10090', (7, 13))	('LIF', 'Var', (41, 44))	('atrophy', 'Disease', 'MESH:D001284', (103, 110))	('colon carcinoma', 'Disease', 'MESH:D003110', (18, 33))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
51424	33291708	An experimental lesion in the area postrema of the brainstem lesion ablates the anorexia and the accompanying loss of muscle.	('loss', 'NegReg', (110, 114))	('anorexia', 'Phenotype', 'HP:0002039', (80, 88))	('lesion', 'Var', (16, 22))	('muscle', 'MPA', (118, 124))	('postrema of the brainstem lesion ablates the anorexia', 'Disease', 'None', (35, 88))
51425	33291708	Lesions in this area of the brainstem also attenuate TNFalpha-induced anorexia in rats (8).	('anorexia', 'Disease', 'MESH:D000855', (70, 78))	('rats', 'Species', '10116', (82, 86))	('TNFalpha-induced', 'Gene', (53, 69))	('anorexia', 'Phenotype', 'HP:0002039', (70, 78))	('anorexia', 'Disease', (70, 78))	('attenuate', 'NegReg', (43, 52))	('Lesions', 'Var', (0, 7))
51440	33291708	Blockade of ActRIIB reduces tumor size and metastasis in mice bearing the Lewis lung carcinoma; an activin receptor-like kinase inhibitor, SB-431542, has been developed but has not yet entered clinical use.	('mice', 'Species', '10090', (57, 61))	('activin', 'molecular_function', 'GO:0016915', ('99', '106'))	('tumor', 'Disease', (28, 33))	('lung carcinoma', 'Disease', (80, 94))	('lung carcinoma', 'Disease', 'MESH:D008175', (80, 94))	('Blockade', 'Var', (0, 8))	('activin', 'Gene', (99, 106))	('reduces', 'NegReg', (20, 27))	('SB-431542', 'Chemical', 'MESH:C459179', (139, 148))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('121', '137'))	('activin', 'Gene', '83729', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('activin', 'molecular_function', 'GO:0005160', ('99', '106'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ActRIIB', 'Gene', (12, 19))
51466	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))
51467	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))
51474	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))
51493	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))	('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))
51495	32548799	Very interestingly, abnormal MAGE-A expression is more commonly detected in cancer cells that are malignant with invasive and metastatic capacity.	('abnormal', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('detected', 'Reg', (64, 72))	('MAGE-A', 'Chemical', '-', (29, 35))	('MAGE-A', 'Gene', (29, 35))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('expression', 'MPA', (36, 46))
51496	32548799	Patients with cancer and abnormal expression of MAGE-A have a poor prognosis.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MAGE-A', 'Protein', (48, 54))	('abnormal expression', 'Var', (25, 44))	('MAGE-A', 'Chemical', '-', (48, 54))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
51543	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))
51552	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))
51555	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))	('regulation of E3', 'biological_process', 'GO:1904666', ('9', '25'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('ubiquitin', 'molecular_function', 'GO:0031386', ('31', '40'))
51559	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))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('MAGE-A', 'Chemical', '-', (68, 74))	('esophageal squamous cell carcinoma', 'Disease', (168, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('aberrant expression', 'MPA', (45, 64))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('0', '19'))	('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))
51580	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))
51586	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))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('EMT', 'biological_process', 'GO:0001837', ('129', '132'))	('modulating', 'Reg', (114, 124))	('induce', 'PosReg', (51, 57))	('cancer', 'Disease', (98, 104))	('overexpression', 'Var', (18, 32))	('MAGE-A3', 'Gene', '4102', (10, 17))
51594	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))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('83', '106'))	('chemoresistance', 'CPA', (112, 127))	('MAGE-A', 'Gene', (42, 48))	('expression', 'Var', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('apoptosis', 'CPA', (97, 106))
51598	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))
51600	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))
51615	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.	('innate immune response', 'biological_process', 'GO:0045087', ('80', '102'))	('autoimmunity', 'CPA', (143, 155))	('Aberrant expression', 'Var', (0, 19))	('inflammation', 'Disease', 'MESH:D007249', (160, 172))	('inflammation', 'Disease', (160, 172))	('autoimmunity', 'Phenotype', 'HP:0002960', (143, 155))	('activate', 'PosReg', (104, 112))	('innate immune response', 'MPA', (80, 102))	('immune system', 'CPA', (117, 130))	('inflammation', 'biological_process', 'GO:0006954', ('160', '172'))	('LINE-1 retrotransposon', 'Gene', (23, 45))	('induce', 'Reg', (136, 142))
51630	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', 'biological_process', 'GO:0044028', ('63', '82'))	('DNA hypomethylation', 'Var', (63, 82))	('hallmark of cancer', 'Disease', (108, 126))	('hallmark of cancer', 'Disease', 'MESH:D009369', (108, 126))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('LINE-1', 'Gene', (0, 6))
51633	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))
51636	32850797	It has been reported that global DNA hypomethylation promotes aggressive tumor behavior by amplifying oncogenes or through abnormal expression of microRNAs.	('amplifying', 'PosReg', (91, 101))	('promotes', 'PosReg', (53, 61))	('global DNA hypomethylation', 'Var', (26, 52))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('aggressive tumor', 'Disease', 'MESH:D001523', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('33', '52'))	('aggressive tumor', 'Disease', (62, 78))	('oncogenes', 'CPA', (102, 111))	('expression', 'MPA', (132, 142))
51637	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))
51638	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))
51639	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))
51640	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))
51643	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))
51644	32850797	In breast cancer, Morse and colleagues first proposed that hypomethylation activates LINE-1 which can utilize the target primed reverse transcription pathway to insert into the oncogene MYC, causing tumor-specific rearrangement and amplification.	('tumor', 'Disease', (199, 204))	('MYC', 'Gene', '4609', (186, 189))	('amplification', 'MPA', (232, 245))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('hypomethylation', 'Var', (59, 74))	('rearrangement', 'MPA', (214, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('insert', 'Reg', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('MYC', 'Gene', (186, 189))	('causing', 'Reg', (191, 198))	('activates', 'PosReg', (75, 84))	('reverse transcription', 'biological_process', 'GO:0001171', ('128', '149'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
51646	32850797	LINE-1 can mediate the deletion of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('deletion', 'Var', (23, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))
51648	32850797	reported that LINE-1 insertion disrupts the tumor suppressor gene APC, which can lead to gene inactivation.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('disrupts', 'NegReg', (31, 39))	('APC', 'Gene', (66, 69))	('APC', 'cellular_component', 'GO:0005680', ('66', '69'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('insertion', 'Var', (21, 30))	('APC', 'Gene', '324', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))
51649	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.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('FGGY', 'Gene', (91, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('tumor', 'Disease', (163, 168))	('insertion', 'Var', (54, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('cell proliferation', 'CPA', (105, 123))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('invasion', 'CPA', (128, 136))	('promotes', 'PosReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('facilitates', 'PosReg', (151, 162))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
51652	32850797	In breast cancer, high expression of nuclear ORF1 is associated with distant metastasis and poor prognosis.	('ORF1', 'Gene', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('nuclear', 'Protein', (37, 44))	('associated', 'Reg', (53, 63))	('high', 'Var', (18, 22))	('ORF1', 'Gene', '55354', (45, 49))	('distant metastasis', 'CPA', (69, 87))
51666	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))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))	('LINE-1', 'Gene', (0, 6))
51667	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))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('metabolic disorders', 'Disease', 'MESH:D008659', (124, 143))	('DNA methylation', 'biological_process', 'GO:0006306', ('56', '71'))	('T2DM', 'Disease', (102, 106))	('metabolic disorders', 'Disease', (124, 143))
51668	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.	('LDL cholesterol', 'Disease', (52, 67))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('HDL', 'molecular_function', 'GO:0005321', ('82', '85'))	('HDL cholesterol levels', 'MPA', (82, 104))	('LINE-1', 'Gene', (0, 6))	('increase', 'Reg', (134, 142))	('decreased', 'NegReg', (72, 81))	('cholesterol', 'Chemical', 'MESH:D002784', (86, 97))	('decreased HDL cholesterol', 'Phenotype', 'HP:0003233', (72, 97))	('cholesterol', 'Chemical', 'MESH:D002784', (56, 67))	('increased', 'PosReg', (42, 51))	('DNA methylation', 'biological_process', 'GO:0006306', ('7', '22'))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (155, 177))	('methylation', 'Var', (11, 22))	('increased LDL', 'Phenotype', 'HP:0003141', (42, 55))	('cardiovascular disease', 'Disease', 'MESH:D002318', (155, 177))	('DNA methylation', 'Var', (7, 22))	('LDL', 'molecular_function', 'GO:0005322', ('52', '55'))	('cardiovascular disease', 'Disease', (155, 177))
51671	32850797	Therefore, the methylation status of LINE-1 can be a predictor of some metabolic diseases.	('metabolic diseases', 'Disease', 'MESH:D008659', (71, 89))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('methylation status', 'Var', (15, 33))	('metabolic diseases', 'Disease', (71, 89))	('predictor', 'Reg', (53, 62))
51672	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))	('glycerolipid metabolism', 'biological_process', 'GO:0046486', ('121', '144'))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('71', '86'))	('arachidonic acid metabolism', 'biological_process', 'GO:0019369', ('88', '115'))	('insertions', 'Var', (28, 38))	('upregulate', 'PosReg', (60, 70))	('arachidonic acid metabolism', 'MPA', (88, 115))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('71', '86'))	('arachidonic acid', 'Chemical', 'MESH:D016718', (88, 104))	('FGGY', 'Gene', (46, 50))	('glycerolipid metabolism', 'Disease', (121, 144))	('cytochrome P450', 'Enzyme', (71, 86))
51675	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.	('carcinomas', 'Disease', 'MESH:D009369', (50, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('deficiency', 'Var', (70, 80))	('increased', 'PosReg', (140, 149))	('retrotransposition', 'biological_process', 'GO:0032197', ('89', '107'))	('increased', 'PosReg', (108, 117))	('ORF2', 'Gene', (123, 127))	('copy', 'MPA', (128, 132))	('retrotransposition', 'biological_process', 'GO:0032197', ('211', '229'))	('ORF2', 'Gene', '100128274', (123, 127))	('retrotransposition', 'MPA', (89, 107))	('ATM', 'Gene', '472', (234, 237))	('ATM', 'Gene', '472', (66, 69))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (35, 60))	('carcinomas', 'Disease', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('ATM', 'Gene', (234, 237))	('LINE-1', 'Gene', (82, 88))	('ATM', 'Gene', (66, 69))
51676	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))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('methyl CpG binding', 'molecular_function', 'GO:0008327', ('75', '93'))	('Rett syndrome', 'Disease', (39, 52))	('methylation', 'biological_process', 'GO:0032259', ('226', '237'))	('MeCP2', 'Gene', '4204', (201, 206))	('methyl CpG binding protein 2', 'Gene', '4204', (75, 103))
51678	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))
51679	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))
51683	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))
51685	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))
51686	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))
51687	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))
51688	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))
51689	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))
51690	32850797	Hypomethylated and highly expressed LINE-1 has been found in autoimmune diseases such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), and psoriasis.	('found', 'Reg', (52, 57))	('autoimmune diseases', 'Disease', (61, 80))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (61, 80))	('Hypomethylated', 'Var', (0, 14))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (89, 117))	("Sjogren's syndrome", 'Disease', 'MESH:D012859', (125, 143))	('psoriasis', 'Phenotype', 'HP:0003765', (154, 163))	('LINE-1', 'Gene', (36, 42))	('psoriasis', 'Disease', 'MESH:D011565', (154, 163))	("Sjogren's syndrome", 'Disease', (125, 143))	('autoimmune diseases', 'Disease', 'MESH:D001327', (61, 80))	('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))
51708	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))
51711	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', 'biological_process', 'GO:0009315', ('104', '119'))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('dysregulation', 'Var', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('drug resistance', 'biological_process', 'GO:0042493', ('104', '119'))	('LINE-1', 'Gene', (58, 64))	('tumor', 'Disease', (98, 103))
51737	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.	('LINE-1', 'Protein', (173, 179))	('carboplatin', 'Chemical', 'MESH:D016190', (150, 161))	('carboplatin', 'Var', (150, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('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))
51755	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))	('lipid metabolism', 'biological_process', 'GO:0006629', ('120', '136'))	('inhibition', 'Var', (94, 104))	('lipid metabolism', 'biological_process', 'GO:0006629', ('68', '84'))	('LINE-1', 'Gene', (21, 27))
51867	32328196	It has been previously shown that the mutations of somatic point identified in a tumor can be utilized to identify its site of inception with restricted precision.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
51868	32328196	have hypothesized that higher exactness could be accomplished by classification algorithm in light of the accompanying capabilities: 1) the quantity of non-synonymous point mutations in a set of 232 specific cancer-associated genes, 2) frequencies of the 96 classes of single-nucleotide substitution dictated by the flanking bases, and 3) copy number profiles, if accessible.	('cancer', 'Disease', (208, 214))	('non-synonymous', 'MPA', (152, 166))	('single-nucleotide substitution', 'Var', (269, 299))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
51874	32328196	Aneuploidy is seen in 70 percent of patients with abnormalities in the short arm of chromosome 1(1p), and chromosome 12 have been identified.	('short arm', 'Phenotype', 'HP:0009824', (71, 80))	('patients', 'Species', '9606', (36, 44))	('abnormalities', 'Var', (50, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('Aneuploidy', 'Disease', (0, 10))
51875	32328196	The existence of isochromosome12, i(12p) or deletion in 12p describes the germ cell origin tumour and represents patients with midline nodal CUP metastases.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('midline', 'cellular_component', 'GO:0031430', ('127', '134'))	('patients', 'Species', '9606', (113, 121))	('midline nodal CUP metastases', 'Disease', (127, 155))	('tumour', 'Disease', (91, 97))	('deletion', 'Var', (44, 52))	('midline nodal CUP metastases', 'Disease', 'MESH:D009362', (127, 155))	('germ cell origin', 'CPA', (74, 90))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('isochromosome12', 'Var', (17, 32))
51877	32328196	The presence of this marker predicted for a response to cisplatin-based chemotherapy.	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('predicted for', 'Reg', (28, 41))	('response', 'MPA', (44, 52))	('presence', 'Var', (4, 12))	('response to cisplatin', 'biological_process', 'GO:0072718', ('44', '65'))
51878	32328196	Multiple chromosomal rearrangements were detected (15 changes) involving mostly chromosomes 1, 3, 6,7,11, while others were characteristic of different histological subtypes (4q31, 6q15, 10q25 and 13q22; more frequently encountered in adenocarcinomas).	('adenocarcinomas', 'Disease', (235, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (240, 250))	('adenocarcinomas', 'Disease', 'MESH:D000230', (235, 250))	('involving', 'Reg', (63, 72))	('4q31', 'Var', (175, 179))	('Multiple chromosomal rearrangements', 'Phenotype', 'HP:0040012', (0, 35))	('6q15', 'Var', (181, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('13q22', 'Var', (197, 202))	('10q25', 'Var', (187, 192))
51879	32328196	Additionally, complex karyotyping is a prognostic for worse survival compared to patients with up to five alterations.	('complex karyotyping', 'Var', (14, 33))	('patients', 'Species', '9606', (81, 89))	('worse', 'NegReg', (54, 59))
51882	32328196	PCR failed to identify mutations in Exons 18, 19 or 21 of EGFR in any of the 50 tumours.	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('EGFR', 'Gene', (58, 62))	('mutations in Exons', 'Var', (23, 41))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))
51883	32328196	(2015) performed comprehensive genomic profiling for 200 patients with CUP and showed that mutations of human epidermal growth factor receptor 2 (HER-2) were more frequent in adenocarcinomas of unknown primary site (13 patients [10%]) than in non-adenocarcinomas of unknown primary site (3 patients [4%]).	('patients', 'Species', '9606', (290, 298))	('human', 'Species', '9606', (104, 109))	('patients', 'Species', '9606', (219, 227))	('HER-2', 'Gene', '2064', (146, 151))	('HER-2', 'Gene', (146, 151))	('adenocarcinomas', 'Disease', 'MESH:D000230', (247, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('adenocarcinomas', 'Disease', (247, 262))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('epidermal growth factor receptor 2', 'Gene', '2064', (110, 144))	('adenocarcinomas', 'Disease', 'MESH:D000230', (175, 190))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('110', '133'))	('patients', 'Species', '9606', (57, 65))	('adenocarcinomas', 'Disease', (175, 190))	('mutations', 'Var', (91, 100))	('epidermal growth factor receptor 2', 'Gene', (110, 144))	('frequent', 'Reg', (163, 171))
51884	32328196	Besides, alterations in EGFR (10 patients [8%]) were more common in adenocarcinomas of unknown primary site than in non-adenocarcinomas of unknown primary site.	('common', 'Reg', (58, 64))	('adenocarcinomas', 'Disease', 'MESH:D000230', (120, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (33, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('EGFR', 'Gene', (24, 28))	('adenocarcinomas', 'Disease', (68, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('adenocarcinomas', 'Disease', (120, 135))	('alterations', 'Var', (9, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('adenocarcinomas', 'Disease', 'MESH:D000230', (68, 83))
51898	32328196	Only 26% of tumours showed mutated P53, suggesting a relatively low frequency of P53 mutations in CUP.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('P53', 'Gene', (81, 84))	('P53', 'Gene', '7157', (81, 84))	('tumours', 'Disease', (12, 19))	('mutations', 'Var', (85, 94))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('P53', 'Gene', (35, 38))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('P53', 'Gene', '7157', (35, 38))
51902	32328196	The frequency of inactivation of PTEN in somatic cancer is high, and it is ranked the second most mutated tumour suppressor gene after P53 .	('inactivation', 'Var', (17, 29))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('P53', 'Gene', '7157', (135, 138))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('tumour', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('P53', 'Gene', (135, 138))	('cancer', 'Disease', (49, 55))
51906	32328196	identified genomic alterations in PTEN in 200 (7%) of patients with CUP.	('patients', 'Species', '9606', (54, 62))	('PTEN', 'Gene', (34, 38))	('genomic alterations', 'Var', (11, 30))	('PTEN', 'Gene', '5728', (34, 38))
51909	32328196	BRCA1 mutation carriers are at high risk of CUP (relative risk [RR] = 3.45, 95% confidence interval [CI] = 2.35-5.07, P < 0.001).	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('CUP', 'Disease', (44, 47))
51910	32328196	completed an institutional review board-approved study and identified deleterious mutations in BRCA1 and BRCA2 in four patients with CUP.	('BRCA1', 'Gene', (95, 100))	('patients', 'Species', '9606', (119, 127))	('BRCA2', 'Gene', (105, 110))	('mutations', 'Var', (82, 91))	('BRCA2', 'Gene', '675', (105, 110))	('BRCA1', 'Gene', '672', (95, 100))
51912	32328196	showed that only one patient harboured a mutation in Kiss-1 out of fifty patients with CUP using PCR- single-strand conformation polymorphism (PCR-SSCP) and direct sequencing.	('patient', 'Species', '9606', (21, 28))	('mutation', 'Var', (41, 49))	('Kiss-1', 'Gene', '3814', (53, 59))	('patient', 'Species', '9606', (73, 80))	('Kiss-1', 'Gene', (53, 59))	('patients', 'Species', '9606', (73, 81))
51913	32328196	For example, the varying impact of P53-regulating factors such as murine double minute-2, p14 alternate reading frame and p21 due to presence of mutations outside Exons 5-9 of p53 .	('p21', 'Gene', (122, 125))	('p21', 'Gene', '12575', (122, 125))	('p53', 'Gene', (176, 179))	('mutations', 'Var', (145, 154))	('p14', 'Gene', '20024', (90, 93))	('p14', 'Gene', (90, 93))	('p53', 'Gene', '22060', (176, 179))	('P53', 'Gene', (35, 38))	('murine', 'Species', '10090', (66, 72))	('P53', 'Gene', '7157', (35, 38))	('presence', 'Reg', (133, 141))
51924	32328196	Sell and Pierce (1994) proposed that a cancer cell arises as a result of stem cell mutation rather than somatic cell differentiation.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutation', 'Var', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cell differentiation', 'biological_process', 'GO:0030154', ('112', '132'))
51944	32328196	For example, more focused investigations including tests for activating mutations of EGFR and re-arrangements of Anaplastic lymphoma kinase (ALK) and proto-oncogene receptor tyrosine kinase ROS1 are evident in patients with CUP in the form of non-small cell lung cancer.	('EGFR', 'Gene', (85, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (258, 269))	('ROS1', 'Gene', (190, 194))	('non-small cell lung cancer', 'Disease', (243, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (210, 218))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (247, 269))	('Anaplastic lymphoma kinase', 'Gene', '238', (113, 139))	('activating', 'PosReg', (61, 71))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (243, 269))	('ROS1', 'Gene', '6098', (190, 194))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))	('ALK', 'Gene', '238', (141, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (243, 269))	('Anaplastic lymphoma kinase', 'Gene', (113, 139))	('ALK', 'Gene', (141, 144))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (113, 132))
51954	32328196	In theory, suppress apoptosis and increased cell survival triggered by aberrant EGFR signalling would allow CUP cells to escape cell death, accumulate genetic damage and develop an early metastasis phenotype.	('death', 'Disease', (133, 138))	('cell survival', 'CPA', (44, 57))	('EGFR signalling', 'Gene', (80, 95))	('cell death', 'biological_process', 'GO:0008219', ('128', '138'))	('early metastasis', 'CPA', (181, 197))	('signalling', 'biological_process', 'GO:0023052', ('85', '95'))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('apoptosis', 'biological_process', 'GO:0097194', ('20', '29'))	('apoptosis', 'biological_process', 'GO:0006915', ('20', '29'))	('apoptosis', 'CPA', (20, 29))	('genetic damage', 'Disease', 'MESH:D030342', (151, 165))	('develop', 'PosReg', (170, 177))	('genetic damage', 'Disease', (151, 165))	('accumulate', 'PosReg', (140, 150))	('increased', 'PosReg', (34, 43))	('death', 'Disease', 'MESH:D003643', (133, 138))	('aberrant', 'Var', (71, 79))
51955	32328196	One hypothesis is that a tumour-suppressor gene for metastasis is located on this chromosome (1p); therefore, its alteration leads to high propensity for metastasis, although it is subject for further investigation.	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('leads to', 'Reg', (125, 133))	('metastasis', 'CPA', (154, 164))	('alteration', 'Var', (114, 124))	('tumour', 'Disease', (25, 31))
51991	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))
52033	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))	('aging', 'Disease', (160, 165))	('aging', 'biological_process', 'GO:0007568', ('160', '165'))	('arthritis', 'Disease', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('pathogenesis', 'biological_process', 'GO:0009405', ('138', '150'))	('cancer', 'Disease', (182, 188))	('arthritis', 'Disease', 'MESH:D001168', (167, 176))	('cell fate determination', 'biological_process', 'GO:0001709', ('95', '118'))	('arthritis', 'Phenotype', 'HP:0001369', (167, 176))	('dysfunction', 'Var', (68, 79))
52039	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.	('MIR31HG', 'Gene', (97, 104))	('MIR31HG', 'Gene', (9, 16))	('MIR31HG', 'Gene', '554202', (97, 104))	('MIR31HG', 'Gene', '554202', (9, 16))	('knockdown', 'Var', (84, 93))	('arrest', 'Disease', (149, 155))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('gefitinib sensitivity', 'MPA', (181, 202))	('gefitinib', 'Chemical', 'MESH:D000077156', (181, 190))	('higher', 'PosReg', (37, 43))	('expression', 'MPA', (17, 27))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('138', '155'))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('promote', 'PosReg', (111, 118))	('induce', 'Reg', (174, 180))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('cell apoptosis', 'CPA', (119, 133))	('NSCLC', 'Disease', (67, 72))
52045	32280307	The pooled results of subgroup analysis as per the tumor types demonstrated that high MIR31HG expression predicted unfavorable OS in patients with lung cancer and other cancers, and poor RFS in all selected studies, respectively.	('cancers', 'Disease', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (81, 85))	('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))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MIR31HG', 'Gene', (86, 93))	('predicted', 'Reg', (105, 114))	('unfavorable', 'Disease', (115, 126))	('MIR31HG', 'Gene', '554202', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
52057	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))	('transactivation', 'biological_process', 'GO:2000144', ('51', '66'))	('sphere-forming ability', 'CPA', (68, 90))
52075	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))
52087	31959982	MAITs are defined by their semi-invariant TCR gene segment usage consisting of TRAV1-2 rearranged with TRAJ33, 12 or 20, paired with a limited repertoire of TCR-beta chains, including but not limited to TRBV6 and TRBV20.	('TRAV1-2', 'Gene', (79, 86))	('TCR', 'Gene', (42, 45))	('TCR', 'biological_process', 'GO:0006283', ('157', '160'))	('TCR', 'Gene', '6962', (157, 160))	('TCR', 'biological_process', 'GO:0006283', ('42', '45'))	('TRAV1-2', 'Gene', '28692;28691', (79, 86))	('TCR', 'Gene', '6962', (42, 45))	('TCR', 'cellular_component', 'GO:0042101', ('42', '45'))	('TCR', 'Gene', (157, 160))	('TRAJ33', 'Gene', '28722', (103, 109))	('TCR', 'cellular_component', 'GO:0042101', ('157', '160'))	('TRAJ33', 'Gene', (103, 109))	('rearranged', 'Var', (87, 97))
52088	31959982	More recent evidence shows that recognition of MR1-associated ligands can be accomplished by a wider range of TCR rearrangements including those using TRAV14, TRAV21 and TRAV36 chains and that MR1 can present a broader range of ligands than those from the riboflavin biosynthetic pathway, incorporating diverse chemical scaffolds which includes drugs and drug-like molecules.	('TCR', 'Gene', (110, 113))	('TCR', 'cellular_component', 'GO:0042101', ('110', '113'))	('MR1-associated', 'Gene', (47, 61))	('TCR', 'biological_process', 'GO:0006283', ('110', '113'))	('TRAV36', 'Var', (170, 176))	('TRAV21', 'Gene', (159, 165))	('TCR', 'Gene', '6962', (110, 113))	('rat', 'Species', '10116', (296, 299))	('riboflavin', 'Chemical', 'MESH:D012256', (256, 266))	('TRAV21', 'Gene', '28662', (159, 165))
52103	31959982	As MC.7.G5 preferentially killed cancer cells independently of classical MHC molecules we set-out to uncover its mechanism of action.	('MC.7.G5', 'Var', (3, 10))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
52110	31959982	CRISPR-mediated knockout of MR1 from A549 and melanoma MM909.24 (frame-shift deletion mutation shown in Supplementary Fig.	('frame-shift deletion mutation', 'Var', (65, 94))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('MM909', 'CellLine', 'CVCL:AV81', (55, 60))	('MR1', 'Gene', (28, 31))	('A549', 'CellLine', 'CVCL:0023', (37, 41))
52113	31959982	2b), and slightly enhanced recognition of melanoma MM909.24 (Fig.	('melanoma', 'Disease', (42, 50))	('MM909', 'CellLine', 'CVCL:AV81', (51, 56))	('enhanced', 'PosReg', (18, 26))	('MM909.24', 'Var', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
52119	31959982	Accordingly, MC.7.G5 did not recognize C1R cells transduced with the MR1 K43A mutant (Fig.	('MR1', 'Gene', (69, 72))	('K43A', 'Mutation', 'p.K43A', (73, 77))	('K43A', 'Var', (73, 77))	('C1R', 'Gene', (39, 42))	('C1R', 'Gene', '715', (39, 42))
52125	31959982	These results indicate that MC.7.G5 does not exclusively recognize MR1 per se, nor MR1 by known mechanisms, but rather MR1 with bound cargo that is specific to, or associated with, cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('rat', 'Species', '10116', (112, 115))	('bound', 'Interaction', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cargo', 'molecular_function', 'GO:0140355', ('134', '139'))	('MR1', 'Var', (119, 122))	('cancer', 'Disease', (181, 187))
52127	31959982	In order to assess the safety of using the MC.7.G5 TCR for cancer immunotherapy we undertook further testing of healthy cells from various tissues.	('TCR', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('TCR', 'cellular_component', 'GO:0042101', ('51', '54'))	('TCR', 'Gene', '6962', (51, 54))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('MC.7.G5', 'Var', (43, 50))	('G5 T', 'CellLine', 'CVCL:M731', (48, 52))	('TCR', 'biological_process', 'GO:0006283', ('51', '54'))
52134	31959982	Furthermore, a normal renal epithelial cell line did not become targets when treated with tBHP or H2O2 (ROS detection, Supplementary Fig.	('tBHP', 'Var', (90, 94))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('H2O2', 'Chemical', 'MESH:D006861', (98, 102))	('H2O2', 'Var', (98, 102))	('tBHP', 'Chemical', 'MESH:D020122', (90, 94))
52138	31959982	Mice receiving MC.7.G5 had significantly less Jurkat cells at days 12 and 18 (Fig.	('Jurkat', 'CellLine', 'CVCL:0065', (46, 52))	('Mice', 'Species', '10090', (0, 4))	('MC.7.G5', 'Var', (15, 22))	('less', 'NegReg', (41, 45))	('Jurkat cells', 'CPA', (46, 58))
52142	31959982	The in vivo targeting of Jurkat cells by MC.7.G5 was dependent on MR1 expression, as shown by co-transfer experiments with differentially labelled Jurkat wild-type and Jurkat MR1-/- cells to the same mice (Fig.	('Jurkat', 'CellLine', 'CVCL:0065', (168, 174))	('Jurkat', 'CellLine', 'CVCL:0065', (147, 153))	('MC.7.G5', 'Var', (41, 48))	('Jurkat', 'CellLine', 'CVCL:0065', (25, 31))	('Jurkat MR1', 'CellLine', 'CVCL:0065', (168, 178))	('MR1', 'Gene', (66, 69))	('mice', 'Species', '10090', (200, 204))
52144	31959982	These data demonstrate that MC.7.G5 maintained its reactivity towards cancer cells in an in vivo setting thus reducing cancer burden and enhancing survival.	('rat', 'Species', '10116', (18, 21))	('enhancing', 'PosReg', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MC.7.G5', 'Var', (28, 35))	('survival', 'CPA', (147, 155))	('reactivity', 'MPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('reducing', 'NegReg', (110, 118))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
52153	31959982	Indeed, the level of MR1 surface expression required for cancer cell recognition by MC.7.G5 was often below the threshold required for staining with antibody, suggesting that the MC.7.G5 TCR might be capable of responding to a low copy number of MR1 ligand, akin to T cells that recognize pMHC and MAIT TCR recognition of MR1.	('pMHC', 'Chemical', '-', (289, 293))	('G5 T', 'CellLine', 'CVCL:M731', (184, 188))	('TCR', 'biological_process', 'GO:0006283', ('303', '306'))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ligand', 'molecular_function', 'GO:0005488', ('250', '256'))	('antibody', 'cellular_component', 'GO:0019814', ('149', '157'))	('TCR', 'Gene', (303, 306))	('TCR', 'Gene', '6962', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('antibody', 'molecular_function', 'GO:0003823', ('149', '157'))	('antibody', 'cellular_component', 'GO:0042571', ('149', '157'))	('TCR', 'cellular_component', 'GO:0042101', ('187', '190'))	('responding', 'MPA', (211, 221))	('TCR', 'biological_process', 'GO:0006283', ('187', '190'))	('MC.7.G5', 'Var', (179, 186))	('TCR', 'Gene', (187, 190))	('TCR', 'Gene', '6962', (303, 306))	('cell recognition', 'biological_process', 'GO:0008037', ('64', '80'))	('TCR', 'cellular_component', 'GO:0042101', ('303', '306'))	('antibody', 'cellular_component', 'GO:0019815', ('149', '157'))
52156	31959982	Knowledge of known MR1-restricted ligands suggests that the MC.7.G5 TCR ligand may be a cancer-specific or -associated metabolite.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('TCR', 'Gene', '6962', (68, 71))	('ligand', 'molecular_function', 'GO:0005488', ('72', '78'))	('MC.7.G5', 'Var', (60, 67))	('TCR', 'cellular_component', 'GO:0042101', ('68', '71'))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TCR', 'Gene', (68, 71))	('G5 T', 'CellLine', 'CVCL:M731', (65, 69))	('TCR', 'biological_process', 'GO:0006283', ('68', '71'))
52161	31959982	Stage IV metastatic melanoma patients MM909.11 and MM909.24 underwent rapid tumor infiltrating therapy for at the Centre for Cancer Immunotherapy (CCIT), Herlev Hospital, Copenhagen (ethics reference EudraCT no.	('CCIT', 'Disease', 'None', (147, 151))	('patients', 'Species', '9606', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('MM909', 'CellLine', 'CVCL:AV81', (38, 43))	('MM909', 'CellLine', 'CVCL:AV81', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('rat', 'Species', '10116', (88, 91))	('CCIT', 'Disease', (147, 151))	('Cancer', 'Disease', (125, 131))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('MM909.24', 'Var', (51, 59))	('melanoma', 'Disease', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('MM909.11', 'Var', (38, 46))
52172	31959982	Primary melanomas lines MM909.11, MM909.20 and MM909.21 were sourced from the CCIT and used directly from cryopreserved samples for killing assays without prior culture.	('MM909', 'CellLine', 'CVCL:AV81', (34, 39))	('CCIT', 'Disease', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('MM909', 'CellLine', 'CVCL:AV81', (24, 29))	('MM909.20', 'Var', (34, 42))	('melanomas', 'Disease', 'MESH:D008545', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('MM909.21', 'Var', (47, 55))	('MM909', 'CellLine', 'CVCL:AV81', (47, 52))	('CCIT', 'Disease', 'None', (78, 82))	('melanomas', 'Disease', (8, 17))
52179	31959982	Clone 40E.22 was confirmed as CD1a-restricted using CRISPR-Cas9 ablation of CD1a, b, c or d (data not shown).	('CD1a', 'Gene', (76, 80))	('CD1a', 'Gene', '909', (30, 34))	('ablation', 'Var', (64, 72))	('CD1a', 'Gene', (30, 34))	('Cas', 'cellular_component', 'GO:0005650', ('59', '62'))	('CD1a', 'Gene', '909', (76, 80))
52191	31959982	For flow-based killing assays 5,000-10,000 cancer or healthy cell lines were plated in 96U well plates, and MC.7.G5 added to give the desired T cell to cell line ratio (experimental wells).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('rat', 'Species', '10116', (162, 165))	('desired T', 'Disease', 'MESH:D020018', (134, 143))	('desired T', 'Disease', (134, 143))	('cancer', 'Disease', (43, 49))	('MC.7.G5', 'Var', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
52193	31959982	The cells were washed 3 times with chilled D-PBS EDTA (2 mM) then stained in the assay plates with Fixable Live/Dead Violet Dye (VIVID, Thermo Fisher Scientific) then CD3 PerCP (clone UCHT1, BioLegend) and/or anti-TRBV25.1 APC TCR (TRBV11 Arden nomenclature: clone C21, Beckman Coulter, Brea, California, USA) Abs to allow dead cells and T cells to be gated-out leaving viable target cells for analyses (Supplementary Fig.	('TCR', 'Gene', (227, 230))	('VIVID', 'Disease', (129, 134))	('TCR', 'cellular_component', 'GO:0042101', ('227', '230'))	('TCR', 'Gene', '6962', (227, 230))	('APC', 'Disease', 'MESH:D011125', (223, 226))	('APC', 'Disease', (223, 226))	('APC', 'cellular_component', 'GO:0005680', ('223', '226'))	('CD3', 'Var', (167, 170))	('VIVID', 'Disease', 'None', (129, 134))	('TRBV25.1', 'Gene', (214, 222))	('D-PBS EDTA', 'Chemical', '-', (43, 53))	('TRBV25.1', 'Gene', '28562', (214, 222))	('TCR', 'biological_process', 'GO:0006283', ('227', '230'))
52206	31959982	Post therapy PBMCs were obtained from TIL patients MM909.11 and MM909.24 and CD8 and CD4 T cells purified by magnetic enrichment (Miltenyi Biotec Ltd).	('CD8', 'Gene', (77, 80))	('MM909', 'CellLine', 'CVCL:AV81', (64, 69))	('CD8', 'Gene', '925', (77, 80))	('MM909', 'CellLine', 'CVCL:AV81', (51, 56))	('MM909.24', 'Var', (64, 72))	('patients', 'Species', '9606', (42, 50))
52244	31746589	Changes in AKR1C1-1C3 and NQO1 expression by NRF2 knockout or use of NRF2 activators were confirmed by qPCR, immunoblots, and enzyme activity assays.	('NRF2', 'Gene', (45, 49))	('knockout', 'Var', (50, 58))	('NQO1', 'molecular_function', 'GO:0003955', ('26', '30'))	('NQO1', 'Gene', (26, 30))	('AKR1C1', 'Gene', (11, 17))	('AKR1C1', 'Gene', '1645', (11, 17))	('enzyme activity', 'molecular_function', 'GO:0003824', ('126', '141'))
52248	31746589	Inhalation of 3-NBA and other nitrated-polycyclic aromatic hydrocarbons (NO2-PAHs) may increase the risk of lung cancer in individuals exposed to diesel exhaust and urban air pollution.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('increase', 'PosReg', (87, 95))	('3-NBA', 'Chemical', 'MESH:C117220', (14, 19))	('NO2-PAHs', 'Chemical', '-', (73, 81))	('lung cancer', 'Disease', (108, 119))	('nitrated-polycyclic aromatic hydrocarbons', 'Chemical', '-', (30, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('3-NBA', 'Var', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
52255	31746589	We found that the catalytic efficiencies of NQO1, AKR1C1, and AKR1C3 are equivalent for the reduction of 3-NBA and that these enzymes contribute equally in the reduction of 3-NBA in human bronchial epithelial cells in vitro.	('AKR1C3', 'Gene', (62, 68))	('AKR1C3', 'Gene', '8644', (62, 68))	('AKR1C1', 'Gene', '1645', (50, 56))	('human', 'Species', '9606', (182, 187))	('reduction', 'MPA', (92, 101))	('AKR1C1', 'Gene', (50, 56))	('NQO1', 'molecular_function', 'GO:0003955', ('44', '48'))	('3-NBA', 'Chemical', 'MESH:C117220', (173, 178))	('3-NBA', 'Chemical', 'MESH:C117220', (105, 110))	('NQO1', 'Var', (44, 48))
52261	31746589	Remarkably, AKR1C1-1C3 genes are induced 4.8-39-fold in human cell lines following activation of NRF2, whereas NQO1 is induced 1.2-4.8-fold.	('AKR1C1', 'Gene', (12, 18))	('NQO1', 'molecular_function', 'GO:0003955', ('111', '115'))	('AKR1C1', 'Gene', '1645', (12, 18))	('human', 'Species', '9606', (56, 61))	('NRF2', 'Gene', (97, 101))	('activation', 'Var', (83, 93))
52266	31746589	We were able to manipulate expression of AKR1C1-1C3 and NQO1 in A549 cells with heterozygous and homozygous genetic knockout of NRF2 via CRISPR-Cas9 in order to determine the effect of dysregulation of NRF2 on the toxication of 3-NBA.	('NQO1', 'Gene', (56, 60))	('AKR1C1', 'Gene', (41, 47))	('NRF2', 'Gene', (128, 132))	('knockout', 'Var', (116, 124))	('Cas9', 'Chemical', '-', (144, 148))	('NQO1', 'molecular_function', 'GO:0003955', ('56', '60'))	('dysregulation', 'Var', (185, 198))	('Cas', 'cellular_component', 'GO:0005650', ('144', '147'))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('AKR1C1', 'Gene', '1645', (41, 47))	('3-NBA', 'Chemical', 'MESH:C117220', (228, 233))	('manipulate', 'Reg', (16, 26))
52323	31746589	Results were analyzed with a two-way ANOVA to compare cell viability within each 3-NBA dose by NRF2 knockout or induction status.	('knockout', 'Var', (100, 108))	('NRF2', 'Gene', (95, 99))	('3-NBA', 'Chemical', 'MESH:C117220', (81, 86))
52329	31746589	The percentage of dead cells was calculated as  Results were analyzed with a two-way ANOVA to compare cell death within each 3-NBA dose by NRF2 knockout or induction status.	('3-NBA', 'Chemical', 'MESH:C117220', (125, 130))	('knockout', 'Var', (144, 152))	('cell death', 'biological_process', 'GO:0008219', ('102', '112'))	('NRF2', 'Gene', (139, 143))
52332	31746589	As expected, wildtype A549 cells expressed high levels of AKR1C1-1C3 and NQO1 due to constitutive activation of NRF2 caused by somatic mutation in KEAP1 and epigenetic alteration by methylation in the KEAP1 promoter.	('KEAP1', 'Gene', '9817', (147, 152))	('A549', 'CellLine', 'CVCL:0023', (22, 26))	('activation', 'PosReg', (98, 108))	('NQO1', 'molecular_function', 'GO:0003955', ('73', '77'))	('KEAP1', 'Gene', (147, 152))	('AKR1C1', 'Gene', (58, 64))	('methylation', 'Var', (182, 193))	('KEAP1', 'Gene', '9817', (201, 206))	('epigenetic alteration', 'Var', (157, 178))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('NQO1', 'Gene', (73, 77))	('KEAP1', 'Gene', (201, 206))	('AKR1C1', 'Gene', '1645', (58, 64))	('NRF2', 'Gene', (112, 116))
52333	31746589	Consequently, wildtype A549 cells exhibited high constitutive NRF2 activity, and expression of AKR1C1-1C3 and NQO1 in all A549 cell line variants were unresponsive to NRF2 activators such as SFN and CDDO-Im (Figure S1).	('constitutive', 'MPA', (49, 61))	('NQO1', 'molecular_function', 'GO:0003955', ('110', '114'))	('SFN', 'Chemical', 'MESH:C016766', (191, 194))	('CDDO-Im', 'Chemical', '-', (199, 206))	('AKR1C1', 'Gene', (95, 101))	('NRF2', 'Enzyme', (62, 66))	('activity', 'MPA', (67, 75))	('AKR1C1', 'Gene', '1645', (95, 101))	('NQO1', 'Gene', (110, 114))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('variants', 'Var', (137, 145))
52337	31746589	AKR1C2 transcript levels were virtually unchanged (0.3% decrease) in the heterozygous knockout and reduced by 98.7% in the homozygous NRF2 knockout.	('knockout', 'Var', (139, 147))	('AKR1C2', 'Gene', (0, 6))	('AKR1C2', 'Gene', '1646', (0, 6))	('reduced', 'NegReg', (99, 106))	('decrease', 'NegReg', (56, 64))	('transcript levels', 'MPA', (7, 24))
52340	31746589	When these three cell lines (A549 NRF2-KO, A549 NRF2-Het, and A549 wt) were assayed by Western blot, we confirmed complete knockout of NRF2 in the nuclear fraction in the NRF2-KO cells and a partial knockdown in the NRF2-Het cells (Figure 3A,B).	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('knockout', 'Var', (123, 131))	('NRF2', 'Gene', (135, 139))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('A549 NRF2-Het', 'CellLine', 'CVCL:0023', (43, 56))	('A549', 'CellLine', 'CVCL:0023', (43, 47))
52341	31746589	A slight decrease in the molecular weight of NRF2 in the NRF2-Het cells was observed which is likely due to a deletion of the DLG region of the NFE2L2 gene targeted by the CRISPR-Cas9 gRNA that was repaired inframe.	('NFE2L2', 'Gene', '4780', (144, 150))	('molecular weight', 'MPA', (25, 41))	('Cas9', 'Chemical', '-', (179, 183))	('NFE2L2', 'Gene', (144, 150))	('Cas', 'cellular_component', 'GO:0005650', ('179', '182'))	('decrease', 'NegReg', (9, 17))	('deletion', 'Var', (110, 118))
52346	31746589	The abundance of AKR1C1/2 protein was also reduced in NRF2-Het cells, compared to the A549 wt cells.	('NRF2-Het', 'Var', (54, 62))	('AKR1C1/2', 'Gene', '1645;1646', (17, 25))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('AKR1C1/2', 'Gene', (17, 25))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('protein', 'Protein', (26, 33))	('reduced', 'NegReg', (43, 50))	('abundance', 'MPA', (4, 13))
52350	31746589	Enzyme activity measurements differed slightly from immunoblot results, and we found a 29% reduction of NQO1 activity in NRF2-Het cells compared with A549 wt cells, which suggests that the partial NRF2 knockout leads to slightly reduced NQO1 activity levels.	('NQO1', 'Enzyme', (104, 108))	('A549', 'CellLine', 'CVCL:0023', (150, 154))	('NQO1', 'molecular_function', 'GO:0003955', ('104', '108'))	('NQO1 activity levels', 'MPA', (237, 257))	('reduced', 'NegReg', (229, 236))	('reduction', 'NegReg', (91, 100))	('knockout', 'Var', (202, 210))	('NRF2', 'Gene', (197, 201))	('activity', 'MPA', (109, 117))	('NQO1', 'molecular_function', 'GO:0003955', ('237', '241'))	('Enzyme activity', 'molecular_function', 'GO:0003824', ('0', '15'))
52352	31746589	Given that heterozygous and homozygous knockout of NRF2 drastically reduced mRNA and protein levels of AKR1C1-1C3 and NQO1, we next examined the effect of these phenotypes on 3-NBA activation.	('AKR1C1', 'Gene', (103, 109))	('3-NBA', 'Chemical', 'MESH:C117220', (175, 180))	('NRF2', 'Gene', (51, 55))	('knockout', 'Var', (39, 47))	('NQO1', 'MPA', (118, 122))	('amine', 'Chemical', 'MESH:D000588', (134, 139))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('reduced', 'NegReg', (68, 75))	('NQO1', 'molecular_function', 'GO:0003955', ('118', '122'))	('AKR1C1', 'Gene', '1645', (103, 109))
52357	31746589	BCA results also confirmed that average protein levels of A549 NRF2-KO cells were approximately 35% lower than that of A549 wt cells 24 h after plating 1 x 104 cells (data not shown).	('A549 NRF2-KO', 'Var', (58, 70))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('lower', 'NegReg', (100, 105))	('protein levels', 'MPA', (40, 54))	('A549', 'CellLine', 'CVCL:0023', (119, 123))
52358	31746589	Heterozygous NRF2 knockout led to 53% +- 8.2% and 52% +- 15.7% decreases in total 3-ABA formation in A549 NRF2-Het cells following exposure to a low dose (1.25 muM) and high dose (10 muM) of 3-NBA, respectively (Figure 4).	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('decreases', 'NegReg', (63, 72))	('3-ABA formation', 'MPA', (82, 97))	('A549 NRF2-Het', 'CellLine', 'CVCL:0023', (101, 114))	('knockout', 'Var', (18, 26))	('3-ABA', 'Chemical', 'MESH:C475568', (82, 87))	('NRF2', 'Gene', (13, 17))	('3-NBA', 'Chemical', 'MESH:C117220', (191, 196))
52359	31746589	Meanwhile, homozygous NRF2 knockout led to 80% +- 5.5% and 78% +- 9.0% decreases in total 3-ABA formation in A549 NRF2-KO cells following exposure to a low dose (1.25 muM) and high dose (10 muM) of 3-NBA, respectively.	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('3-ABA', 'Chemical', 'MESH:C475568', (90, 95))	('knockout', 'Var', (27, 35))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('3-NBA', 'Chemical', 'MESH:C117220', (198, 203))	('decreases', 'NegReg', (71, 80))	('NRF2', 'Gene', (22, 26))	('3-ABA formation', 'MPA', (90, 105))
52363	31746589	Given that NRF2 signaling increases the antioxidant capacity of the cell and plays a critical role in the cellular defense against oxidative and electrophilic stressors, we examined the effect of NRF2 signaling on cell viability and death following 3-NBA exposure.	('signaling', 'biological_process', 'GO:0023052', ('16', '25'))	('NRF2', 'Gene', (11, 15))	('signaling', 'Var', (16, 25))	('amine', 'Chemical', 'MESH:D000588', (175, 180))	('increases', 'PosReg', (26, 35))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('3-NBA', 'Chemical', 'MESH:C117220', (249, 254))	('antioxidant capacity of the cell', 'MPA', (40, 72))
52409	31746589	Small reductions in cell viability were observed due to 1.25 muM and 10 muM of 3-NBA treatment, but these were not statistically significant.	('reductions', 'NegReg', (6, 16))	('3-NBA', 'Chemical', 'MESH:C117220', (79, 84))	('1.25 muM', 'Var', (56, 64))	('cell viability', 'CPA', (20, 34))
52416	31746589	Given the importance of AKR1C1-1C3 and NQO1 nitroreductase activity, we sought to determine the role of NRF2-KEAP1 signaling on 3-NBA toxication in vitro as measured by 3-ABA formation, cell viability, and cytotoxicity in two human lung cell lines: A549 cells that harbor somatic mutations in KEAP1 and epigenetic silencing of its promoter which lead to high consititutive NRF2 expression and HBEC3-KT cells with wildtype KEAP1 that are sensitive to NRF2 activators.	('HBEC3-KT', 'CellLine', 'CVCL:X491', (393, 401))	('3-ABA', 'Chemical', 'MESH:C475568', (169, 174))	('3-NBA', 'Chemical', 'MESH:C117220', (128, 133))	('nitro', 'Chemical', '-', (44, 49))	('KEAP1', 'Gene', '9817', (422, 427))	('KEAP1', 'Gene', (422, 427))	('cytotoxicity', 'Disease', (206, 218))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('AKR1C1', 'Gene', '1645', (24, 30))	('cytotoxicity', 'Disease', 'MESH:D064420', (206, 218))	('high consititutive', 'MPA', (354, 372))	('KEAP1', 'Gene', '9817', (293, 298))	('AKR1C1', 'Gene', (24, 30))	('NRF2', 'Gene', (373, 377))	('KEAP1', 'Gene', (293, 298))	('KEAP1', 'Gene', '9817', (109, 114))	('formation', 'biological_process', 'GO:0009058', ('175', '184'))	('human', 'Species', '9606', (226, 231))	('NQO1', 'molecular_function', 'GO:0003955', ('39', '43'))	('KEAP1', 'Gene', (109, 114))	('expression', 'MPA', (378, 388))	('mutations', 'Var', (280, 289))	('epigenetic silencing', 'Var', (303, 323))	('A549', 'CellLine', 'CVCL:0023', (249, 253))
52418	31746589	We found that AKR1C1-1C3 were most sensitive to NRF2 knockout and that NRF2 signaling was essential for their transcription.	('AKR1C1', 'Gene', (14, 20))	('AKR1C1', 'Gene', '1645', (14, 20))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('knockout', 'Var', (53, 61))	('NRF2', 'Gene', (48, 52))	('sensitive', 'Reg', (35, 44))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))
52423	31746589	We found decreases of 52-53% and 72-80% in 3-NBA activation due to heterozygous and homozygous NRF2 knockout, respectively.	('3-NBA', 'Chemical', 'MESH:C117220', (43, 48))	('3-NBA activation', 'MPA', (43, 59))	('decreases', 'NegReg', (9, 18))	('knockout', 'Var', (100, 108))	('NRF2', 'Gene', (95, 99))
52433	31746589	It is well appreciated that mRNA transcript levels do not always accurately predict protein levels, but these changes in protein were sufficient to increase total 3-NBA bioactivation by 40-60%.	('increase', 'PosReg', (148, 156))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('3-NBA bioactivation', 'MPA', (163, 182))	('3-NBA', 'Chemical', 'MESH:C117220', (163, 168))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('changes', 'Var', (110, 117))
52447	31746589	More work is required to quantify DNA adducts in humans following exposure to NRF2 activators and NO2-PAHs.	('activators', 'Var', (83, 93))	('NO2-PAHs', 'Chemical', '-', (98, 106))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('NRF2', 'Gene', (78, 82))	('humans', 'Species', '9606', (49, 55))
52515	31551472	Other parameters were set as follows: trypsin digested; maximum missed cleavage sites of 2; oxidation (+15.995 Da) of methionine as a dynamic modification and carbamidomethylation (+57.021 Da) of cysteine as a static modification.	('methionine', 'Chemical', 'MESH:D008715', (118, 128))	('+15.995 Da', 'Var', (103, 113))	('cysteine', 'Chemical', 'MESH:D003545', (196, 204))	('+57.021 Da', 'Var', (181, 191))	('oxidation', 'MPA', (92, 101))	('carbamidomethylation', 'Chemical', 'None', (159, 179))
52520	31551472	From 6 days after the tail-vein injection of Walker-256 cells, the average body weight of tail-vein injection rats was lower than that of the control rats (Fig.	('rats', 'Species', '10116', (110, 114))	('tail-vein injection', 'Var', (90, 109))	('rats', 'Species', '10116', (150, 154))	('lower', 'NegReg', (119, 124))
52542	31551472	5) Among these seven differential proteins (LG3BP, A1AG, ABHEB, CO4, GGT1, APOE, ALBU), five of them (LG3BP, A1AG, CO4, APOE, ALBU) had been reported as lung cancer diagnostic or prognostic biomarkers, while two of them (LG3BP, GGT1) were associated with breast cancer metastasis.	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('CO4', 'Gene', '720', (115, 118))	('breast cancer metastasis', 'Disease', (255, 279))	('A1AG', 'Gene', (51, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('associated', 'Reg', (239, 249))	('LG3BP', 'Var', (102, 107))	('ALBU', 'Gene', '213', (81, 85))	('A1AG', 'Gene', '24614', (51, 55))	('CO4', 'Gene', '720', (64, 67))	('CO4', 'Gene', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ALBU', 'Gene', (81, 85))	('ALBU', 'Gene', '213', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('lung cancer', 'Disease', (153, 164))	('A1AG', 'Gene', (109, 113))	('ALBU', 'Gene', (126, 130))	('CO4', 'Gene', (64, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('A1AG', 'Gene', '24614', (109, 113))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (255, 279))
52548	31551472	In addition, the expression of APOE was also reported to promote lung adenocarcinoma proliferation and migration, which are regarded as potential survival markers in lung cancer.	('promote', 'PosReg', (57, 64))	('lung adenocarcinoma proliferation', 'Disease', (65, 98))	('rat', 'Species', '10116', (106, 109))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('rat', 'Species', '10116', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('expression', 'Var', (17, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('APOE', 'Gene', (31, 35))	('lung adenocarcinoma proliferation', 'Disease', 'MESH:C538231', (65, 98))	('migration', 'CPA', (103, 112))
52555	31551472	Samples at different lung tumor progression stages were almost clustered together using either the Triple TOF 5600 (Fig.	('lung tumor', 'Phenotype', 'HP:0100526', (21, 31))	('Triple TOF 5600', 'Var', (99, 114))	('lung tumor', 'Disease', (21, 31))	('lung tumor', 'Disease', 'MESH:D008175', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
52575	31175176	Human and mouse ILC2 express beta2 integrins and these have been proposed to be involved in cell trafficking since blocking beta2 integrins results in reduced ILC2 numbers in the lung following allergen challenge.	('Human', 'Species', '9606', (0, 5))	('beta2', 'Gene', '15130', (124, 129))	('beta2', 'Gene', (29, 34))	('beta2', 'Gene', (124, 129))	('reduced', 'NegReg', (151, 158))	('mouse', 'Species', '10090', (10, 15))	('beta2', 'Gene', '15130', (29, 34))	('blocking', 'Var', (115, 123))	('ILC2', 'Gene', (159, 163))
52609	31175176	S4, C and D) and hence represented IL-13+ activated ILC2, referred from here on as ILC2 for simplicity.	('C and', 'Var', (4, 9))	('IL-13', 'molecular_function', 'GO:0005144', ('35', '40'))	('IL-13', 'Gene', '16163', (35, 40))	('IL-13', 'Gene', (35, 40))
52632	31175176	4C) of rIL-33 treated mice compared to PBS treated control mice.	('mice', 'Species', '10090', (59, 63))	('rIL-33', 'Gene', '361749', (7, 13))	('treated', 'Var', (14, 21))	('rIL-33', 'Gene', (7, 13))	('mice', 'Species', '10090', (22, 26))
52648	31175176	Using the same modified Boyden chamber assay, we found that CCL8 also induced human ILC2 chemotaxis in a dose-dependent manner, peaking at 10nM CCL8 (Fig.	('human', 'Species', '9606', (78, 83))	('chemotaxis', 'biological_process', 'GO:0006935', ('89', '99'))	('CCL', 'molecular_function', 'GO:0044101', ('60', '63'))	('CCL8', 'Var', (144, 148))	('CCL', 'molecular_function', 'GO:0044101', ('144', '147'))	('induced', 'Reg', (70, 77))	('human', 'CPA', (78, 83))
52651	31175176	Our live PCLS data showed that blocking CCR8 significantly reduced ILC2 accumulation in the peribronchial region compared to control mice (Fig.	('mice', 'Species', '10090', (133, 137))	('reduced', 'NegReg', (59, 66))	('CCR', 'molecular_function', 'GO:0043880', ('40', '43'))	('CCR8', 'Gene', (40, 44))	('blocking', 'Var', (31, 39))	('CCR8', 'Gene', '12776', (40, 44))	('ILC2 accumulation in the peribronchial region', 'MPA', (67, 112))
52656	31175176	In chronically inflamed lung tissue, as observed during asthma, aberrant ECM expression from tissue-remodelling can further influence immune cell activation and survival, thereby altering inflammatory immune responses.	('immune cell activation', 'biological_process', 'GO:0045321', ('134', '156'))	('altering', 'Reg', (179, 187))	('asthma', 'Disease', (56, 62))	('survival', 'CPA', (161, 169))	('ECM expression', 'Gene', (73, 87))	('asthma', 'Disease', 'MESH:D001249', (56, 62))	('inflammatory immune', 'MPA', (188, 207))	('asthma', 'Phenotype', 'HP:0002099', (56, 62))	('influence', 'Reg', (124, 133))	('aberrant', 'Var', (64, 72))	('immune cell activation', 'CPA', (134, 156))
52663	31175176	We noticed a qualitative difference in the SHG signal with the collagen fibres in perivascular / peribroncheal areas of rIL-33 treated mice appearing 'spikier' than those in PBS treated control mice.	('rIL-33', 'Gene', '361749', (120, 126))	('rIL-33', 'Gene', (120, 126))	('mice', 'Species', '10090', (194, 198))	('SHG signal', 'MPA', (43, 53))	('collagen', 'molecular_function', 'GO:0005202', ('63', '71'))	('mice', 'Species', '10090', (135, 139))	('treated', 'Var', (127, 134))
52664	31175176	5E) GLCM SHG analysis of the perivascular / peribronchial area from IL-33 treated mice gave steeper decays than the controls, indicating a more disordered arrangement of shorter fibres.	('mice', 'Species', '10090', (82, 86))	('IL-33', 'Gene', (68, 73))	('treated', 'Var', (74, 81))	('decays', 'MPA', (100, 106))	('IL-33', 'molecular_function', 'GO:0002112', ('68', '73'))
52732	31175176	Interestingly, blockade of collagen fibrillogenesis significantly increased ILC2 speed and travel distance after rIL-33 treatment.	('blockade', 'Var', (15, 23))	('travel distance', 'CPA', (91, 106))	('increased', 'PosReg', (66, 75))	('rIL-33', 'Gene', '361749', (113, 119))	('rIL-33', 'Gene', (113, 119))	('collagen', 'molecular_function', 'GO:0005202', ('27', '35'))	('collagen fibrillogenesis', 'CPA', (27, 51))	('ILC2 speed', 'MPA', (76, 86))
52764	31175176	ILC2 were enriched from whole blood using RosetteSepTM Human ILC2 Enrichment Kit (STEMCELL Technologies) and further sorted by FACs using CD45+ Lineageneg (CD1a, CD3, CD4, CD5, CD8, CD11c, CD14, CD16, CD19, CD20, CD34, FcgammaRI and CD123) (Biolegend), CD161+, CD127+, CRTH2+ and C-Kitvar (Biolegend).	('CD1a', 'Gene', (156, 160))	('CD14', 'Gene', (189, 193))	('CD3', 'Gene', (162, 165))	('CD19', 'Var', (201, 205))	('CD34', 'Gene', '947', (213, 217))	('CD14', 'Gene', '929', (189, 193))	('CRTH2', 'Gene', '11251', (269, 274))	('CD161', 'Gene', (253, 258))	('CD8', 'Gene', (177, 180))	('CD161', 'Gene', '3820', (253, 258))	('CD127+', 'Var', (261, 267))	('ILC2', 'Gene', (61, 65))	('CD123', 'Gene', (233, 238))	('CD11c', 'Var', (182, 187))	('Human', 'Species', '9606', (55, 60))	('CD20', 'Gene', (207, 211))	('CD3', 'Gene', '12501', (162, 165))	('CD3', 'Gene', (213, 216))	('CRTH2', 'Gene', (269, 274))	('FcgammaRI', 'Gene', (219, 228))	('CD1a', 'Gene', '909', (156, 160))	('CD20', 'Gene', '54474', (207, 211))	('CD123', 'Gene', '3563', (233, 238))	('CD16', 'Var', (195, 199))	('CD34', 'Gene', (213, 217))	('CD8', 'Gene', '925', (177, 180))	('FcgammaRI', 'Gene', '2209', (219, 228))	('CD3', 'Gene', '12501', (213, 216))
52801	31240265	Foxp2-/-; Foxp1+/- compound mutant mice die at birth owing to respiratory failure caused by increased severity of airway morphogenesis and differentiation defects.	('mutant', 'Var', (28, 34))	('respiratory failure', 'Disease', (62, 81))	('respiratory failure', 'Disease', 'MESH:D012131', (62, 81))	('Foxp1', 'Gene', (10, 15))	('airway morphogenesis', 'CPA', (114, 134))	('respiratory failure', 'Phenotype', 'HP:0002878', (62, 81))	('mice', 'Species', '10090', (35, 39))	('morphogenesis', 'biological_process', 'GO:0009653', ('121', '134'))	('Foxp2', 'Gene', '114142', (0, 5))	('differentiation defects', 'CPA', (139, 162))	('Foxp1', 'Gene', '108655', (10, 15))	('Foxp2', 'Gene', (0, 5))
52814	31240265	We show that MCRIP1 is highly expressed in lung epithelium during alveolar sac formation, and promotes the expression of the surfactant proteins by preventing Foxp1/2 and CtBP-mediated epigenetic gene silencing.	('Foxp1/2', 'Gene', '108655;114142', (159, 166))	('CtBP', 'Gene', '18521', (171, 175))	('gene silencing', 'biological_process', 'GO:0016458', ('196', '210'))	('Foxp1/2', 'Gene', (159, 166))	('sac', 'cellular_component', 'GO:0035003', ('75', '78'))	('MCRIP1', 'Gene', '348262', (13, 19))	('sac', 'biological_process', 'GO:0071173', ('75', '78'))	('expression', 'MPA', (107, 117))	('epigenetic gene silencing', 'Var', (185, 210))	('MCRIP1', 'Gene', (13, 19))	('preventing', 'NegReg', (148, 158))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('CtBP', 'Gene', (171, 175))	('promotes', 'PosReg', (94, 102))
52821	31240265	Disruption of the Mcrip1 gene in heterozygous (+/-) and homozygous (-/-) mutant mice was confirmed by PCR genotyping using genomic DNA and a pair of primers designed to detect both wild-type and mutant alleles (Fig.	('Mcrip1', 'Gene', (18, 24))	('mutant', 'Var', (73, 79))	('Mcrip1', 'Gene', '348262', (18, 24))	('mice', 'Species', '10090', (80, 84))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('mutant', 'Var', (195, 201))
52825	31240265	An analysis of 156 1-week-old pups resulting from heterozygous mating revealed that the distributions of the Mcrip1 mutant genotype did not follow the Mendelian law (Supplementary Fig.	('mating', 'biological_process', 'GO:0007618', ('63', '69'))	('Mcrip1', 'Gene', '348262', (109, 115))	('mating', 'biological_process', 'GO:1990277', ('63', '69'))	('mutant', 'Var', (116, 122))	('Mcrip1', 'Gene', (109, 115))	('mating', 'biological_process', 'GO:0000747', ('63', '69'))
52837	31240265	These findings thus indicate that MCRIP1 expression in pulmonary epithelia is a prerequisite for the robust inflation of alveolar sacs at birth and that genetic depletion of MCRIP1 leads to postnatal lethality caused by impaired lung inflation and the resulting respiratory failure.	('impaired lung inflation', 'Disease', 'MESH:D009422', (220, 243))	('MCRIP1', 'Gene', '348262', (34, 40))	('leads to', 'Reg', (181, 189))	('impaired lung inflation', 'Disease', (220, 243))	('respiratory failure', 'Disease', (262, 281))	('pulmonary epithelia', 'Disease', (55, 74))	('postnatal lethality', 'CPA', (190, 209))	('MCRIP1', 'Gene', (174, 180))	('MCRIP1', 'Gene', (34, 40))	('respiratory failure', 'Disease', 'MESH:D012131', (262, 281))	('MCRIP1', 'Gene', '348262', (174, 180))	('genetic depletion', 'Var', (153, 170))	('pulmonary epithelia', 'Disease', 'MESH:D008171', (55, 74))	('respiratory failure', 'Phenotype', 'HP:0002878', (262, 281))
52845	31240265	Alternatively, it is also possible that MCRIP1 depletion does not affect AEC2 differentiation, but selectively inhibits the synthesis of these surfactant proteins in AEC2s.	('MCRIP1', 'Gene', '348262', (40, 46))	('MCRIP1', 'Gene', (40, 46))	('depletion', 'Var', (47, 56))	('inhibits', 'NegReg', (111, 119))	('synthesis of these surfactant proteins', 'MPA', (124, 162))	('synthesis', 'biological_process', 'GO:0009058', ('124', '133'))
52888	31240265	In contrast, the ablation of MCRIP1 by CRISPR/Cas9-mediated gene editing led to recruitment of CtBP1 to the promoter region of Sftpb, resulting in reduced acetylation of H3K9, but increased H3K9 methylation, probably due to the CtBP-mediated recruitment of HDACs and HMTs to the promoter (Fig.	('increased', 'PosReg', (180, 189))	('Sftpb', 'Gene', '20388', (127, 132))	('CtBP', 'Gene', (95, 99))	('CtBP', 'Gene', '18521', (95, 99))	('Cas', 'cellular_component', 'GO:0005650', ('46', '49'))	('reduced', 'NegReg', (147, 154))	('methylation', 'MPA', (195, 206))	('CtBP', 'Gene', (228, 232))	('CtBP', 'Gene', '18521', (228, 232))	('ablation', 'Var', (17, 25))	('acetylation', 'MPA', (155, 166))	('H3K9', 'Protein', (170, 174))	('methylation', 'biological_process', 'GO:0032259', ('195', '206'))	('MCRIP1', 'Gene', (29, 35))	('Sftpb', 'Gene', (127, 132))	('MCRIP1', 'Gene', '348262', (29, 35))	('CtBP1', 'Gene', (95, 100))	('CtBP1', 'Gene', '13016', (95, 100))	('H3K9', 'Protein', (190, 194))
52890	31240265	Overall, these results indicate that MCRIP1 promoted the expression of SP-B and SP-C, which are essential for robust inflation of alveolar sacs at the neonatal stage, by releasing these surfactant genes from CtBP-mediated epigenetic silencing during lung development as summarized in Fig.	('expression', 'MPA', (57, 67))	('MCRIP1', 'Gene', '348262', (37, 43))	('promoted', 'PosReg', (44, 52))	('lung development', 'biological_process', 'GO:0030324', ('250', '266'))	('CtBP', 'Gene', (208, 212))	('CtBP', 'Gene', '18521', (208, 212))	('SP-B', 'Gene', (71, 75))	('releasing', 'PosReg', (170, 179))	('SP-C', 'Gene', (80, 84))	('epigenetic silencing', 'Var', (222, 242))	('MCRIP1', 'Gene', (37, 43))
52896	31240265	We found that the expression of the surfactant proteins, SP-B and SP-C, which reduces the surface tension of the alveolar air-liquid interface, was substantially repressed at both the mRNA and protein levels in AEC2s of Mcrip1-/- mice, which results in the collapse of alveoli and small airways.	('collapse', 'CPA', (257, 265))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('mice', 'Species', '10090', (230, 234))	('results in', 'Reg', (242, 252))	('Mcrip1', 'Gene', (220, 226))	('SP-B', 'Var', (57, 61))	('SP-C', 'Gene', (66, 70))	('Mcrip1', 'Gene', '348262', (220, 226))
52899	31240265	To date, mutations of the genes encoding SP-B, SP-C, ABCA3, and colony stimulating factor 2 receptor alpha and beta subunits (CSF2RA and CSF2RB) have been identified in some cases of familial RDS, but other causative genes remain to be uncovered.	('CSF2RA', 'Gene', (126, 132))	('ABCA3', 'Gene', (53, 58))	('mutations', 'Var', (9, 18))	('identified', 'Reg', (155, 165))	('CSF2RA', 'Gene', '12982', (126, 132))	('ABCA3', 'Gene', '27410', (53, 58))	('CSF2RB', 'Gene', '12983', (137, 143))	('SP-B', 'Gene', (41, 45))	('familial RDS', 'Disease', (183, 195))	('SP-C', 'Gene', (47, 51))	('CSF2RB', 'Gene', (137, 143))
52900	31240265	Our results imply that MCRIP1 may be a potential target of mutational inactivation in human hereditary RDS.	('hereditary RDS', 'Disease', (92, 106))	('MCRIP1', 'Gene', '348262', (23, 29))	('MCRIP1', 'Gene', (23, 29))	('human', 'Species', '9606', (86, 91))	('mutational inactivation', 'Var', (59, 82))
52907	31240265	Genetic ablation of endogenous MCRIP1 profoundly inhibited the promoter activity and the expression of SP-B as well as of SP-C in the cultured lung cells and in mouse lung tissues.	('expression', 'MPA', (89, 99))	('inhibited', 'NegReg', (49, 58))	('MCRIP1', 'Gene', '348262', (31, 37))	('MCRIP1', 'Gene', (31, 37))	('promoter activity', 'MPA', (63, 80))	('ablation', 'Var', (8, 16))	('mouse', 'Species', '10090', (161, 166))	('SP-B', 'Gene', (103, 107))
52916	31240265	4d, e), which also implies that, once Mcrip1 has been genetically ablated, the SP-B expression is epigenetically silenced at the level of chromatin remodeling through the orchestrating processes mediated by CtBP and histone modification enzymes.	('histone modification', 'biological_process', 'GO:0016570', ('216', '236'))	('Mcrip1', 'Gene', (38, 44))	('Mcrip1', 'Gene', '348262', (38, 44))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('138', '158'))	('CtBP', 'Gene', (207, 211))	('ablated', 'Var', (66, 73))	('CtBP', 'Gene', '18521', (207, 211))	('chromatin', 'cellular_component', 'GO:0000785', ('138', '147'))	('silenced', 'NegReg', (113, 121))	('expression', 'MPA', (84, 94))	('SP-B', 'Gene', (79, 83))
52935	31240265	Thus, MCRIP1 depletion elicits abnormal epigenetic silencing of these surfactant protein genes, resulting in fatal respiratory failure at birth, which resembles human RDS.	('human', 'Species', '9606', (161, 166))	('resulting in', 'Reg', (96, 108))	('depletion', 'Var', (13, 22))	('epigenetic silencing', 'MPA', (40, 60))	('respiratory failure', 'Disease', (115, 134))	('surfactant protein genes', 'Gene', (70, 94))	('respiratory failure', 'Disease', 'MESH:D012131', (115, 134))	('MCRIP1', 'Gene', '348262', (6, 12))	('elicits', 'Reg', (23, 30))	('MCRIP1', 'Gene', (6, 12))	('respiratory failure', 'Phenotype', 'HP:0002878', (115, 134))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
52943	31240265	Foxp2 mutants were constructed using PCR-based site-directed mutagenesis.	('mutagenesis', 'biological_process', 'GO:0006280', ('61', '72'))	('Foxp2', 'Gene', '114142', (0, 5))	('mutants', 'Var', (6, 13))	('Foxp2', 'Gene', (0, 5))
52964	31240265	Sections were stained with the following primary rabbit antibodies: anti-MCRIP1 (Atlas; 1:400); anti-SP-B (Santa Cruz; 1:300); anti-SP-C (Abcam; 1:1000), anti-CtBP1 (Abcam; 1:500) and anti-CtBP2 (Abcam; 1:500); anti-Foxp1 (CST; 1:200) and anti-Foxp2 (CST; 1:2000).	('Foxp1', 'Gene', (216, 221))	('Foxp2', 'Gene', (244, 249))	('rabbit', 'Species', '9986', (49, 55))	('CST; 1', 'Gene', '65945', (251, 257))	('CST; 1', 'Gene', (251, 257))	('CST; 1', 'Gene', (223, 229))	('Foxp2', 'Gene', '114142', (244, 249))	('CtBP1', 'Gene', (159, 164))	('CtBP2', 'Gene', '13017', (189, 194))	('CST; 1', 'Gene', '65945', (223, 229))	('anti-SP-C', 'Var', (127, 136))	('CtBP1', 'Gene', '13016', (159, 164))	('CtBP2', 'Gene', (189, 194))	('Foxp1', 'Gene', '108655', (216, 221))	('MCRIP1', 'Gene', '348262', (73, 79))	('MCRIP1', 'Gene', (73, 79))
52972	31240265	Cells were seeded in a 24-well plate and transfected with the luciferase reporter plasmids, pGL4-SP-B (-3000/+450) or pGL4-SP-C (-3000/+120), pcDNA3-Foxp2, pcDNA3-CtBP2, and pcDNA3-MCRIP1 as indicated, together with the Renilla luciferase plasmid as an internal control.	('pGL4-SP-C (-3000/+120', 'Var', (118, 139))	('CtBP2', 'Gene', (163, 168))	('Foxp2', 'Gene', '114142', (149, 154))	('MCRIP1', 'Gene', '348262', (181, 187))	('pGL', 'molecular_function', 'GO:0004598', ('118', '121'))	('Foxp2', 'Gene', (149, 154))	('MCRIP1', 'Gene', (181, 187))	('pGL', 'molecular_function', 'GO:0004598', ('92', '95'))	('CtBP2', 'Gene', '13017', (163, 168))
52977	31240265	The following rabbit antibodies were used: anti-Histone H3 (CST; 1 mug/sample), anti-Pan-Methyl-Histone H3 (K9) (CST; 1 mug/sample), anti-Acetyl-Histone H3 (K9) (CST; 1 mug/sample), anti-CtBP1 (Abcam; 1 mug/sample), anti-Foxp1 (CST; 1 mug/sample), and anti-Foxp2 (Abcam; 1 mug/sample).	('rabbit', 'Species', '9986', (14, 20))	('mug', 'molecular_function', 'GO:0043739', ('67', '70'))	('Acetyl-Histone', 'Chemical', '-', (138, 152))	('CtBP1', 'Gene', (187, 192))	('anti-Acetyl-Histone', 'Var', (133, 152))	('CST; 1', 'Gene', (162, 168))	('CtBP1', 'Gene', '13016', (187, 192))	('anti-Pan-Methyl-Histone', 'Var', (80, 103))	('CST; 1', 'Gene', '65945', (60, 66))	('CST; 1', 'Gene', (113, 119))	('Foxp2', 'Gene', '114142', (257, 262))	('CST; 1', 'Gene', '65945', (228, 234))	('Foxp1', 'Gene', (221, 226))	('CST; 1', 'Gene', '65945', (162, 168))	('CST; 1', 'Gene', '65945', (113, 119))	('Foxp1', 'Gene', '108655', (221, 226))	('mug', 'molecular_function', 'GO:0043739', ('169', '172'))	('CST; 1', 'Gene', (228, 234))	('mug', 'molecular_function', 'GO:0043739', ('203', '206'))	('Foxp2', 'Gene', (257, 262))	('mug', 'molecular_function', 'GO:0043739', ('120', '123'))	('mug', 'molecular_function', 'GO:0043739', ('273', '276'))	('mug', 'molecular_function', 'GO:0043739', ('235', '238'))	('CST; 1', 'Gene', (60, 66))
53019	31018549	This sets up a chronic active situation that promotes genomic instability and mutation, altered epigenetic events, inappropriate gene expression, changed microRNA translation, enhanced proliferation of the initiated cells, enabling resistance to cell death, antagonism of immune surveillance, and neo-vascularization.	('gene', 'Gene', (129, 133))	('translation', 'biological_process', 'GO:0006412', ('163', '174'))	('promotes', 'PosReg', (45, 53))	('enhanced', 'PosReg', (176, 184))	('altered', 'Reg', (88, 95))	('cell death', 'biological_process', 'GO:0008219', ('246', '256'))	('resistance to cell death', 'CPA', (232, 256))	('genomic', 'MPA', (54, 61))	('epigenetic events', 'MPA', (96, 113))	('inappropriate', 'Disease', 'MESH:D007177', (115, 128))	('changed', 'Reg', (146, 153))	('inappropriate', 'Disease', (115, 128))	('microRNA translation', 'MPA', (154, 174))	('expression', 'MPA', (134, 144))	('gene expression', 'biological_process', 'GO:0010467', ('129', '144'))	('proliferation', 'CPA', (185, 198))	('neo-vascularization', 'CPA', (297, 316))	('mutation', 'Var', (78, 86))	('enabling', 'PosReg', (223, 231))	('rat', 'Species', '10116', (192, 195))
53032	31018549	While none of these compounds have been extracted from red beetroot and evaluated for chemopreventive potential, data derived about these compounds extracted from other sources (see below) suggest that the polyphenols in red beetroot should have chemopreventive qualities.	('beet', 'Species', '161934', (59, 63))	('chemopreventive qualities', 'CPA', (246, 271))	('polyphenols', 'Chemical', 'MESH:D059808', (206, 217))	('beet', 'Species', '161934', (225, 229))	('polyphenols', 'Var', (206, 217))
53043	31018549	In vitro studies have indicated that p-CA moderately inhibits the growth of some tumor cell lines.	('rat', 'Species', '10116', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p-CA', 'Chemical', 'MESH:C495469', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('inhibits', 'NegReg', (53, 61))	('tumor', 'Disease', (81, 86))	('p-CA', 'Var', (37, 41))
53044	31018549	p-CA inhibits the AKT and ERK signaling pathways that are responsible for angiogenesis and reduces the mRNA expression of VEGF and bFGF, two of the most important angiogenic factors that stimulate the permeability, proliferation, and migration.	('ERK', 'Gene', '5594', (26, 29))	('bFGF', 'Gene', '2247', (131, 135))	('rat', 'Species', '10116', (237, 240))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('proliferation', 'CPA', (215, 228))	('AKT', 'Gene', '207', (18, 21))	('VEGF', 'Gene', '7422', (122, 126))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('rat', 'Species', '10116', (222, 225))	('ERK', 'Gene', (26, 29))	('VEGF', 'Gene', (122, 126))	('inhibits', 'NegReg', (5, 13))	('migration', 'CPA', (234, 243))	('bFGF', 'Gene', (131, 135))	('p-CA', 'Var', (0, 4))	('angiogenesis', 'biological_process', 'GO:0001525', ('74', '86'))	('mRNA expression', 'MPA', (103, 118))	('p-CA', 'Chemical', 'MESH:C495469', (0, 4))	('AKT', 'Gene', (18, 21))	('reduces', 'NegReg', (91, 98))
53046	31018549	p-CA also exerts moderate protection against 1,2-dimethylhydrazine-induced colon cancer in rats, and has been shown to impede aberrant crypt development in 1,2-dimethylhydrazine (DMH)-treated animals.	('1,2-dimethylhydrazine', 'Chemical', 'MESH:D019813', (45, 66))	('rats', 'Species', '10116', (91, 95))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('DMH', 'Chemical', 'MESH:D019813', (179, 182))	('rat', 'Species', '10116', (91, 94))	('p-CA', 'Var', (0, 4))	('aberrant crypt development', 'CPA', (126, 152))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('1,2-dimethylhydrazine', 'Chemical', 'MESH:D019813', (156, 177))	('colon cancer', 'Disease', (75, 87))	('rat', 'Species', '10116', (21, 24))	('impede', 'NegReg', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('p-CA', 'Chemical', 'MESH:C495469', (0, 4))
53047	31018549	The compound was found to down-regulate the cell cycle regulating genes cyclin B1, cdc2 and mdm3 and the immediate early response genes c-fos, c-jun, and c-myc in p-CA and DMH treated rats verses rats that only received DMH.	('DMH', 'Var', (172, 175))	('c-jun', 'Gene', '3725', (143, 148))	('c-jun', 'Gene', (143, 148))	('cdc2', 'Gene', '54237', (83, 87))	('c-fos', 'Gene', '314322', (136, 141))	('c-myc', 'Gene', '24577', (154, 159))	('p-CA', 'Var', (163, 167))	('cell', 'CPA', (44, 48))	('mdm3', 'Gene', (92, 96))	('p-CA', 'Chemical', 'MESH:C495469', (163, 167))	('rats', 'Species', '10116', (184, 188))	('DMH', 'Chemical', 'MESH:D019813', (172, 175))	('DMH', 'Chemical', 'MESH:D019813', (220, 223))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('c-fos', 'Gene', (136, 141))	('cyclin', 'molecular_function', 'GO:0016538', ('72', '78'))	('c-myc', 'Gene', (154, 159))	('rats', 'Species', '10116', (196, 200))	('down-regulate', 'NegReg', (26, 39))	('cyclin B1', 'Gene', (72, 81))	('cdc2', 'Gene', (83, 87))
53049	31018549	p-CA also augmented detoxification in the colon by modulating the nuclear to cytoplasmic ratio of Nfr2 and the accompanying up-regulation of the down-stream phase II xenobiotic detoxifying genes heme oxygenase (decycling) 1, Uridine 5'-diphospho-glucuronosyltransferase, NAD(P)H dehydrogenase [quinone] 1, thioredoxin, and glutathione S-transferase.	('augmented', 'PosReg', (10, 19))	('NAD(P)H dehydrogenase', 'molecular_function', 'GO:0016651', ('271', '292'))	('II xenobiotic', 'Phenotype', 'HP:0031838', (163, 176))	('modulating', 'Reg', (51, 61))	('NAD(P)H dehydrogenase [quinone] 1', 'Gene', '1728', (271, 304))	('regulation', 'biological_process', 'GO:0065007', ('127', '137'))	('oxygenase', 'molecular_function', 'GO:0016701', ('200', '209'))	('detoxification', 'biological_process', 'GO:0098754', ('20', '34'))	('up-regulation', 'PosReg', (124, 137))	('thioredoxin', 'molecular_function', 'GO:0000008', ('306', '317'))	('detoxification', 'MPA', (20, 34))	('nuclear to cytoplasmic ratio', 'MPA', (66, 94))	('p-CA', 'Var', (0, 4))	('thioredoxin', 'Gene', '7295', (306, 317))	('NAD(P)H dehydrogenase', 'molecular_function', 'GO:0008751', ('271', '292'))	('thioredoxin', 'molecular_function', 'GO:0030508', ('306', '317'))	('glutathione S-transferase', 'Gene', '373156', (323, 348))	('p-CA', 'Chemical', 'MESH:C495469', (0, 4))	('rat', 'Species', '10116', (89, 92))	('Nfr2', 'Gene', (98, 102))	('glutathione S-transferase', 'Gene', (323, 348))	('thioredoxin', 'Gene', (306, 317))	('Uridine', 'Enzyme', (225, 232))
53114	31018549	In vitro DNA damage in cultured human liver hepatoma cells caused by exogenous H2O2 was reduced in cells incubated with betalains.	('H2O2', 'Chemical', 'MESH:D006861', (79, 83))	('liver hepatoma cells', 'Disease', 'MESH:D006528', (38, 58))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('betalains', 'Chemical', 'MESH:D050858', (120, 129))	('human', 'Species', '9606', (32, 37))	('liver hepatoma cells', 'Disease', (38, 58))	('reduced', 'NegReg', (88, 95))	('exogenous', 'Var', (69, 78))	('H2O2', 'Var', (79, 83))
53139	31018549	Strand break rejoining is normally rapid, but treatment with H2O2 induces additional breaks and slows down the repair process.	('slows down', 'NegReg', (96, 106))	('induces', 'Reg', (66, 73))	('breaks', 'MPA', (85, 91))	('repair process', 'CPA', (111, 125))	('H2O2', 'Chemical', 'MESH:D006861', (61, 65))	('H2O2', 'Var', (61, 65))
53150	31018549	We showed that E162-drinking water inhibited esophageal carcinogenesis in carcinogen-treated rats with a concomitant reduction of inflammation and angiogenesis, and increased apoptosis.	('reduction', 'NegReg', (117, 126))	('inflammation', 'biological_process', 'GO:0006954', ('130', '142'))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (45, 70))	('esophageal carcinogenesis', 'Disease', (45, 70))	('apoptosis', 'CPA', (175, 184))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('E162-drinking', 'Var', (15, 28))	('angiogenesis', 'CPA', (147, 159))	('inflammation', 'Disease', 'MESH:D007249', (130, 142))	('inhibited', 'NegReg', (35, 44))	('E162', 'Chemical', '-', (15, 19))	('rats', 'Species', '10116', (93, 97))	('inflammation', 'Disease', (130, 142))	('angiogenesis', 'biological_process', 'GO:0001525', ('147', '159'))	('increased', 'PosReg', (165, 174))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('water', 'Chemical', 'MESH:D014867', (29, 34))
53162	31018549	If so, red beetroot powder, anthocyanins, and E162 dye would be equally effective in reducing carcinogenesis and their combination would not inhibit the development of tumors any better that the individual agents.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('reducing', 'NegReg', (85, 93))	('E162', 'Var', (46, 50))	('beet', 'Species', '161934', (11, 15))	('anthocyanins', 'Chemical', 'MESH:D000872', (28, 40))	('E162', 'Chemical', '-', (46, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('carcinogenesis', 'Disease', (94, 108))
53199	31118660	Then, the EGFR mutation status of the specimens obtained by bronchoscopy was investigated, and the result showed both exon 19 deletions and an L858R point in exon 21.	('EGFR', 'Gene', '1956', (10, 14))	('exon 19 deletions', 'Var', (118, 135))	('L858R', 'Var', (143, 148))	('EGFR', 'Gene', (10, 14))	('L858R', 'Mutation', 'rs121434568', (143, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))
53200	31118660	Then icotinib (125 mg) (patent number WO2003082830; Zhejiang Bata Pharma Ltd., Hangzhou, People's Republic of China) was orally administered three times a day after the result was EGFR mutation-positive.	("People's Republic", 'Disease', (89, 106))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('Bata', 'Species', '295399', (61, 65))	('mutation-positive', 'Var', (185, 202))	("People's Republic", 'Disease', 'MESH:D006212', (89, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('icotinib', 'Chemical', 'MESH:C531470', (5, 13))
53237	31118660	Different variations of CDKN2B-AS1 loci are known to be associated with lung adenocarcinoma and prostate cancer.	('lung adenocarcinoma and prostate cancer', 'Disease', 'MESH:D011471', (72, 111))	('CDKN2B-AS1', 'Gene', '100048912', (24, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('associated', 'Reg', (56, 66))	('variations', 'Var', (10, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CDKN2B-AS1', 'Gene', (24, 34))
53323	30421009	The PARP (poly ADP-ribose) family of enzymes are essential for repairing single-stranded DNA breaks.	('PARP', 'Gene', '142', (4, 8))	('PARP', 'Gene', (4, 8))	('single-stranded', 'Var', (73, 88))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))
53324	30421009	PARP inhibitors effectively trap PARP and induce apoptosis in cells harboring defects in their homologous recombination (HR) or double-stranded DNA repair functions, commonly seen in BRCA1/2 mutated tumors, causing a "synthetic lethality".	('tumors', 'Disease', (199, 205))	('induce', 'PosReg', (42, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('DNA repair', 'biological_process', 'GO:0006281', ('144', '154'))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('homologous recombination', 'biological_process', 'GO:0035825', ('95', '119'))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('BRCA', 'Gene', '672', (183, 187))	('PARP', 'Gene', '142', (33, 37))	('double-stranded DNA', 'Var', (128, 147))	('PARP', 'Gene', (33, 37))	('PARP', 'Gene', '142', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('PARP', 'Gene', (0, 4))	('synthetic', 'Species', '1440148', (218, 227))	('mutated', 'Var', (191, 198))	('BRCA', 'Gene', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('apoptosis', 'CPA', (49, 58))
53325	30421009	Although approved as single agents in breast and ovarian cancers, mostly in those with BRCA 1/2 mutations, many studies are investigating the combination of PARP inhibitors with immune checkpoint blockade in all-comers.	('BRCA 1/2', 'Gene', (87, 95))	('ovarian cancers', 'Phenotype', 'HP:0100615', (49, 64))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (38, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('PARP', 'Gene', (157, 161))	('BRCA 1/2', 'Gene', '672;675', (87, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('PARP', 'Gene', '142', (157, 161))	('mutations', 'Var', (96, 105))
53332	30421009	reported the interim results of a phase II basket study (MEDIOLA) of durvalumab plus olaparib in 32 patients with platinum-sensitive relapsed ovarian cancer and germline BRCA 1/2 mutations.	('olaparib', 'Chemical', 'MESH:C531550', (85, 93))	('platinum', 'Chemical', 'MESH:D010984', (114, 122))	('BRCA 1/2', 'Gene', (170, 178))	('ovarian cancer', 'Disease', (142, 156))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('patients', 'Species', '9606', (100, 108))	('BRCA 1/2', 'Gene', '672;675', (170, 178))	('mutations', 'Var', (179, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (142, 156))	('durvalumab', 'Chemical', 'MESH:C000613593', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
53335	30421009	The TOPACIO trial is a phase I/II study of pembrolizumab plus niraparib in women with both BRCA mutated and wild-type (WT) ovarian cancers and TNBC.	('mutated', 'Var', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('BRCA', 'Gene', (91, 95))	('wild-type (WT) ovarian cancers', 'Disease', 'MESH:D010051', (108, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('women', 'Species', '9606', (75, 80))	('ovarian cancers', 'Phenotype', 'HP:0100615', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pembrolizumab', 'Chemical', 'MESH:C582435', (43, 56))	('TNBC', 'Chemical', '-', (143, 147))	('BRCA', 'Gene', '672', (91, 95))	('niraparib', 'Chemical', 'MESH:C545685', (62, 71))
53341	30421009	Combination PARP and immunotherapy represents one of the most promising areas in ovarian cancer with impressive response rates in both BRCA 1/2 mutated and WT patients.	('BRCA 1/2', 'Gene', (135, 143))	('mutated', 'Var', (144, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('PARP', 'Gene', '142', (12, 16))	('ovarian cancer', 'Disease', (81, 95))	('BRCA 1/2', 'Gene', '672;675', (135, 143))	('patients', 'Species', '9606', (159, 167))	('PARP', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
53358	30421009	As a result, there is an ongoing study comparing TPIV200 with GM-CSF vs. GM-CSF alone as a maintenance therapy after upfront chemotherapy in ovarian cancer (NCT02978222).	('GM-CSF', 'Gene', (73, 79))	('GM-CSF', 'Gene', (62, 68))	('GM-CSF', 'Gene', '1437', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('ovarian cancer', 'Disease', 'MESH:D010051', (141, 155))	('GM-CSF', 'Gene', '1437', (73, 79))	('TPIV200', 'Var', (49, 56))	('ovarian cancer', 'Disease', (141, 155))
53362	30421009	It has become clear through efforts such as the cancer genome atlas project (TCGA) that endometrial cancers are a heterogeneous group of diseases that can be divided into four categories based on genomic characteristics: POLE ultramutated, microsatellite instability (MSI) hypermutated, copy number-low, and copy number-high.	('endometrial cancers', 'Disease', 'MESH:D016889', (88, 107))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('endometrial cancers', 'Disease', (88, 107))	('microsatellite', 'MPA', (240, 254))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('MSI', 'Disease', 'None', (268, 271))	('copy number-high', 'Var', (308, 324))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('endometrial cancer', 'Phenotype', 'HP:0012114', (88, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('copy number-low', 'Var', (287, 302))	('MSI', 'Disease', (268, 271))
53367	30421009	Although successful in the MSI-H subtype of endometrial cancer, checkpoint blockade monotherapy in those with microsatellite stability (MSS) has proven less effective.	('microsatellite stability', 'Var', (110, 134))	('MSI-H subtype of endometrial cancer', 'Disease', (27, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MSI-H subtype of endometrial cancer', 'Disease', 'MESH:D016889', (27, 62))	('endometrial cancer', 'Phenotype', 'HP:0012114', (44, 62))
53437	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))
53440	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))	('cell death', 'biological_process', 'GO:0008219', ('82', '92'))	('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))
53462	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))
53471	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))	('SPC', 'molecular_function', 'GO:0009004', ('36', '39'))	('human', 'Species', '9606', (88, 93))	('NSCLC', 'Disease', (0, 5))	('H1299', 'CellLine', 'CVCL:0060', (58, 63))
53540	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))
53545	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))	('MMP', 'molecular_function', 'GO:0004235', ('66', '69'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('32', '54'))	('decreased', 'NegReg', (75, 84))
53546	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))
53568	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))
53571	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))	('cell viability', 'CPA', (260, 274))	('si', 'Chemical', 'MESH:D012825', (251, 253))	('si-1244', 'Var', (251, 258))	('GSDMD', 'Gene', (55, 60))	('PC9', 'Gene', '255738', (135, 138))	('si-1031', 'Var', (86, 93))	('si', 'Chemical', 'MESH:D012825', (233, 235))	('PC9', 'Gene', (32, 35))	('proliferation', 'CPA', (311, 324))
53573	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))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('76', '98'))	('caspase-3', 'Gene', '836', (116, 125))
53583	30106450	Six-week-old male Balb/c nude mice were injected subcutaneously with PC9 cells transduced with shGsd or shNeg.	('PC9', 'Gene', '255738', (69, 72))	('PC9', 'Gene', (69, 72))	('nude mice', 'Species', '10090', (25, 34))	('shGsd', 'Var', (95, 100))
53626	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('149', '167'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('Akt', 'Gene', (89, 92))	('cell proliferation', 'CPA', (149, 167))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('copy numbers', 'Var', (28, 40))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('mutation', 'Var', (5, 13))
53629	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.	('PI3K', 'molecular_function', 'GO:0016303', ('140', '144'))	('Akt', 'Gene', (145, 148))	('GSDMD', 'Gene', '79792', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('GSDMD', 'Gene', '79792', (28, 33))	('knockdown', 'Var', (15, 24))	('negative feedback regulation', 'MPA', (92, 120))	('GSDMD', 'Gene', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('interrupting', 'NegReg', (75, 87))	('inflammatory responses', 'CPA', (46, 68))	('activating', 'MPA', (125, 135))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('impairs', 'NegReg', (34, 41))	('cancer', 'Disease', (261, 267))	('Akt', 'Gene', '207', (145, 148))	('GSDMD', 'Gene', (28, 33))
53649	29976229	The Ki67 proliferation index and the rate of apoptosis of the metastatic tumor cells were diminished in Sdc1-/- vs. Sdc1+/+ animals, and leucocyte density was indistinguishable.	('Ki67', 'Gene', '17345', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Sdc1-/-', 'Var', (104, 111))	('tumor', 'Disease', (73, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('Ki67', 'Gene', (4, 8))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('diminished', 'NegReg', (90, 100))
53701	29976229	The average size of metastatic lesions was not significantly different between Sdc1-/- and Sdc1+/+ mice (Fig.	('mice', 'Species', '10090', (99, 103))	('metastatic lesions', 'CPA', (20, 38))	('Sdc1-/-', 'Var', (79, 86))
53702	29976229	1d; p = 0.11) - presumably because of the small number of metastases in the Sdc1-/- mice and the high variability of the size of metastatic lesions in the Sdc1+/+ mice.	('mice', 'Species', '10090', (163, 167))	('metastases', 'Disease', (58, 68))	('Sdc1-/-', 'Var', (76, 83))	('mice', 'Species', '10090', (84, 88))	('metastases', 'Disease', 'MESH:D009362', (58, 68))
53704	29976229	The E0771 mammary tumor cells metastasize primarily to the lungs of C57BL/6 mice, similar to 4T1 cells in BALB/cJ animals.	('E0771', 'Var', (4, 9))	('tumor', 'Disease', (18, 23))	('metastasize', 'CPA', (30, 41))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
53705	29976229	The results with C57BL/6 animals mirrored our observations in BALB/cJ mice, as the number of metastases per mouse (Additional file 1: Figure S1A, B; p = 0.013) and the metastatic burden (Additional file 1: Figure S1C; p = 0.038) were significantly reduced in Sdc1-/- compared to Sdc1+/+ animals.	('metastases', 'Disease', (93, 103))	('reduced', 'NegReg', (248, 255))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('mice', 'Species', '10090', (70, 74))	('mouse', 'Species', '10090', (108, 113))	('metastatic burden', 'CPA', (168, 185))	('Sdc1-/-', 'Var', (259, 266))
53706	29976229	The average size of metastatic lesions was not significantly reduced in Sdc1-/- compared to Sdc1+/+ mice (Additional file 1: Figure S1D; p = 0.37).	('mice', 'Species', '10090', (100, 104))	('Sdc1-/-', 'Var', (72, 79))	('reduced', 'NegReg', (61, 68))
53708	29976229	Previous work by our group and others has shown that Sdc1 is induced in stromal fibroblasts of breast carcinomas in both humans and in mice and that stromal Sdc1 can stimulate tumor growth and angiogenesis and create an invasion-permissive microenvironment.	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast carcinomas', 'Disease', (95, 112))	('angiogenesis', 'CPA', (193, 205))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('invasion-permissive', 'CPA', (220, 239))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('tumor', 'Disease', (176, 181))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('Sdc1', 'Gene', (53, 57))	('stromal', 'Var', (149, 156))	('mice', 'Species', '10090', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('angiogenesis', 'biological_process', 'GO:0001525', ('193', '205'))	('humans', 'Species', '9606', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('stimulate', 'PosReg', (166, 175))
53709	29976229	However, in this model, the average weight of mammary fat pad tumors grown in Sdc1+/+ or Sdc1-/- mice did not differ significantly (Additional file 2: Figure S2A).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mice', 'Species', '10090', (97, 101))	('Sdc1+/+', 'Var', (78, 85))
53712	29976229	However, in this model, no difference in microvessel density was detected between tumors arising in Sdc1+/+ or Sdc1-/- mice (Additional file 2: Figure S2C).	('mice', 'Species', '10090', (119, 123))	('Sdc1+/+', 'Var', (100, 107))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
53716	29976229	The density of intratumoral alphaSMA-positive cells was similar in Sdc1+/+ and Sdc1-/- host animals (Additional file 2: Figure S2D).	('alphaSMA', 'Gene', '11475', (28, 36))	('Sdc1+/+', 'Var', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('alphaSMA', 'Gene', (28, 36))
53720	29976229	There was no significant difference in the amount of collagen (SHG signal intensity/area; not shown) nor in the mean angles between collagen fibers and the tumor boundary when comparing Sdc1+/+ and Sdc1-/- mice (Additional file 2: Figure S2F).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mice', 'Species', '10090', (206, 210))	('collagen', 'molecular_function', 'GO:0005202', ('132', '140'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Sdc1+/+', 'Var', (186, 193))	('tumor', 'Disease', (156, 161))	('collagen', 'molecular_function', 'GO:0005202', ('53', '61'))
53725	29976229	2d) were significantly reduced in Sdc1-/- mice compared to Sdc1+/+ animals (p < 0.0001 for all comparisons).	('reduced', 'NegReg', (23, 30))	('mice', 'Species', '10090', (42, 46))	('Sdc1-/-', 'Var', (34, 41))
53727	29976229	Similarly, in the C57BL/6 model, the number of metastatic lesions (Additional file 3: Figure S3A, B; p = 0.045) and the metastatic burden (Additional file 3: Figure S3C; p = 0.037) were lower in Sdc1-/- mice, and the average size of the metastatic lesions was not significantly different (Additional file 3: Figure S3D).	('mice', 'Species', '10090', (203, 207))	('Sdc1-/-', 'Var', (195, 202))	('lower', 'NegReg', (186, 191))	('metastatic burden', 'CPA', (120, 137))	('metastatic lesions', 'CPA', (47, 65))
53740	29976229	Leucocyte density was indistinguishable between metastases arising in Sdc1+/+ vs. Sdc1 -/- mice, and therefore it is unlikely that an Sdc1-mediated increase or decrease in inflammation/immune cell infiltration is responsible for differences in metastatic efficiency.	('mice', 'Species', '10090', (91, 95))	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('inflammation', 'Disease', 'MESH:D007249', (172, 184))	('inflammation', 'Disease', (172, 184))	('inflammation', 'biological_process', 'GO:0006954', ('172', '184'))	('metastases', 'Disease', (48, 58))	('Sdc1+/+', 'Var', (70, 77))
53744	29976229	The proportion of apoptotic carcinoma cells - identified by active caspase 3 expression - was also lower in Sdc1-/- animals by 64% (Fig.	('lower', 'NegReg', (99, 104))	('carcinoma cell', 'Disease', 'MESH:C538614', (28, 42))	('carcinoma cell', 'Disease', (28, 42))	('caspase 3', 'Gene', (67, 76))	('Sdc1-/-', 'Var', (108, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('caspase 3', 'Gene', '12367', (67, 76))
53774	29976229	Beauvais and coworkers have shown that clustering of Sdc1 on the cell surface results in the assembly of a trimeric complex that also contains an alphav containing integrin and insulin-like growth factor 1 receptor (IGF1R).	('IGF1R', 'Gene', '16001', (216, 221))	('insulin-like growth factor 1 receptor', 'Gene', '16001', (177, 214))	('IGF1R', 'Gene', (216, 221))	('cell surface', 'cellular_component', 'GO:0009986', ('65', '77'))	('results in', 'Reg', (78, 88))	('assembly', 'MPA', (93, 101))	('Sdc1', 'Gene', (53, 57))	('clustering', 'Var', (39, 49))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('177', '203'))	('trimeric complex', 'MPA', (107, 123))	('insulin-like growth factor 1 receptor', 'Gene', (177, 214))	('alphav containing integrin', 'Protein', (146, 172))
53779	29976229	In our study, no significant difference was identified in CD4+ or CD8+ lymphocytes between Sdc1+/+ and Sdc1-/- animals.	('CD4', 'Gene', '12504', (58, 61))	('CD8+ lymphocytes', 'CPA', (66, 82))	('Sdc1+/+', 'Var', (91, 98))	('CD4', 'Gene', (58, 61))
53793	29632898	We also observed a significant positive association between lifetime physical inactivity and lung cancer mortality [Hazard ratio (HR)=1.40, 95% CI: 1.14-1.71]; the association remained significant in non-smokers (HR=1.51, 95% CI: 1.16-1.95).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('physical inactivity', 'Var', (69, 88))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
53794	29632898	These data add to the body of evidence suggesting that physical inactivity is an independent risk and prognostic factor for cancer.	('physical inactivity', 'Var', (55, 74))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
53841	29632898	We also observed positive associations between lifetime physical inactivity and lung cancer risk in every subgroup we examined.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('lung cancer', 'Disease', (80, 91))	('physical inactivity', 'Var', (56, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
53855	29632898	In multivariable Cox regression models, we observed significant positive associations of lifetime physical inactivity with all-cause mortality (HR=1.31, 95% CI: 1.09-1.58) and lung cancer-specific mortality (HR=1.40, 95% CI: 1.14-1.71) in the overall study population.	('physical inactivity', 'Var', (98, 117))	('Cox', 'Gene', '1351', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('Cox', 'Gene', (17, 20))	('all-cause mortality', 'CPA', (123, 142))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
53858	29632898	Among women, we observed a significant association between lifetime physical inactivity and all-cause mortality (HR=1.35, 95% CI: 1.02-1.79), and the association for lung-cancer specific mortality was borderline significant (HR=1.32, 95% CI: 0.97-1.80) (Table 4).	('physical inactivity', 'Var', (68, 87))	('women', 'Species', '9606', (6, 11))	('lung-cancer', 'Disease', 'MESH:D008175', (166, 177))	('lung-cancer', 'Disease', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('all-cause', 'CPA', (92, 101))
53867	29632898	Herein, we observed a significant positive association between lifetime physical inactivity and lung cancer risk among never smokers and non-smokers who had quit at least one year prior to study enrollment, but the association was only borderline significant among current smokers.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('physical inactivity', 'Var', (72, 91))	('men', 'Species', '9606', (201, 204))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
53911	29632898	Further, it is possible that more active individuals have increased exposure to vitamin D, and vitamin D directly correlates with FEV in chronic obstructive pulmonary disorder (COPD) patients and is also directly associated with improved survival in early-stage lung cancer patients.	('chronic obstructive pulmonary disorder', 'Disease', (137, 175))	('exposure', 'MPA', (68, 76))	('vitamin', 'Var', (95, 102))	('lung cancer', 'Disease', (262, 273))	('associated', 'Reg', (213, 223))	('patients', 'Species', '9606', (274, 282))	('improved', 'PosReg', (229, 237))	('increased', 'PosReg', (58, 67))	('lung cancer', 'Disease', 'MESH:D008175', (262, 273))	('vitamin D', 'Chemical', 'MESH:D014807', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('COPD', 'Phenotype', 'HP:0006510', (177, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('vitamin D', 'Chemical', 'MESH:D014807', (95, 104))	('COPD', 'Disease', 'MESH:D029424', (177, 181))	('patients', 'Species', '9606', (183, 191))	('chronic obstructive pulmonary disorder', 'Phenotype', 'HP:0006510', (137, 175))	('COPD', 'Disease', (177, 181))	('FEV', 'Disease', (130, 133))	('obstructive pulmonary disorder', 'Phenotype', 'HP:0006536', (145, 175))	('chronic obstructive pulmonary disorder', 'Disease', 'MESH:D029424', (137, 175))
53921	29632898	OR odds ratio HR hazard ratio CI confidence intervals RPCI Roswell Park Cancer Institute PEDS Patient Epidemiology Data System BMI body mass index RERI Relative Excess Risk due to Interaction FEV Forced Expiratory Volume FVC Forced Vital Capacity	('Roswell Park Cancer', 'Disease', (59, 78))	('Patient', 'Species', '9606', (94, 101))	('Interaction FEV', 'Var', (180, 195))	('Roswell Park Cancer', 'Disease', 'MESH:D013341', (59, 78))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Forced Expiratory Volume FVC Forced Vital', 'MPA', (196, 237))
53922	29258181	PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis.	('APR', 'Gene', (24, 27))	('apoptosis', 'CPA', (244, 253))	('PRIMA-1', 'Gene', '145270', (12, 19))	('PRIMA-1', 'Gene', (0, 7))	('PRIMA', 'Gene', '145270', (0, 5))	('p53', 'Gene', '7157', (167, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('244', '253'))	('PRIMA', 'Gene', (12, 17))	('apoptosis', 'biological_process', 'GO:0006915', ('244', '253'))	('Tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('222', '239'))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (167, 170))	('triggering', 'Reg', (211, 221))	('PRIMA-1', 'Gene', (12, 19))	('arrest', 'Disease', (233, 239))	('PRIMA', 'Gene', (0, 5))	('p53', 'Gene', (56, 59))	('Mutant/Wild', 'Var', (39, 50))	('PRIMA-1', 'Gene', '145270', (0, 7))	('PRIMA', 'Gene', '145270', (12, 17))	('APR', 'Gene', '5366', (24, 27))	('arrest', 'Disease', 'MESH:D006323', (233, 239))
53923	29258181	Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('degradation', 'MPA', (142, 153))	('protein', 'Protein', (161, 168))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('degradation', 'biological_process', 'GO:0009056', ('142', '153'))	('p53 pathway', 'Pathway', (16, 27))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('missense mutations', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Inactivation', 'NegReg', (0, 12))	('human', 'Species', '9606', (61, 66))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
53924	29258181	The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress.	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('APR', 'Gene', '5366', (138, 141))	('APR', 'Gene', (138, 141))	('PRIMA-1Met', 'Var', (126, 136))
53926	29258181	p53, so called "the guardian of the genome", appears as a key factor in the carcinogenesis.	('p53', 'Var', (0, 3))	('carcinogenesis', 'Disease', (76, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))
53928	29258181	The outcome of mutations in the tumor suppressor gene p53 results in the loss of the wild-type p53 (wt-p53) activity and the gain of oncogenic functions such as resistance to apoptosis and escalation in genome instability.	('loss', 'NegReg', (73, 77))	('escalation', 'Reg', (189, 199))	('activity', 'MPA', (108, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('gain', 'PosReg', (125, 129))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('p53', 'Gene', (54, 57))	('genome instability', 'CPA', (203, 221))	('oncogenic functions', 'CPA', (133, 152))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('resistance to apoptosis', 'CPA', (161, 184))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))
53929	29258181	In addition, such mutations push cancer cells to acquire new properties, promoting invasion, migration, angiogenesis, proliferation, genomic instability, or drug resistance.	('drug resistance', 'CPA', (157, 172))	('drug resistance', 'Phenotype', 'HP:0020174', (157, 172))	('rat', 'Species', '10116', (125, 128))	('drug resistance', 'biological_process', 'GO:0009315', ('157', '172'))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('promoting', 'PosReg', (73, 82))	('migration', 'CPA', (93, 102))	('drug resistance', 'biological_process', 'GO:0042493', ('157', '172'))	('angiogenesis', 'biological_process', 'GO:0001525', ('104', '116'))	('proliferation', 'CPA', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('invasion', 'CPA', (83, 91))	('genomic instability', 'CPA', (133, 152))	('angiogenesis', 'CPA', (104, 116))	('rat', 'Species', '10116', (96, 99))	('mutations', 'Var', (18, 27))
53930	29258181	Mutant-p53 are, consequently, associated with aggressive tumor phenotypes and poor patient survival.	('associated', 'Reg', (30, 40))	('Mutant-p53', 'Var', (0, 10))	('aggressive tumor', 'Disease', 'MESH:D001523', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patient', 'Species', '9606', (83, 90))	('aggressive tumor', 'Disease', (46, 62))
53939	29258181	Boecker et al., 2008 focused their studies on a specific hot mutation in p53 (Y220C) and they designed Y220C-targeting compounds based on in silico analysis of the crystal structure of the p53 core domain including PK083 and PK7088.	('core', 'cellular_component', 'GO:0019013', ('193', '197'))	('PK083', 'Var', (215, 220))	('Y220C', 'Mutation', 'rs121912666', (78, 83))	('PK7088', 'Var', (225, 231))	('Y220C', 'Mutation', 'rs121912666', (103, 108))
53940	29258181	These molecules have shown to induce Y220C-dependent apoptosis in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Y220C', 'Mutation', 'rs121912666', (37, 42))	('induce', 'PosReg', (30, 36))	('tumor', 'Disease', (66, 71))	('Y220C-dependent', 'Var', (37, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
53944	29258181	(2002) screened compounds that could suppress the proliferation of human tumor cells harboring mutation in p53.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('p53', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('proliferation', 'CPA', (50, 63))	('suppress', 'NegReg', (37, 45))	('tumor', 'Disease', (73, 78))	('rat', 'Species', '10116', (57, 60))	('human', 'Species', '9606', (67, 72))	('mutation', 'Var', (95, 103))
53964	29258181	Indeed, although the tested doses were cytotoxic for non-small cell lung cancer, prostate cancer or soft tissue sarcoma cell lines, neither modification of the cell cycle, nor apoptotic bodies under microscope evaluation, nor PARP cleavage were observed, regardless of the p53 status (wild type, mutated, or absent).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (53, 79))	('soft tissue sarcoma', 'Disease', (100, 119))	('prostate cancer', 'Disease', (81, 96))	('non-small cell lung cancer', 'Disease', (53, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('160', '170'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (57, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (53, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (100, 119))	('cell cycle', 'CPA', (160, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('mutated', 'Var', (296, 303))
53965	29258181	To demonstrate the reactivation of mutant-p53 under PRIMA-1/APR-246 treatment, several points have been evaluated.	('mutant-p53', 'Var', (35, 45))	('PRIMA-1/APR-246', 'Gene', '145270', (52, 67))	('reactivation', 'MPA', (19, 31))	('PRIMA-1/APR-246', 'Gene', (52, 67))	('rat', 'Species', '10116', (10, 13))
53967	29258181	(2009) reported that both PRIMA-1 and APR-246 were converted in compounds, as MQ (methylene quinuclidinone), that reacted covalently with thiol groups of mutant, as well as wild-type p53.	('APR', 'Gene', '5366', (38, 41))	('methylene quinuclidinone', 'Chemical', '-', (82, 106))	('APR', 'Gene', (38, 41))	('thiol', 'Chemical', 'MESH:D013438', (138, 143))	('MQ', 'Chemical', '-', (78, 80))	('mutant', 'Var', (154, 160))
53969	29258181	Secondly, the effects on the p53 protein in mutant-p53 cells treated with PRIMA-1/APR-246, were assessed.	('mutant-p53', 'Var', (44, 54))	('PRIMA-1/APR-246', 'Gene', '145270', (74, 89))	('PRIMA-1/APR-246', 'Gene', (74, 89))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))
53971	29258181	Thirdly, the activity of p53 in cells with mutant-p53 treated with PRIMA-1/APR-246 has been explored.	('mutant-p53', 'Var', (43, 53))	('PRIMA-1/APR-246', 'Gene', '145270', (67, 82))	('PRIMA-1/APR-246', 'Gene', (67, 82))
53972	29258181	The restoration of transcriptional activity of mutant p53 has also been assessed.	('rat', 'Species', '10116', (9, 12))	('transcriptional activity', 'MPA', (19, 43))	('mutant', 'Var', (47, 53))	('p53', 'Gene', (54, 57))
53977	29258181	This dependency has been tested directly, introducing mutant-p53 protein previously treated with PRIMA-1 into cells without p53, using the Chariot protein transfer reagent: this introduction induced cell death, G2 cell cycle arrest, phosphorylation at Ser15, expression of Bax, PUMA, and Noxa, improvement of specific DNA binding, and/or caspases activation.	('G2', 'CellLine', 'CVCL:Z793', (211, 213))	('Bax', 'Gene', (273, 276))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('214', '231'))	('phosphorylation', 'biological_process', 'GO:0016310', ('233', '248'))	('arrest', 'Disease', 'MESH:D006323', (225, 231))	('caspases', 'Gene', (338, 346))	('Bax', 'Gene', '581', (273, 276))	('induced', 'Reg', (191, 198))	('Ser', 'cellular_component', 'GO:0005790', ('252', '255'))	('cell death', 'CPA', (199, 209))	('cell death', 'biological_process', 'GO:0008219', ('199', '209'))	('Ser15', 'Chemical', '-', (252, 257))	('caspases', 'Gene', '842', (338, 346))	('Noxa', 'Gene', '5366', (288, 292))	('DNA binding', 'molecular_function', 'GO:0003677', ('318', '329'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (214, 231))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('activation', 'PosReg', (347, 357))	('arrest', 'Disease', (225, 231))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('Noxa', 'Gene', (288, 292))	('DNA', 'cellular_component', 'GO:0005574', ('318', '321'))	('phosphorylation', 'MPA', (233, 248))	('improvement', 'PosReg', (294, 305))	('mutant-p53', 'Var', (54, 64))	('specific DNA binding', 'Interaction', (309, 329))
53980	29258181	Although mutant-p53-dependency appeared to be verified in five studies for breast cancer and four studies for thyroid cancer, the conclusions must be nuanced because of several results were obtained using the same cell lines and by the same team (, and, respectively).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('thyroid cancer', 'Phenotype', 'HP:0002890', (110, 124))	('thyroid cancer', 'Disease', (110, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('thyroid cancer', 'Disease', 'MESH:D013964', (110, 124))	('mutant-p53-dependency', 'Var', (9, 30))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
53981	29258181	On the contrary, the mutant-p53-independency of PRIMA-1/APR-246 effects in myeloma cells were verified by three different teams, using varied cell lines.	('myeloma', 'Disease', (75, 82))	('PRIMA-1/APR-246', 'Gene', '145270', (48, 63))	('PRIMA-1/APR-246', 'Gene', (48, 63))	('mutant-p53-independency', 'Var', (21, 44))	('myeloma', 'Disease', 'MESH:D009101', (75, 82))
53982	29258181	Finally, it clearly appeared that PRIMA-1/APR-246 are tumor suppressor molecules, inducing apoptosis by the caspases activation in varied mutant-p53 cells.	('PRIMA-1/APR-246', 'Gene', (34, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('apoptosis', 'CPA', (91, 100))	('mutant-p53', 'Var', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('caspases', 'Gene', (108, 116))	('inducing', 'PosReg', (82, 90))	('PRIMA-1/APR-246', 'Gene', '145270', (34, 49))	('tumor', 'Disease', (54, 59))	('activation', 'PosReg', (117, 127))	('caspases', 'Gene', '842', (108, 116))
53983	29258181	If the proof of its mutant-p53 reactivation property has also been made in several cancer models, the variability of the results incites to look forward other elements likely to influence the effects of PRIMA-1/APR-246, as a cell content dependency, or unexpected cytotoxic mechanisms.	('PRIMA-1/APR-246', 'Gene', '145270', (203, 218))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PRIMA-1/APR-246', 'Gene', (203, 218))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutant-p53', 'Var', (20, 30))	('cancer', 'Disease', (83, 89))
53984	29258181	The possibility of effects of PRIMA-1/APR-246 that were different from apoptosis and mutant-p53 reactivation has been underlined by the use of cell lines without p53 (p53-null), or with a knock-down of p53 (p53-KD).	('knock-down', 'Var', (188, 198))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('PRIMA-1/APR-246', 'Gene', '145270', (30, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('mutant-p53', 'Var', (85, 95))	('PRIMA-1/APR-246', 'Gene', (30, 45))
53997	29258181	On the contrary, the conversion of TrxR1 enzyme into a dedicated NADPH oxidase produced an increase oxidant activity.	('increase oxidant activity', 'Phenotype', 'HP:0025464', (91, 116))	('conversion', 'Var', (21, 31))	('TrxR1', 'Gene', (35, 40))	('increase', 'PosReg', (91, 99))	('TrxR1', 'Gene', '7296', (35, 40))	('NADPH oxidase', 'molecular_function', 'GO:0016174', ('65', '78'))	('NADPH oxidase', 'molecular_function', 'GO:0008753', ('65', '78'))	('oxidant activity', 'MPA', (100, 116))
54000	29258181	(2009) observed that APR-246 causes increased oxidation in a mutant p53-dependent manner.	('APR', 'Gene', (21, 24))	('APR', 'Gene', '5366', (21, 24))	('oxidation', 'MPA', (46, 55))	('p53-dependent', 'Gene', (68, 81))	('mutant', 'Var', (61, 67))
54001	29258181	The implication of mutant p53 proteins in the redox effects of APR-246 has been recently reported by Liu et al.	('APR', 'Gene', '5366', (63, 66))	('APR', 'Gene', (63, 66))	('p53', 'Gene', (26, 29))	('redox effects', 'MPA', (46, 59))	('mutant', 'Var', (19, 25))	('proteins', 'Protein', (30, 38))
54002	29258181	(2017), considering that mutant p53 sensitized tumor cells to APR-246 induced oxidative stress, inhibiting the glutathione synthesis through the inhibition of system xc.	('mutant', 'Var', (25, 31))	('oxidative stress', 'Phenotype', 'HP:0025464', (78, 94))	('APR', 'Gene', '5366', (62, 65))	('APR', 'Gene', (62, 65))	('system xc', 'Enzyme', (159, 168))	('glutathione synthesis', 'MPA', (111, 132))	('p53', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('glutathione', 'Chemical', 'MESH:D005978', (111, 122))	('oxidative stress', 'MPA', (78, 94))	('inhibiting', 'NegReg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('glutathione synthesis', 'biological_process', 'GO:0006750', ('111', '132'))	('sensitized', 'Reg', (36, 46))	('tumor', 'Disease', (47, 52))	('inhibition', 'NegReg', (145, 155))
54009	29258181	(2016), knocking-down CHOP, a specific factor mediating the ER stress-induced apoptosis, that led to a significant cytotoxicity decrease in p53-null cells.	('CHOP', 'Gene', '1649', (22, 26))	('ER stress-induced apoptosis', 'biological_process', 'GO:0070059', ('60', '87'))	('knocking-down', 'Var', (8, 21))	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('CHOP', 'Gene', (22, 26))	('decrease', 'NegReg', (128, 136))	('cytotoxicity', 'Disease', (115, 127))
54022	29258181	(2012), which demonstrated no effect of PRIMA-1 on thyroid cancer cells without p53, but with wild-type p73.	('p53', 'Var', (80, 83))	('thyroid cancer', 'Phenotype', 'HP:0002890', (51, 65))	('p73', 'Gene', '7161', (104, 107))	('thyroid cancer', 'Disease', 'MESH:D013964', (51, 65))	('p73', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rat', 'Species', '10116', (21, 24))	('thyroid cancer', 'Disease', (51, 65))
54027	29258181	Basically, the chemotherapy drugs which lead to DNA damages and interfere with DNA synthesis were supposed to trigger p53 activation, and thus, to synergize with PRIMA-1/APR-246 in mutant-p53 cells.	('mutant-p53', 'Var', (181, 191))	('p53', 'Gene', (118, 121))	('DNA synthesis', 'biological_process', 'GO:0071897', ('79', '92'))	('PRIMA-1/APR-246', 'Gene', '145270', (162, 177))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('interfere', 'NegReg', (64, 73))	('activation', 'PosReg', (122, 132))	('PRIMA-1/APR-246', 'Gene', (162, 177))	('DNA synthesis', 'MPA', (79, 92))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
54033	29258181	Similarly, with topo-isomerase inhibitors, the results of their association with PRIMA-1/APR-246 varied as a synergic effect was obtained in lung, colon and osteosarcoma cell lines with camptothecin, but not in pancreatic cancer with irinotecan.	('PRIMA-1/APR-246', 'Gene', (81, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('pancreatic cancer', 'Disease', (211, 228))	('camptothecin', 'Chemical', 'MESH:D002166', (186, 198))	('colon and osteosarcoma', 'Disease', 'MESH:D012516', (147, 169))	('irinotecan', 'Chemical', 'MESH:D000077146', (234, 244))	('pancreatic cancer', 'Disease', 'MESH:D010190', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('PRIMA-1/APR-246', 'Gene', '145270', (81, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (211, 228))	('camptothecin', 'Var', (186, 198))	('association', 'Interaction', (64, 75))
54042	29258181	In pre-clinical studies, 3-BrPA, a halogenated pyruvate derivative and an alkylating agent, depleting the cellular ATP pool and inhibiting glycolysis, has been associated to PRIMA-1.	('glycolysis', 'MPA', (139, 149))	('3-BrPA', 'Var', (25, 31))	('cellular ATP pool', 'MPA', (106, 123))	('pyruvate', 'Chemical', 'MESH:D019289', (47, 55))	('glycolysis', 'biological_process', 'GO:0006096', ('139', '149'))	('3-BrPA', 'Chemical', '-', (25, 31))	('depleting', 'NegReg', (92, 101))	('PRIMA-1', 'Disease', (174, 181))	('inhibiting', 'NegReg', (128, 138))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))
54043	29258181	The association led to an enhanced anti-proliferative effect in mutant KRAS (Kirsten rat sarcoma viral oncogene homolog) lung cancer and melanoma cells, and in mutant-p53 bladder cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('enhanced', 'PosReg', (26, 34))	('rat', 'Species', '10116', (85, 88))	('rat', 'Species', '10116', (47, 50))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('mutant', 'Var', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('lung cancer', 'Disease', (121, 132))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('mutant-p53', 'Var', (160, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('KRAS', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('anti-proliferative effect', 'CPA', (35, 60))
54046	29258181	APR-246 sensitized to irradiation the mutant-p53, and p53-null cells, but had no impact on wt-p53 cells.	('APR', 'Gene', (0, 3))	('APR', 'Gene', '5366', (0, 3))	('sensitized', 'Reg', (8, 18))	('mutant-p53', 'Var', (38, 48))
54048	29258181	Combined with the PARP-inhibitor, olaparib, APR-246 sensitized lung cancer cell lines to the targeted therapy, independently of p53 status; besides, the combination restored the sensitivity to olaparib in mutant-p53 cells that were previously olaparib-resistant.	('APR', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('sensitivity', 'MPA', (178, 189))	('olaparib', 'Chemical', 'MESH:C531550', (34, 42))	('restored', 'PosReg', (165, 173))	('APR', 'Gene', '5366', (44, 47))	('lung cancer', 'Disease', (63, 74))	('mutant-p53', 'Var', (205, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('olaparib', 'Chemical', 'MESH:C531550', (193, 201))	('olaparib', 'Chemical', 'MESH:C531550', (243, 251))
54049	29258181	In breast cancer cell lines, the combination had a cytotoxic synergic effect in mutant p53 cells.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cytotoxic synergic effect', 'MPA', (51, 76))
54050	29258181	With the mTOR inhibitor, rapamycin, APR-246 had a cytotoxic synergic effect in a mutant-p53 AML cell line and in primary cultures.	('AML', 'Disease', 'MESH:D015470', (92, 95))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (9, 13))	('mutant-p53', 'Var', (81, 91))	('cytotoxic', 'CPA', (50, 59))	('APR', 'Gene', '5366', (36, 39))	('AML', 'Phenotype', 'HP:0004808', (92, 95))	('AML', 'Disease', (92, 95))	('APR', 'Gene', (36, 39))
54052	29258181	Strikingly and similarly, p53 reactivation by APR-246 also broke intrinsic and acquired resistance and synergized with the MEK inhibitor pimasertib to induce massive apoptosis in NRAS-mutant melanoma cells with wild-type or mutant-p53, identifying MITF/Bcl-2 as a key mechanism underlying resistance of mutant-NRAS melanoma cells to apoptosis by MEK inhibitors and propose clinically relevant drug combinations able to prevent or reverse it.	('Bcl-2', 'molecular_function', 'GO:0015283', ('253', '258'))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanoma', 'Disease', (191, 199))	('NRAS', 'Gene', '4893', (310, 314))	('p53', 'Gene', (26, 29))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('broke', 'NegReg', (59, 64))	('Bcl-2', 'Gene', '596', (253, 258))	('MITF', 'Gene', (248, 252))	('pimasertib', 'Chemical', 'MESH:C550600', (137, 147))	('melanoma', 'Disease', 'MESH:D008545', (315, 323))	('APR', 'Gene', (46, 49))	('MEK', 'Gene', '5609', (123, 126))	('MEK', 'Gene', '5609', (346, 349))	('apoptosis', 'biological_process', 'GO:0097194', ('333', '342'))	('apoptosis', 'biological_process', 'GO:0006915', ('333', '342'))	('NRAS', 'Gene', '4893', (179, 183))	('MEK', 'Gene', (123, 126))	('MEK', 'Gene', (346, 349))	('NRAS', 'Gene', (310, 314))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('induce', 'Reg', (151, 157))	('mutant-p53', 'Var', (224, 234))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('melanoma', 'Disease', (315, 323))	('Bcl-2', 'Gene', (253, 258))	('APR', 'Gene', '5366', (46, 49))	('NRAS', 'Gene', (179, 183))	('MITF', 'Gene', '4286', (248, 252))	('intrinsic', 'MPA', (65, 74))
54053	29258181	Combined with a tyrosine kinase inhibitor, erlotinib, PRIMA-1 synergized in mutant-p53 head and neck cancer and pancreas cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutant-p53', 'Var', (76, 86))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('25', '41'))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('pancreas cancer', 'Disease', (112, 127))	('erlotinib', 'Chemical', 'MESH:D000069347', (43, 52))	('pancreas cancer', 'Disease', 'MESH:D010190', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('neck', 'cellular_component', 'GO:0044326', ('96', '100'))	('pancreas cancer', 'Phenotype', 'HP:0002894', (112, 127))	('head and neck cancer', 'Disease', 'MESH:D006258', (87, 107))
54054	29258181	The anti-tumoral effect of PRIMA-1/APR-246 was enhanced when combined to the proteasome inhibitor, bortezomib, in mutant-p53 pancreas cancer cells, in wt-p53 Waldenstrom cells and in myeloma cells, independently of p53 status, with a restoration to sensitivity in bortezomib-resistant cells.	('proteasome', 'cellular_component', 'GO:0000502', ('77', '87'))	('rat', 'Species', '10116', (239, 242))	('mutant-p53', 'Var', (114, 124))	('myeloma', 'Disease', 'MESH:D009101', (183, 190))	('tumor', 'Disease', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('combined', 'Interaction', (61, 69))	('PRIMA-1/APR-246', 'Gene', '145270', (27, 42))	('pancreas cancer', 'Disease', 'MESH:D010190', (125, 140))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('enhanced', 'PosReg', (47, 55))	('pancreas cancer', 'Phenotype', 'HP:0002894', (125, 140))	('myeloma', 'Disease', (183, 190))	('pancreas cancer', 'Disease', (125, 140))	('bortezomib', 'Chemical', 'MESH:D000069286', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PRIMA-1/APR-246', 'Gene', (27, 42))	('bortezomib', 'Chemical', 'MESH:D000069286', (264, 274))	('proteasome', 'molecular_function', 'GO:0004299', ('77', '87'))
54055	29258181	According to the essential role of ROS production and glutathione content in PRIMA-1/APR-246 efficacy, associations between inhibitors of glutathione synthesis or cysteine transporter and PRIMA-1/APR-246 appear particularly relevant: thus, an inhibitor of the system xc, (cystine/glutamate antiporter), sulfasalazine, had a synergic anti-tumor effect with APR-246 in mutant p53 oesophageal adenocarcinoma cells and xenografts.	('APR', 'Gene', '5366', (85, 88))	('APR', 'Gene', '5366', (356, 359))	('APR', 'Gene', '5366', (196, 199))	('tumor', 'Disease', (338, 343))	('glutathione', 'Chemical', 'MESH:D005978', (138, 149))	('PRIMA-1/APR-246', 'Gene', '145270', (77, 92))	('mutant', 'Var', (367, 373))	('PRIMA-1/APR-246', 'Gene', '145270', (188, 203))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('APR', 'Gene', (85, 88))	('APR', 'Gene', (356, 359))	('APR', 'Gene', (196, 199))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (379, 404))	('oesophageal adenocarcinoma', 'Disease', (378, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (378, 404))	('PRIMA-1/APR-246', 'Gene', (77, 92))	('p53', 'Gene', (374, 377))	('PRIMA-1/APR-246', 'Gene', (188, 203))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('sulfasalazine', 'Chemical', 'MESH:D012460', (303, 316))	('glutathione', 'Chemical', 'MESH:D005978', (54, 65))	('cystine', 'Chemical', 'MESH:D003553', (272, 279))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))	('glutathione synthesis', 'biological_process', 'GO:0006750', ('138', '159'))
54058	29258181	In vivo, an increase of the anti-tumor impacts has been observed when PRIMA-1 was associated to Deazaneplanocin A (a negative regulator of polycomb group actions that inhibits histone methyltransferase activity) in mutant-p53 thyroid cancer xenografts, and with 2aG4 (a monoclonal anti-body that binds specifically to the surface of tumor blood vessels and disrupts tumor vasculature) in breast cancer xenografts.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (388, 401))	('histone methyltransferase activity', 'MPA', (176, 210))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('thyroid cancer', 'Disease', 'MESH:D013964', (226, 240))	('histone methyltransferase activity', 'molecular_function', 'GO:0042054', ('176', '210'))	('breast cancer', 'Disease', 'MESH:D001943', (388, 401))	('increase', 'PosReg', (12, 20))	('breast cancer', 'Disease', (388, 401))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', (33, 38))	('thyroid cancer', 'Phenotype', 'HP:0002890', (226, 240))	('histone methyltransferase activity', 'molecular_function', 'GO:0008469', ('176', '210'))	('tumor', 'Disease', (366, 371))	('disrupts tumor', 'Disease', (357, 371))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('mutant-p53', 'Var', (215, 225))	('tumor', 'Disease', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('disrupts tumor', 'Disease', 'MESH:D019958', (357, 371))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('thyroid cancer', 'Disease', (226, 240))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('Deazaneplanocin A', 'Chemical', '-', (96, 113))	('inhibits', 'NegReg', (167, 175))
54059	29258181	Altogether, these multiple efficient associations between PRIMA-1 or APR-246 and anti-cancer treatments make conceivable to treat many malignant diseases, and in particular, tumor sub-types, currently associated with poor prognosis because of genetic profile (mutant p53, KRAS, or BRAF) or acquired resistance to treatment (doxorubicin, cisplatin, olaparib, bortezomib, or vemurafenib).	('APR', 'Gene', '5366', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('bortezomib', 'Chemical', 'MESH:D000069286', (358, 368))	('cisplatin', 'Disease', (337, 346))	('APR', 'Gene', (69, 72))	('olaparib', 'Chemical', 'MESH:C531550', (348, 356))	('doxorubicin', 'Chemical', 'MESH:D004317', (324, 335))	('vemurafenib', 'Chemical', 'MESH:D000077484', (373, 384))	('cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutant', 'Var', (260, 266))	('tumor', 'Disease', (174, 179))	('malignant diseases', 'Disease', (135, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (337, 346))	('KRAS', 'CPA', (272, 276))	('BRAF', 'Gene', '673', (281, 285))	('BRAF', 'Gene', (281, 285))	('p53', 'Gene', (267, 270))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('malignant diseases', 'Disease', 'MESH:D009369', (135, 153))
54061	29258181	PRIMA-1 as well as APR-246 triggers an upregulation of genes involved in cell cycle control and apoptosis in mutant-p53 and wild-type p53 cancer cells.	('APR', 'Gene', (19, 22))	('cancer', 'Disease', (138, 144))	('cell cycle control', 'biological_process', 'GO:1901987', ('73', '91'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('upregulation', 'PosReg', (39, 51))	('cell cycle', 'CPA', (73, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('mutant-p53', 'Var', (109, 119))	('APR', 'Gene', '5366', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
54063	29258181	Combined with chemotherapies, ionizing radiations or targeted therapies, PRIMA-1 and APR-246 could offer new perspectives to treat the more aggressive tumor sub-types such as mutant-cKIT metastatic melanoma, HPV (Human papillomavirus)-positive head and neck squamous cell carcinoma, and anaplastic thyroid cancer.	('Human papillomavirus', 'Species', '10566', (213, 233))	('APR', 'Gene', '5366', (85, 88))	('aggressive tumor', 'Disease', 'MESH:D001523', (140, 156))	('ionizing radiations', 'Disease', 'MESH:D004194', (30, 49))	('ionizing radiations', 'Disease', (30, 49))	('APR', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (287, 312))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('aggressive tumor', 'Disease', (140, 156))	('mutant-cKIT', 'Var', (175, 186))	('neck squamous cell carcinoma', 'Disease', (253, 281))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (287, 312))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (253, 281))	('HPV', 'Species', '10566', (208, 211))	('thyroid cancer', 'Phenotype', 'HP:0002890', (298, 312))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('neck', 'cellular_component', 'GO:0044326', ('253', '257'))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('anaplastic thyroid cancer', 'Disease', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
54065	29258181	Three clinical trials are currently recruiting, with the objectives to test the safety and efficacy of APR-246 treatment in advanced oesophageal carcinoma (NCT02999893), high grade serous ovarian cancer (NCT02098343), and mutant p53 hematologic myeloid malignant disease (NCT03072043).	('serous ovarian cancer', 'Disease', 'MESH:D010051', (181, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('hematologic myeloid malignant disease', 'Disease', 'MESH:D019337', (233, 270))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (133, 154))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (133, 154))	('p53', 'Gene', (229, 232))	('oesophageal carcinoma', 'Disease', (133, 154))	('APR', 'Gene', '5366', (103, 106))	('mutant', 'Var', (222, 228))	('APR', 'Gene', (103, 106))	('serous ovarian cancer', 'Disease', (181, 202))	('hematologic myeloid malignant disease', 'Disease', (233, 270))
54075	28442076	Lung resection is associated with marked reductions in exercise capacity (i.e., peak rate of oxygen consumption [VO2peak]) and health-related quality of life (HRQoL).	('O2', 'Chemical', 'MESH:D010100', (114, 116))	('peak rate of oxygen consumption', 'MPA', (80, 111))	('reductions in exercise capacity', 'Phenotype', 'HP:0003546', (41, 72))	('reductions', 'NegReg', (41, 51))	('exercise', 'MPA', (55, 63))	('Lung resection', 'Var', (0, 14))	('health-related quality of life', 'CPA', (127, 157))
54163	27471561	Because no proteins were significantly differentially expressed after FDR correction when AA and CA tumor samples were compared, overrepresentation analysis was used to highlight any qualitative differences between these groups (Figure 3).	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('correction', 'Var', (74, 84))
54187	27471561	Inhibition of fatty acid synthase suppressed the growth of multiple prostate cancer cell lines, including castration-resistant prostate cancer cells, via both androgen receptor-dependent and independent mechanisms.	('multiple prostate cancer', 'Disease', (59, 83))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('suppressed', 'NegReg', (34, 44))	('prostate cancer', 'Disease', (127, 142))	('fatty acid synthase suppressed', 'Phenotype', 'HP:0003524', (14, 44))	('Inhibition', 'Var', (0, 10))	('growth', 'MPA', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))	('multiple prostate cancer', 'Disease', 'MESH:D011471', (59, 83))
54189	27471561	Theories to explain the role of fatty acid synthase in tumor survival include 1) the synthesis of fatty acid chains generates oxidative power in an anaerobic environment to balance redox conditions; 2) the activation of some oncogenes occurs by palmitoylation; 3) fatty acid synthase alters membrane phospholipid composition and thus affects signaling; and 4) fatty acid synthase may help preserve function of the endoplasmic reticulum (reviewed in).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('oncogenes', 'Gene', (225, 234))	('alters', 'Reg', (284, 290))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('414', '435'))	('fatty acid', 'Chemical', 'MESH:D005227', (98, 108))	('fatty acid', 'Chemical', 'MESH:D005227', (360, 370))	('phospholipid', 'Chemical', 'MESH:D010743', (300, 312))	('fatty acid', 'Chemical', 'MESH:D005227', (264, 274))	('signaling', 'MPA', (342, 351))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('function', 'MPA', (398, 406))	('membrane', 'cellular_component', 'GO:0016020', ('291', '299'))	('signaling', 'biological_process', 'GO:0023052', ('342', '351'))	('palmitoylation', 'Var', (245, 259))	('fatty acid', 'Chemical', 'MESH:D005227', (32, 42))	('affects', 'Reg', (334, 341))	('activation', 'PosReg', (206, 216))	('men', 'Species', '9606', (165, 168))	('synthesis', 'biological_process', 'GO:0009058', ('85', '94'))	('membrane phospholipid composition', 'MPA', (291, 324))	('tumor', 'Disease', (55, 60))
54228	27471561	Altered integrin expression is well-documented in prostate cancer and includes not only downregulation, but aberrant expression patterns.	('downregulation', 'NegReg', (88, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('integrin', 'Protein', (8, 16))	('prostate cancer', 'Disease', (50, 65))	('aberrant', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('men', 'Species', '9606', (40, 43))	('Altered', 'Reg', (0, 7))	('expression patterns', 'MPA', (117, 136))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
54276	33474631	A list of key questions regarding lung NENs was generated concerning diagnosis, prognosis, classification, tumor subtypes, carcinoid, small cell carcinoma, large cell neuroendocrine carcinoma, variant subtype, prediction, immunohistochemistry, clinical implications, genetic/epigenetic changes, and development of biomolecular models.	('NENs', 'Phenotype', 'HP:0100634', (39, 43))	('small cell carcinoma', 'Disease', 'MESH:D018288', (134, 154))	('variant', 'Var', (193, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor', 'Disease', (107, 112))	('carcinoid', 'Phenotype', 'HP:0100570', (123, 132))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (167, 191))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('small cell carcinoma', 'Disease', (134, 154))	('carcinoid', 'Disease', (123, 132))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (134, 154))	('carcinoid', 'Disease', 'MESH:D002276', (123, 132))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (167, 191))	('neuroendocrine carcinoma', 'Disease', (167, 191))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('large cell neuroendocrine carcinoma', 'Phenotype', 'HP:0030360', (156, 191))
54283	33474631	In SCLC, combined variants are defined by the association with any other subtype of non-small cell carcinoma (NSCC) (LCNEC, adenocarcinoma, squamous cell carcinoma, sarcomatoid carcinoma, or large cell carcinoma), while combined LCNEC shows adjuncts exclusively of other NSCC subtypes.	('carcinoma', 'Disease', (154, 163))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (88, 108))	('LCNEC', 'Phenotype', 'HP:0030360', (229, 234))	('carcinoma', 'Disease', (202, 211))	('sarcomatoid carcinoma', 'Disease', (165, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (165, 186))	('association', 'Interaction', (46, 57))	('carcinoma', 'Disease', (177, 186))	('LCNEC', 'Phenotype', 'HP:0030360', (117, 122))	('carcinoma', 'Disease', 'MESH:D009369', (129, 138))	('carcinoma', 'Disease', 'MESH:D009369', (99, 108))	('variants', 'Var', (18, 26))	('carcinoma', 'Disease', 'MESH:D009369', (154, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('adenocarcinoma', 'Disease', (124, 138))	('carcinoma', 'Disease', 'MESH:D009369', (202, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('non-small cell carcinoma', 'Disease', (84, 108))	('SCLC', 'Phenotype', 'HP:0030357', (3, 7))	('carcinoma', 'Disease', 'MESH:D009369', (177, 186))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (165, 186))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('SCLC', 'Gene', '7864', (3, 7))	('SCLC', 'Gene', (3, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (191, 211))	('carcinoma', 'Disease', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('carcinoma', 'Disease', (99, 108))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (84, 108))
54308	33474631	In a case series examined by Swarts et al., 7/55 (13%) of pulmonary carcinoids harbored MEN1 mutations associated with reduced mRNA expression and poor prognosis.	('carcinoid', 'Phenotype', 'HP:0100570', (68, 77))	('carcinoids', 'Phenotype', 'HP:0100570', (68, 78))	('mutations', 'Var', (93, 102))	('mRNA expression', 'MPA', (127, 142))	('pulmonary carcinoids', 'Disease', 'MESH:D002276', (58, 78))	('pulmonary carcinoids', 'Phenotype', 'HP:0030445', (58, 78))	('pulmonary carcinoids', 'Disease', (58, 78))	('MEN1', 'Gene', (88, 92))	('MEN1', 'Gene', '4221', (88, 92))	('reduced', 'NegReg', (119, 126))
54309	33474631	Also, in mutation-absent tumors, low MEN1 gene expression was correlated with an adverse disease outcome.	('low', 'NegReg', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutation-absent', 'Var', (9, 24))	('MEN1', 'Gene', (37, 41))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('MEN1', 'Gene', '4221', (37, 41))	('expression', 'MPA', (47, 57))
54311	33474631	On the other hand, Mucin 6 (MUC6) and spectrin alpha erythrocytic 1 (SPTA1) were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively.	('spectrin alpha erythrocytic 1', 'Gene', (38, 67))	('MUC6', 'Gene', (28, 32))	('spectrin', 'cellular_component', 'GO:0008091', ('38', '46'))	('mutated', 'Var', (93, 100))	('SPTA1', 'Gene', (69, 74))	('MUC6', 'Gene', '4588', (28, 32))	('spectrin alpha erythrocytic 1', 'Gene', '6708', (38, 67))	('Mucin 6', 'Gene', (19, 26))	('Mucin 6', 'Gene', '4588', (19, 26))	('SPTA1', 'Gene', '6708', (69, 74))
54317	33474631	The mutation frequency increases with the tumor's higher grade or biological malignancy as heralded in other lung cancer subtypes.	('malignancy', 'Disease', (77, 87))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('tumor', 'Disease', (42, 47))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('malignancy', 'Disease', 'MESH:D009369', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
54318	33474631	In this regard, in a paper by Vollbrecht et al., the SMAD family member 4 (SMAD4) mutation was found in TC subtype, while KIT proto-oncogene receptor tyrosine kinase (c-KIT), phosphatase and tensin homolog (PTEN), HNF1 homeobox A (HNF1A), and smoothened frizzled class receptor (SMO) were altered in AC.	('SMAD', 'Gene', (53, 57))	('SMAD', 'Gene', '4089;4089', (75, 79))	('AC', 'Chemical', '-', (300, 302))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('175', '205'))	('phosphatase and tensin homolog', 'Gene', '5728', (175, 205))	('HNF1 homeobox A', 'Gene', '6927', (214, 229))	('mutation', 'Var', (82, 90))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', (122, 165))	('SMAD', 'Gene', (75, 79))	('TC', 'Chemical', '-', (104, 106))	('HNF1A', 'Gene', '6927', (231, 236))	('KIT', 'molecular_function', 'GO:0005020', ('169', '172'))	('KIT', 'molecular_function', 'GO:0005020', ('122', '125'))	('HNF1A', 'Gene', (231, 236))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', '3815', (122, 165))	('PTEN', 'Gene', (207, 211))	('phosphatase', 'molecular_function', 'GO:0016791', ('175', '186'))	('SMAD4', 'Gene', (75, 80))	('c-KIT', 'Gene', (167, 172))	('HNF1 homeobox A', 'Gene', (214, 229))	('c-KIT', 'Gene', '3815', (167, 172))	('altered', 'Reg', (289, 296))	('PTEN', 'Gene', '5728', (207, 211))	('AC', 'Phenotype', 'HP:0030446', (300, 302))	('SMAD', 'Gene', '4089;4089', (53, 57))	('SMAD4', 'Gene', '4089', (75, 80))
54320	33474631	Of note, JAK3 mutations were also found in LCNEC of the thymus, an organ where the classification criteria of NENs are the same as in the lung, which secondarily developed from preexisting AC.	('LCNEC', 'Phenotype', 'HP:0030360', (43, 48))	('JAK3', 'Gene', (9, 13))	('JAK3', 'Gene', '3718', (9, 13))	('AC', 'Phenotype', 'HP:0030446', (189, 191))	('NENs', 'Phenotype', 'HP:0100634', (110, 114))	('found', 'Reg', (34, 39))	('JAK', 'molecular_function', 'GO:0004713', ('9', '12'))	('AC', 'Chemical', '-', (189, 191))	('LCNEC of the thymus', 'Disease', (43, 62))	('mutations', 'Var', (14, 23))
54321	33474631	In experimental models, inhibition of NOTCH gene signaling induces lung progenitor cells to form pulmonary neuroendocrine cells, from which tumors resembling early-stage SCLC grew in immunodeficient mice via RB and TP53 simultaneous blockage and transcriptome enrichment with cell cycle-related RNAs.	('pulmonary neuroendocrine', 'Disease', (97, 121))	('pulmonary neuroendocrine', 'Disease', 'MESH:D018358', (97, 121))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('SCLC', 'Phenotype', 'HP:0030357', (170, 174))	('inhibition', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TC', 'Chemical', '-', (40, 42))	('tumors', 'Disease', (140, 146))	('induces', 'Reg', (59, 66))	('SCLC', 'Gene', '7864', (170, 174))	('SCLC', 'Gene', (170, 174))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('mice', 'Species', '10090', (199, 203))	('RB', 'Gene', '19645', (208, 210))	('NOTCH gene', 'Gene', (38, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('276', '286'))	('immunodeficient', 'Disease', 'MESH:D007153', (183, 198))	('immunodeficient', 'Disease', (183, 198))
54323	33474631	SCLC-like LCNEC share molecular alterations with SCLC and show RB1, tumor protein P53 (TP53), CREB binding protein (CREBBP), E1A binding protein P300 (EP300), and lysine methyltransferase 2A (KMT2A) gene mutations alongside V-myc myelocytomatosis viral oncogene homolog 1 (MYCL1) and FGFR1 amplifications.	('SCLC', 'Gene', '7864', (0, 4))	('myelocytomatosis', 'Disease', 'None', (230, 246))	('lysine methyltransferase 2A', 'Gene', '4297', (163, 190))	('E1A binding protein P300', 'Gene', '2033', (125, 149))	('FGFR1', 'Gene', '2260', (284, 289))	('EP300', 'Gene', (151, 156))	('CREB binding', 'molecular_function', 'GO:0008140', ('94', '106'))	('MYCL1', 'Gene', (273, 278))	('FGFR', 'molecular_function', 'GO:0005007', ('284', '288'))	('CREBBP', 'Gene', '1387', (116, 122))	('CREB binding protein', 'Gene', '1387', (94, 114))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('MYCL1', 'Gene', '4610', (273, 278))	('methyltransferase 2', 'molecular_function', 'GO:0043851', ('170', '189'))	('KMT2A', 'Gene', (192, 197))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('binding', 'molecular_function', 'GO:0005488', ('129', '136'))	('FGFR1', 'Gene', (284, 289))	('SCLC', 'Phenotype', 'HP:0030357', (49, 53))	('mutations', 'Var', (204, 213))	('RB1, tumor protein P53', 'Gene', '5925;7157', (63, 85))	('lysine methyltransferase 2A', 'Gene', (163, 190))	('LCNEC', 'Phenotype', 'HP:0030360', (10, 15))	('myelocytomatosis', 'Disease', (230, 246))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('SCLC', 'Phenotype', 'HP:0030357', (0, 4))	('SCLC', 'Gene', '7864', (49, 53))	('SCLC', 'Gene', (49, 53))	('CREBBP', 'Gene', (116, 122))	('EP300', 'Gene', '2033', (151, 156))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('CREB binding protein', 'Gene', (94, 114))	('KMT2A', 'Gene', '4297', (192, 197))	('E1A binding protein P300', 'Gene', (125, 149))	('SCLC', 'Gene', (0, 4))
54324	33474631	NSCLC-like LCNEC exhibit cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion, transcription termination factor 1 (TTF1) amplifications, and Kelch-like ECH-associated protein 1 (KEAP1) and serine/threonine kinase 11 (STK11) mutations as observed in non-NE tumors.	('CDKN2A', 'Gene', '1029', (63, 69))	('Kelch-like ECH-associated protein 1', 'Gene', (143, 178))	('STK11', 'Gene', (219, 224))	('TTF1', 'Gene', (117, 121))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (25, 61))	('serine/threonine kinase 11', 'Gene', (191, 217))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('deletion', 'Var', (71, 79))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (25, 61))	('STK11', 'Gene', '6794', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('STK11', 'molecular_function', 'GO:0033868', ('219', '224'))	('tumors', 'Disease', (258, 264))	('KEAP1', 'Gene', '9817', (180, 185))	('transcription termination factor 1', 'Gene', '7270', (81, 115))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('25', '58'))	('KEAP1', 'Gene', (180, 185))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('mutations', 'Var', (226, 235))	('LCNEC', 'Phenotype', 'HP:0030360', (11, 16))	('TTF1', 'Gene', '7270', (117, 121))	('CDKN2A', 'Gene', (63, 69))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('42', '58'))	('transcription termination factor 1', 'Gene', (81, 115))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('ECH', 'molecular_function', 'GO:0004300', ('154', '157'))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (143, 178))	('serine/threonine kinase 11', 'Gene', '6794', (191, 217))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('NSCLC', 'Disease', (0, 5))
54325	33474631	Finally, carcinoid-like LCNEC bear MEN1 mutations.	('MEN1', 'Gene', '4221', (35, 39))	('MEN1', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('carcinoid', 'Phenotype', 'HP:0100570', (9, 18))	('LCNEC', 'Phenotype', 'HP:0030360', (24, 29))	('carcinoid', 'Disease', (9, 18))	('carcinoid', 'Disease', 'MESH:D002276', (9, 18))
54329	33474631	Cluster 2 included 14 AC and eight LCNEC showing intermediate features: inactivation of TP53, 40.9%; MEN1, 22.7%; and RB1, 18.2%.	('AC', 'Chemical', '-', (22, 24))	('RB1', 'Gene', (118, 121))	('MEN1', 'Gene', (101, 105))	('LCNEC', 'Phenotype', 'HP:0030360', (35, 40))	('MEN1', 'Gene', '4221', (101, 105))	('inactivation', 'Var', (72, 84))	('RB1', 'Gene', '5925', (118, 121))	('AC', 'Phenotype', 'HP:0030446', (22, 24))	('TP53', 'Protein', (88, 92))
54330	33474631	Cluster 3 comprehended 20 AC and four LCNEC lacking RB1 alterations and having frequent MEN1 (37.5%) and TP53 mutations (16.7%).	('AC', 'Chemical', '-', (26, 28))	('RB1', 'Gene', (52, 55))	('mutations', 'Var', (110, 119))	('alterations', 'Var', (56, 67))	('RB1', 'Gene', '5925', (52, 55))	('TP53', 'Gene', (105, 109))	('MEN1', 'Gene', (88, 92))	('LCNEC', 'Phenotype', 'HP:0030360', (38, 43))	('MEN1', 'Gene', '4221', (88, 92))	('lacking', 'NegReg', (44, 51))	('AC', 'Phenotype', 'HP:0030446', (26, 28))
54332	33474631	performed capture-based ultra-deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC, revealing a molecular signature consisting of RUNX family transcription factor 1 (RUNX1), Erb-B2 receptor tyrosine kinase 4 (ERBB4), breast cancer 1 (BRCA1), and EPH receptor A3 (EPHA3), distinctively mutated in LCNEC.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('LCNEC', 'Phenotype', 'HP:0030360', (332, 337))	('EPHA3', 'Gene', (299, 304))	('transcription', 'biological_process', 'GO:0006351', ('178', '191'))	('ERBB4', 'Gene', '2066', (245, 250))	('ERBB4', 'Gene', (245, 250))	('tumor', 'Disease', (58, 63))	('EPHA3', 'Gene', '2042', (299, 304))	('mutated', 'Var', (321, 328))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('transcription factor', 'molecular_function', 'GO:0000981', ('178', '198'))	('RUNX1', 'Gene', (202, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('RUNX1', 'Gene', '861', (202, 207))	('LCNEC', 'Disease', (332, 337))	('LCNEC', 'Phenotype', 'HP:0030360', (75, 80))	('EPH receptor A3', 'Gene', '2042', (282, 297))	('carcinoma', 'Disease', (93, 102))	('Erb-B2', 'Gene', (210, 216))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('BRCA1', 'Gene', '672', (270, 275))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (82, 102))	('EPH receptor A3', 'Gene', (282, 297))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('BRCA1', 'Gene', (270, 275))	('breast cancer 1', 'Gene', '672', (253, 268))	('breast cancer 1', 'Gene', (253, 268))	('SCLC', 'Gene', '7864', (114, 118))	('SCLC', 'Gene', (114, 118))	('Erb-B2', 'Gene', '2064', (210, 216))	('LCC', 'Phenotype', 'HP:0030360', (104, 107))	('carcinoma', 'Disease', 'MESH:D009369', (93, 102))
54333	33474631	A majority (60%) of LCNEC patients harbored copy number variations (CNVs).	('LCNEC', 'Chemical', '-', (20, 25))	('LCNEC', 'Disease', (20, 25))	('patients', 'Species', '9606', (26, 34))	('LCNEC', 'Phenotype', 'HP:0030360', (20, 25))	('copy number variations', 'Var', (44, 66))
54335	33474631	Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes, thus indicating converging effector mechanisms on carcinogenesis.	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('AKT', 'Gene', (45, 48))	('genetic alterations', 'Var', (13, 32))	('AKT', 'Gene', '207', (45, 48))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))
54339	33474631	In a study by George et al., two molecular subgroups of LCNECs were identified by means of comprehensive genomic and transcriptomic analyses, namely, "type I LCNEC" with biallelic TP53 and serine/threonine kinase 11/Kelch-like ECH-associated protein 1 (STK11/KEAP1) alterations (37%), and "type II LCNECs" enriched for biallelic inactivation of TP53 and RB1 (42%).	('serine/threonine kinase 11/Kelch-like ECH-associated protein 1', 'Gene', '6794;9817', (189, 251))	('STK11', 'Gene', '6794', (253, 258))	('RB1', 'Gene', (354, 357))	('RB1', 'Gene', '5925', (354, 357))	('TP53', 'Gene', (180, 184))	('KEAP1', 'Gene', '9817', (259, 264))	('alterations', 'Var', (266, 277))	('TP53', 'Gene', (345, 349))	('biallelic', 'Var', (319, 328))	('LCNEC', 'Phenotype', 'HP:0030360', (158, 163))	('LCNEC', 'Phenotype', 'HP:0030360', (298, 303))	('LCNEC', 'Phenotype', 'HP:0030360', (56, 61))	('KEAP1', 'Gene', (259, 264))	('STK11', 'Gene', (253, 258))
54342	33474631	SCLC typically has one of the highest mutation rates in cancers, bearing biallelic inactivation of TP53 and RB1 as a hallmark, quite uncommon in TC and AC.	('cancers', 'Disease', (56, 63))	('TP53', 'Gene', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('SCLC', 'Gene', '7864', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (0, 4))	('RB1', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('biallelic inactivation', 'Var', (73, 95))	('RB1', 'Gene', '5925', (108, 111))	('AC', 'Phenotype', 'HP:0030446', (152, 154))	('TC', 'Chemical', '-', (145, 147))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('SCLC', 'Gene', (0, 4))	('AC', 'Chemical', '-', (152, 154))
54351	33474631	Conversely, the longer the preclinical phase, the lower the clinical aggressiveness and the more prolonged the clinical course, in the premise that over time accumulation of diverse gene alterations would cause variably differentiated tumors with progenitor cell properties to arise.	('lower', 'NegReg', (50, 55))	('aggressiveness', 'Disease', 'MESH:D001523', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('alterations', 'Var', (187, 198))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('aggressiveness', 'Disease', (69, 83))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('cause', 'Reg', (205, 210))	('tumors', 'Disease', (235, 241))	('aggressiveness', 'Phenotype', 'HP:0000718', (69, 83))
54354	33474631	Of note, while both the cells of origin and the driver genetic alterations are likely to play a role in shaping ultimate lung cancer phenotypes, the relationship between ancestors and cancer subtypes is not necessarily one-to-one, inasmuch as different sets of genetic/epigenetic alterations could result in variably differentiated and/or reprogrammed cancer cells.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('alterations', 'Var', (63, 74))	('cancer', 'Disease', (352, 358))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('lung cancer', 'Disease', (121, 132))	('genetic/epigenetic alterations', 'Var', (261, 291))	('variably differentiated and/or', 'CPA', (308, 338))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('result in', 'Reg', (298, 307))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
54359	33474631	An early maturation block caused by crucial genetic events (e.g., biallelic inactivation of RB1 and TP53, NOTCH silencing) would promote horizontal or de novo/basal-like expansion and/or re/deprogramming of differentiated and/or progenitor cells.	('RB1', 'Gene', '5925', (92, 95))	('horizontal', 'CPA', (137, 147))	('promote', 'PosReg', (129, 136))	('TP53', 'Gene', (100, 104))	('re/deprogramming', 'CPA', (187, 203))	('NOTCH silencing', 'Var', (106, 121))	('RB1', 'Gene', (92, 95))	('TC', 'Chemical', '-', (108, 110))	('biallelic', 'Var', (66, 75))
54362	33474631	These tumors, which can be further modulated by additional genetic alterations giving rise to similar lesions still dominated by CSCs in pure or combined forms, might derive from primordial adult cells out of a neuroendocrine niche even capable of multidivergent evolution.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('pure', 'molecular_function', 'GO:0034023', ('137', '141'))	('alterations', 'Var', (67, 78))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
54367	33474631	An intermediate maturation block caused by a variety of gene alterations, such as TP53   RB1 mono/biallelic inactivation, NOTCH alteration, KRAS/LKB1/MEN1 mutation, MYC/MYCL/TERT/SDHA/RICTOR amplification, or epithelial-mesenchymal transition, would promote vertical or luminal-like mechanisms and/or re/deprogramming of differentiated cells giving rise to tumors enriched in progenitor cells.	('RB1', 'Gene', '5925', (89, 92))	('KRAS', 'Gene', '3845', (140, 144))	('RICTOR', 'Gene', '253260', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('TERT', 'Gene', (174, 178))	('MYC', 'Gene', (169, 172))	('TERT', 'Gene', '7015', (174, 178))	('MYCL', 'Gene', (169, 173))	('MYC', 'Gene', '4609', (165, 168))	('mono/biallelic inactivation', 'Var', (93, 120))	('LKB1', 'Gene', '6794', (145, 149))	('KRAS', 'Gene', (140, 144))	('vertical or luminal-like mechanisms', 'CPA', (258, 293))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('RICTOR', 'Gene', (184, 190))	('MEN1', 'Gene', '4221', (150, 154))	('MYCL', 'Gene', '4610', (169, 173))	('epithelial-mesenchymal transition', 'CPA', (209, 242))	('tumors', 'Disease', (357, 363))	('MEN1', 'Gene', (150, 154))	('MYC', 'Gene', '4609', (169, 172))	('tumors', 'Disease', 'MESH:D009369', (357, 363))	('RB1', 'Gene', (89, 92))	('LKB1', 'Gene', (145, 149))	('luminal', 'Chemical', 'MESH:D010634', (270, 277))	('SDHA', 'Gene', (179, 183))	('MYC', 'Gene', (165, 168))	('promote', 'PosReg', (250, 257))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('209', '242'))	('alterations', 'Var', (61, 72))	('re/deprogramming of differentiated cells', 'CPA', (301, 341))	('TC', 'Chemical', '-', (124, 126))	('mutation', 'Var', (155, 163))	('SDHA', 'Gene', '6389', (179, 183))
54372	33474631	Other features of these DS-HGNETs/NECs are lower stage at presentation, diagnosis on resection specimens, better prognosis, higher mutational heterogeneity between primaries and related metastases, and greater curability rates.	('curability rates', 'CPA', (210, 226))	('NETs', 'Phenotype', 'HP:0100634', (29, 33))	('mutational', 'Var', (131, 141))	('metastases', 'Disease', (186, 196))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('stage', 'MPA', (49, 54))	('higher', 'PosReg', (124, 130))
54375	33474631	A late maturation block caused by genetic/epigenetic alterations without genetic segregation would promote vertical luminal-like mechanisms giving rise to tumors enriched in differentiated cells, with low-grade dysplastic lesions (e.g., diffuse idiopathic neuroendocrine cell hyperplasia, DIPNECH), long preclinical phase and best prognosis.	('dysplastic lesions', 'Disease', 'MESH:D004416', (211, 229))	('luminal', 'Chemical', 'MESH:D010634', (116, 123))	('dysplastic lesions', 'Disease', (211, 229))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('promote', 'PosReg', (99, 106))	('idiopathic neuroendocrine cell hyperplasia', 'Disease', (245, 287))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('genetic/epigenetic alterations', 'Var', (34, 64))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('idiopathic neuroendocrine cell hyperplasia', 'Disease', 'MESH:D006965', (245, 287))	('giving rise to', 'Reg', (140, 154))
54376	33474631	Transversions C > A are quite uncommon, but these smoking-linked tumors could be at higher risk of progression to DS-HGNETs/NECs.	('DS-HGNETs/NECs', 'Disease', (114, 128))	('Transversions', 'Var', (0, 13))	('NETs', 'Phenotype', 'HP:0100634', (119, 123))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
54520	33509261	This study is supported by grants from the European Commission FP7 project SYSCOL (UE7-SYSCOL-258236), the Novo Nordisk Foundation (NNF16OC0023182), the Danish National Advanced Technology Foundation (056-2010-1), the John and Birthe Meyer Foundation, the Danish Council for Independent Research (Medical Sciences) (DFF-0602-02128B, DFF-4183-00619, DFF-7016-00332B), the Danish Council for Strategic Research (1309-00006B), the Danish Cancer Society (R40-A1965_11_S2, R56-A3110-12-S2, R107-A7035, R133-A8520), the National Cancer Institute of the National Institutes of Health (R01 CA207467), the Aage and Johanne Louis-Hansen's Foundation (17-2-0457), Dansk Kraeftforskningsfond (DKF-2017-26-26), the Knud and Edith Eriksen's Memorial Foundation, the Neye Foundation, and the Manufacturer Einar Willumsen's Memorial Foundation (6000073).	('R40-A1965_11_S2', 'Var', (451, 466))	('Cancer', 'Disease', 'MESH:D009369', (523, 529))	('Cancer', 'Disease', 'MESH:D009369', (435, 441))	('Cancer', 'Disease', (435, 441))	('Cancer', 'Phenotype', 'HP:0002664', (435, 441))	("Manufacturer Einar Willumsen's Memorial", 'Disease', (777, 816))	('R107-A7035', 'Var', (485, 495))	('R107-A7035', 'Mutation', 'p.R107,7035A', (485, 495))	("Manufacturer Einar Willumsen's Memorial", 'Disease', 'MESH:D008569', (777, 816))	('R56-A3110-12-S2', 'Var', (468, 483))	('Cancer', 'Phenotype', 'HP:0002664', (523, 529))	('Cancer', 'Disease', (523, 529))	('DKF-2017-26-26', 'CellLine', 'CVCL:8806', (681, 695))
54559	33511184	The first antibody was anti-Ki-67, anti-Cytochrome c (anti-Cyt), anti-cytokeratin 7 (CK7), anti-CK-pan, anti-thyroid transcription factor 1 (TTF-1), anti-napsin A, anti-calmodulin 5.2 (CAM5.2), anti-CK5/6, anti-p63, anti-Sal-like protein 4 (anti-SALL4), anti-chromogranin (anti-CgA), anti-Sy, and anti-Smuri 100.	('Cytochrome c', 'molecular_function', 'GO:0009461', ('40', '52'))	('cytokeratin 7', 'Gene', (70, 83))	('napsin A', 'Gene', '9476', (154, 162))	('antibody', 'cellular_component', 'GO:0042571', ('10', '18'))	('SALL4', 'Gene', (246, 251))	('CgA', 'Gene', '1113', (278, 281))	('CK5/6', 'Gene', '3852', (199, 204))	('TTF-1', 'Gene', (141, 146))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('antibody', 'cellular_component', 'GO:0019815', ('10', '18'))	('thyroid transcription factor 1', 'Gene', (109, 139))	('napsin A', 'Gene', (154, 162))	('CK5/6', 'Gene', (199, 204))	('CgA', 'Gene', (278, 281))	('Cytochrome c', 'molecular_function', 'GO:0045155', ('40', '52'))	('thyroid transcription factor 1', 'Gene', '7080', (109, 139))	('CK7', 'Gene', (85, 88))	('antibody', 'cellular_component', 'GO:0019814', ('10', '18'))	('anti-CK-pan', 'Var', (91, 102))	('p63', 'Gene', (211, 214))	('Cytochrome c', 'Gene', (40, 52))	('p63', 'Gene', '8626', (211, 214))	('SALL4', 'Gene', '57167', (246, 251))	('transcription factor', 'molecular_function', 'GO:0000981', ('117', '137'))	('Cytochrome c', 'Gene', '54205', (40, 52))	('TTF-1', 'Gene', '7270', (141, 146))	('cytokeratin 7', 'Gene', '3855', (70, 83))	('antibody', 'molecular_function', 'GO:0003823', ('10', '18'))	('CK7', 'Gene', '3855', (85, 88))	('anti-Ki-67', 'Var', (23, 33))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))
54610	33043516	Specifically, studies performed in plants, fungi, Caenorhabditis elegans, and Drosophila melanogaster reporting a posttranscriptional gene silencing mechanism mediated by dsRNA that became referred to as RNA interference or RNAi.	('posttranscriptional gene', 'MPA', (114, 138))	('RNA', 'cellular_component', 'GO:0005562', ('204', '207'))	('Drosophila melanogaster', 'Species', '7227', (78, 101))	('nts', 'Chemical', 'MESH:D009711', (38, 41))	('Caenorhabditis elegans', 'Species', '6239', (50, 72))	('RNAi', 'biological_process', 'GO:0016246', ('224', '228'))	('RNA interference', 'biological_process', 'GO:0016246', ('204', '220'))	('posttranscriptional gene silencing', 'biological_process', 'GO:0016441', ('114', '148'))	('dsRNA', 'Var', (171, 176))
54613	33043516	32 ,  33 ,  34 ,  35 ,  36 ,  37 ,  38 ,  39 ,  40 ,  41 ,  42  The discovery of entire classes of regulatory noncoding RNAs, particularly microRNAs (miRNAs), that control gene expression via the RNAi pathway added additional levels of complexity to the regulation of the transcriptome, 43 ,  44 ,  45 ,  46 ,  47  leading to significant insights into how disruption of miRNA-regulated gene expression contributes to disease states, including cancer.	('RNAi', 'biological_process', 'GO:0016246', ('196', '200'))	('disease', 'Disease', (417, 424))	('contributes', 'Reg', (402, 413))	('regulation', 'biological_process', 'GO:0065007', ('254', '264'))	('gene expression', 'biological_process', 'GO:0010467', ('386', '401'))	('cancer', 'Disease', 'MESH:D009369', (443, 449))	('disruption', 'Var', (356, 366))	('cancer', 'Disease', (443, 449))	('gene expression', 'biological_process', 'GO:0010467', ('172', '187'))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))
54629	33043516	Thus, it is not surprising that the cancer community quickly adopted RNAi-based functional genetic studies, including unbiased screens to study the genetic and epigenetic basis of cancer, and the functional consequences of alterations in specific genes and pathways.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('alterations', 'Var', (223, 234))	('RNAi', 'biological_process', 'GO:0016246', ('69', '73'))	('cancer', 'Disease', (180, 186))
54636	33043516	77   Colorectal tumors frequently exhibit disruption of the WNT-beta-catenin signaling that involves secreted WNT glycoproteins acting as activators of specific receptors, stimulating additional cellular responses, including gene expression changes regulated by beta-catenin and members of the TCF/LEF family of transcription factors.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('Colorectal tumors', 'Disease', 'MESH:D015179', (5, 22))	('gene expression', 'biological_process', 'GO:0010467', ('225', '240'))	('stimulating', 'PosReg', (172, 183))	('Colorectal tumors', 'Disease', (5, 22))	('WNT', 'Gene', (110, 113))	('disruption', 'Var', (42, 52))	('cellular responses', 'MPA', (195, 213))	('WNT', 'Gene', '35975', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('gene expression changes', 'MPA', (225, 248))	('transcription', 'biological_process', 'GO:0006351', ('312', '325'))	('TCF', 'Gene', '6934', (294, 297))	('TCF', 'Gene', (294, 297))	('WNT', 'Gene', '35975', (60, 63))	('WNT', 'Gene', (60, 63))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('beta-catenin', 'Protein', (262, 274))
54641	33043516	79  A study published in the same year reported a genome-wide siRNA screen that also used a beta-catenin-responsive luciferase assay, but this study used DLD1, colon adenocarcinoma cells, that harbor inactivating mutations in the tumor suppressor APC.	('tumor', 'Disease', (230, 235))	('tumor suppressor', 'biological_process', 'GO:0051726', ('230', '246'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('230', '246'))	('APC', 'Disease', 'MESH:D011125', (247, 250))	('colon adenocarcinoma', 'Disease', (160, 180))	('inactivating mutations', 'Var', (200, 222))	('APC', 'Disease', (247, 250))	('APC', 'cellular_component', 'GO:0005680', ('247', '250'))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
54646	33043516	Interestingly, we found that silencing LNX2 in CRC cell lines results in the downregulation of NOTCH-regulated genes and TCF7L2-target genes.	('downregulation', 'NegReg', (77, 91))	('NOTCH-regulated genes', 'Gene', (95, 116))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('LNX2', 'Gene', '222484', (39, 43))	('silencing', 'Var', (29, 38))	('LNX2', 'Gene', (39, 43))	('TCF7L2', 'Gene', (121, 127))	('TCF7L2', 'Gene', '6934', (121, 127))
54649	33043516	83  This analysis and follow-up studies demonstrated the dependency of cells that exhibit high beta-catenin on the function of the transcriptional coactivator YAP1.	('high', 'Var', (90, 94))	('beta-catenin', 'Protein', (95, 107))	('YAP1', 'Gene', (159, 163))	('YAP1', 'Gene', '10413', (159, 163))
54651	33043516	For example, a CRISPR-screen conducted in a pancreatic ductal adenocarcinoma cell line that demonstrated the importance of the Frizzled receptor FZD5 in cells harboring a mutation in RNF43.	('RNF43', 'Gene', '54894', (183, 188))	('RNF43', 'Gene', (183, 188))	('mutation', 'Var', (171, 179))	('pancreatic ductal adenocarcinoma', 'Disease', (44, 76))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (44, 76))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (44, 76))	('FZD5', 'Gene', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FZD5', 'Gene', '7855', (145, 149))
54652	33043516	84  The same group also recently described using a positive-selection assay to identify genes needed for beta-catenin activity in cells harboring APC mutations.	('APC', 'Disease', 'MESH:D011125', (146, 149))	('APC', 'Disease', (146, 149))	('mutations', 'Var', (150, 159))	('APC', 'cellular_component', 'GO:0005680', ('146', '149'))
54654	33043516	Follow-up studies demonstrated that IPO11 regulates the nuclear transport of beta-catenin in APC mutant cells that the activity of IPO11 could represent a mutation-specific vulnerability.	('APC', 'cellular_component', 'GO:0005680', ('93', '96'))	('mutant', 'Var', (97, 103))	('IPO11', 'Gene', '51194', (131, 136))	('nuclear transport of beta-catenin', 'MPA', (56, 89))	('IPO11', 'Gene', (131, 136))	('APC', 'Disease', 'MESH:D011125', (93, 96))	('regulates', 'Reg', (42, 51))	('nuclear transport', 'biological_process', 'GO:0051169', ('56', '73'))	('IPO11', 'Gene', '51194', (36, 41))	('APC', 'Disease', (93, 96))	('IPO11', 'Gene', (36, 41))
54655	33043516	The transcription factor complex NF-kappaB regulates various biological processes, including B-cell development and inflammation, and so alterations in proteins that form part of the NF-kappaB signaling cascade contribute to the initiation and progression of several tumor types.	('NF-kappaB', 'Gene', (33, 42))	('B-cell development', 'CPA', (93, 111))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('inflammation', 'Disease', 'MESH:D007249', (116, 128))	('transcription factor', 'molecular_function', 'GO:0000981', ('4', '24'))	('NF-kappaB', 'Gene', '4790', (33, 42))	('NF-kappaB', 'Gene', (183, 192))	('contribute to', 'Reg', (211, 224))	('regulates', 'Reg', (43, 52))	('transcription factor complex', 'cellular_component', 'GO:0005667', ('4', '32'))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('B-cell development', 'biological_process', 'GO:0030183', ('93', '111'))	('NF-kappaB', 'Gene', '4790', (183, 192))	('inflammation', 'Disease', (116, 128))	('alterations', 'Var', (137, 148))	('signaling cascade', 'biological_process', 'GO:0007165', ('193', '210'))	('proteins', 'Protein', (152, 160))	('inflammation', 'biological_process', 'GO:0006954', ('116', '128'))	('tumor', 'Disease', (267, 272))	('transcription', 'biological_process', 'GO:0006351', ('4', '17'))
54657	33043516	86  This study identified CYLD (CYLD lysine 63 deubiquitinase) as a negative regulator of NF-kappaB that removes ubiquitin from the TNF receptor-associated factor TRAF2; loss of CYLD drives a proliferative signal via the core NF-kappaB regulator, the IKK complex.	('core', 'cellular_component', 'GO:0019013', ('221', '225'))	('CYLD', 'Gene', (178, 182))	('NF-kappaB', 'Gene', '4790', (90, 99))	('TNF', 'Gene', '7124', (132, 135))	('CYLD', 'Gene', (32, 36))	('drives', 'PosReg', (183, 189))	('IKK', 'Gene', '1147;29110', (251, 254))	('CYLD lysine 63 deubiquitinase', 'Gene', (32, 61))	('CYLD', 'Gene', (26, 30))	('IKK', 'Gene', (251, 254))	('CYLD', 'Gene', '1540', (178, 182))	('IKK complex', 'cellular_component', 'GO:0008385', ('251', '262'))	('CYLD', 'Gene', '1540', (32, 36))	('CYLD', 'Gene', '1540', (26, 30))	('NF-kappaB', 'Gene', (226, 235))	('IKK', 'molecular_function', 'GO:0008384', ('251', '254'))	('loss', 'Var', (170, 174))	('ubiquitin', 'MPA', (113, 122))	('NF-kappaB', 'Gene', '4790', (226, 235))	('ubiquitin', 'molecular_function', 'GO:0031386', ('113', '122'))	('TRAF2', 'Gene', (163, 168))	('TNF', 'Gene', (132, 135))	('proliferative signal', 'MPA', (192, 212))	('NF-kappaB', 'Gene', (90, 99))	('CYLD lysine 63 deubiquitinase', 'Gene', '1540', (32, 61))	('TRAF2', 'Gene', '7186', (163, 168))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('47', '61'))
54658	33043516	Interestingly, individuals with cylindromatosis harbor mutations in CYLD that results in multi-focal skin lesions, and so this RNAi-based study prompted the initiation of a clinical trial of the IKKbeta signaling inhibitor salicylic acid.	('cylindromatosis', 'Disease', 'MESH:C536611', (32, 47))	('CYLD', 'Gene', '1540', (68, 72))	('skin lesions', 'Disease', (101, 113))	('IKKbeta', 'Gene', (195, 202))	('IKKbeta', 'Gene', '1147', (195, 202))	('mutations', 'Var', (55, 64))	('RNAi', 'biological_process', 'GO:0016246', ('127', '131'))	('skin lesions', 'Disease', 'MESH:D012871', (101, 113))	('focal skin lesions', 'Phenotype', 'HP:0011355', (95, 113))	('cylindromatosis', 'Disease', (32, 47))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('results in', 'Reg', (78, 88))	('salicylic acid', 'Chemical', 'MESH:D020156', (223, 237))	('CYLD', 'Gene', (68, 72))
54667	33043516	In some cases, genomic rearrangements result in the generation of a fusion oncogene that is the principal driver of tumorigenesis.	('nts', 'Chemical', 'MESH:D009711', (34, 37))	('fusion oncogene', 'Protein', (68, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('result in', 'Reg', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('genomic rearrangements', 'Var', (15, 37))	('tumor', 'Disease', (116, 121))
54672	33043516	Some studies examined the effect of silencing the fusion transcript on the growth of EWS cells in vitro or in vivo, 91 ,  92 ,  93 ,  94 ,  95 ,  96  while other early studies assessed the function of the EWS-FLI1 protein.	('FLI1', 'Gene', (209, 213))	('EWS', 'Phenotype', 'HP:0012254', (205, 208))	('EWS', 'Gene', (205, 208))	('EWS', 'Phenotype', 'HP:0012254', (85, 88))	('EWS', 'Gene', '2130', (205, 208))	('silencing', 'Var', (36, 45))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('EWS', 'Gene', '2130', (85, 88))	('EWS', 'Gene', (85, 88))	('FLI1', 'Gene', '2313', (209, 213))
54674	33043516	98 ,  99  Using the shRNA-inducible system and increasingly sophisticated 'Omic-scale methods to profile the transcriptome and epigenome of EWS cells following the silencing of EWS-FLI1 enabled the identification of many of the cell signaling and metabolism pathway that EWS-FLI1 deregulates as part of the tumorigenic process and the function of EWS-FLI1 as an aberrant transcription factor.	('EWS', 'Phenotype', 'HP:0012254', (347, 350))	('signaling', 'biological_process', 'GO:0023052', ('233', '242'))	('EWS', 'Gene', (177, 180))	('FLI1', 'Gene', '2313', (351, 355))	('transcription factor', 'molecular_function', 'GO:0000981', ('371', '391'))	('tumor', 'Disease', (307, 312))	('transcription', 'biological_process', 'GO:0006351', ('371', '384'))	('EWS', 'Phenotype', 'HP:0012254', (140, 143))	('EWS', 'Gene', (271, 274))	('FLI1', 'Gene', (275, 279))	('FLI1', 'Gene', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('EWS', 'Phenotype', 'HP:0012254', (177, 180))	('EWS', 'Gene', '2130', (347, 350))	('deregulates', 'NegReg', (280, 291))	('EWS', 'Phenotype', 'HP:0012254', (271, 274))	('silencing', 'Var', (164, 173))	('EWS', 'Gene', '2130', (140, 143))	('FLI1', 'Gene', '2313', (275, 279))	('FLI1', 'Gene', '2313', (181, 185))	('EWS', 'Gene', '2130', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('metabolism', 'biological_process', 'GO:0008152', ('247', '257'))	('EWS', 'Gene', '2130', (271, 274))	('EWS', 'Gene', (347, 350))	('FLI1', 'Gene', (351, 355))	('EWS', 'Gene', (140, 143))
54676	33043516	107  One aspect of this and subsequent studies highlighted the dependency of about one-third of Ewing sarcomas that harbor chromosome 22 translocations in intron 8 of the 5' partner gene, EWSR1.	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (96, 110))	('EWSR1', 'Gene', '2130', (188, 193))	('EWS', 'Phenotype', 'HP:0012254', (188, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('translocations', 'Var', (137, 151))	('Ewing sarcomas', 'Disease', (96, 110))	('EWSR1', 'Gene', (188, 193))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (96, 110))
54683	33043516	The inhibition of MDM2, therefore, stabilizes the TP53 protein, potentially activating the TP53 pathway.	('TP53 protein', 'Protein', (50, 62))	('activating', 'PosReg', (76, 86))	('inhibition', 'Var', (4, 14))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('TP53 pathway', 'Pathway', (91, 103))	('MDM2', 'Gene', '4193', (18, 22))	('MDM2', 'Gene', (18, 22))	('stabilizes', 'PosReg', (35, 45))
54684	33043516	A comparison of the relative abundance of the shRNAs present in control and nutlin-3 treated MCF7 cell populations following 14 days of culture identified, as expected, significant enrichment of shRNAs targeting TP53, and shRNAs corresponding to TP53BP1, among others.	('MCF7', 'CellLine', 'CVCL:0031', (93, 97))	('TP53BP1', 'Gene', '7158', (246, 253))	('TP53BP1', 'Gene', (246, 253))	('nutlin-3', 'Chemical', 'MESH:C482205', (76, 84))	('TP53', 'Var', (212, 216))
54689	33043516	Specifically, those cells expressing the lowest level of Tp53 showed an accelerated decrease in survival compared with control mice, and histopathology consistent with that observed in mice bearing Tp53-null tumors.	('decrease', 'NegReg', (84, 92))	('mice', 'Species', '10090', (127, 131))	('survival', 'CPA', (96, 104))	('mice', 'Species', '10090', (185, 189))	('Tp53', 'Var', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
54690	33043516	In contrast, the lymphoma generated by the HSCs expressing an intermediate level of Tp53 showed a different phenotype including, a longer time to lethality and less pronounced systematic disease.	('lymphoma', 'Disease', 'MESH:D008223', (17, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (17, 25))	('Tp53', 'Var', (84, 88))	('lymphoma', 'Disease', (17, 25))
54692	33043516	113  The genomes of OS tumor samples are complex, with almost no consistent genetic changes, except for mutations altering TP53 expression or function.	('OS tumor', 'Disease', (20, 28))	('mutations', 'Var', (104, 113))	('OS tumor', 'Disease', 'MESH:C567932', (20, 28))	('function', 'MPA', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('OS', 'Phenotype', 'HP:0002669', (20, 22))	('expression', 'MPA', (128, 138))	('TP53', 'Gene', (123, 127))
54696	33043516	Furthermore, Perry and co-workers reported that small-molecule inhibition of PI3K and/or mTOR inhibited the growth of mouse and human OS lines, suggesting genetic alterations, including alterations in TP53 function, may sensitize OS cells to disruption of signaling through this pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('alterations', 'Var', (163, 174))	('mTOR', 'Gene', '56717', (89, 93))	('PI3K', 'Pathway', (77, 81))	('function', 'MPA', (206, 214))	('alterations', 'Reg', (186, 197))	('growth', 'CPA', (108, 114))	('OS', 'Phenotype', 'HP:0002669', (134, 136))	('TP53', 'Gene', (201, 205))	('mouse', 'Species', '10090', (118, 123))	('sensitize', 'Reg', (220, 229))	('human', 'Species', '9606', (128, 133))	('OS', 'Phenotype', 'HP:0002669', (230, 232))	('signaling', 'biological_process', 'GO:0023052', ('256', '265'))	('inhibition', 'NegReg', (63, 73))	('inhibited', 'NegReg', (94, 103))	('mTOR', 'Gene', (89, 93))
54700	33043516	A follow-up study by the same group described how several of these candidate genes form a RAS-regulated gene network and suppresses FAS expression by altering DNA methyltransferase, DNMT1 activity.	('altering', 'Reg', (150, 158))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('genes', 'Var', (77, 82))	('FAS', 'Gene', (132, 135))	('DNA methyltransferase', 'Enzyme', (159, 180))	('activity', 'MPA', (188, 196))	('suppresses', 'NegReg', (121, 131))	('DNMT1', 'Gene', (182, 187))	('DNMT1', 'Gene', '1786', (182, 187))
54701	33043516	119   An early attempt to identify proteins that mutant RAS cells are selectively dependent on for cell survival employed a 4000 gene siRNA library to screen the colon cancer cell line DLD-1 that harbors one mutant and one wild-type KRAS allele.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('KRAS', 'Gene', '3845', (233, 237))	('mutant', 'Var', (49, 55))	('colon cancer', 'Disease', (162, 174))	('mutant', 'Var', (208, 214))	('colon cancer', 'Phenotype', 'HP:0003003', (162, 174))	('colon cancer', 'Disease', 'MESH:D015179', (162, 174))	('KRAS', 'Gene', (233, 237))
54704	33043516	121 ,  122 ,  123  Each used slightly different model systems, isogenic cancer cell lines, multiple KRAS mutant and wild-type cell lines, or cell lines exhibiting different dependencies on mutant KRAS activity, and different shRNAs libraries.	('KRAS', 'Gene', (100, 104))	('KRAS', 'Gene', '3845', (100, 104))	('mutant', 'Var', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('KRAS', 'Gene', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutant', 'Var', (105, 111))	('KRAS', 'Gene', '3845', (196, 200))	('cancer', 'Disease', (72, 78))
54711	33043516	Instead, they found that cells harboring mutations in KEAP1 exhibit a dependency on NFE2L2, and cells that have alterations in the expression of SMARCA4 showed a dependency on SMARCA2 function.	('mutations', 'Var', (41, 50))	('KEAP1', 'Gene', (54, 59))	('NFE2L2', 'Gene', (84, 90))	('dependency', 'MPA', (70, 80))	('KEAP1', 'Gene', '9817', (54, 59))	('SMARCA4', 'Gene', (145, 152))	('expression', 'MPA', (131, 141))	('SMARCA4', 'Gene', '6597', (145, 152))	('alterations', 'Reg', (112, 123))	('SMARCA2', 'Gene', (176, 183))	('SMARCA2', 'Gene', '6595', (176, 183))	('NFE2L2', 'Gene', '4780', (84, 90))
54722	33043516	If performed at scale, both approaches can identify: genes coding for proteins with essential functions; proteins that most cancer cells, irrespective of tumor type, depend on for cell growth:pan-cancer dependency genes; and those proteins, that when depleted, alters the survival of a specific subtypes of cancers.	('depleted', 'NegReg', (251, 259))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer dependency', 'Disease', 'MESH:D009369', (196, 213))	('cancer', 'Disease', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer dependency', 'Disease', (196, 213))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('cell growth', 'biological_process', 'GO:0016049', ('180', '191'))	('cancer', 'Disease', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (124, 130))	('genes', 'Var', (214, 219))	('cancers', 'Disease', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('alters', 'Reg', (261, 267))
54724	33043516	134  Screens performed in breast, lung, and cervical cancer cell lines (five in total) demonstrated a cell line-specific dependency on the expression of PIK3CA and the presence of a PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (153, 159))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('presence', 'Reg', (168, 176))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', '5290', (182, 188))	('mutation', 'Var', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PIK3CA', 'Gene', (153, 159))
54731	33043516	136   Complementary efforts, over the same period, focused on the employment of large-scale shRNA libraries, with three of the earliest studies published in 2008 employing libraries of increasing complexity, ranging from ~3000 genes (8000 shRNAs) to 9500 genes (45,000 shRNAs), and a wider variety of cell lines, beginning with three cancer cell lines (two colon lines and one breast line) and one non-transformed line, and by the third study, a screen of 12 cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('one breast line', 'Phenotype', 'HP:0012813', (373, 388))	('cancer', 'Disease', (459, 465))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('8000', 'Var', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Disease', (334, 340))
54734	33043516	Among cell-line specific genetic vulnerabilities, this study also identified the sensitivity of the chronic myelogenous leukemia cell line K562 that harbors the BCR-ABL fusion gene to the shRNAs targeting the BCR or ABL genes.	('ABL', 'Gene', (165, 168))	('ABL', 'Gene', (216, 219))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('chronic myelogenous leukemia', 'Disease', (100, 128))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (100, 128))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (100, 128))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (108, 128))	('BCR-ABL', 'Gene', (161, 168))	('BCR-ABL', 'Gene', '25', (161, 168))	('K562', 'CellLine', 'CVCL:0004', (139, 143))	('ABL', 'Gene', '25', (216, 219))	('fusion', 'Var', (169, 175))	('ABL', 'Gene', '25', (165, 168))
54746	33043516	Enhancing the scale of cancer LOF screens and integrating these data sets with other data, including gene copy number, mutation status, and expression patterns, has the potential to address this deficit.	('LOF', 'NegReg', (30, 33))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('screens', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
54749	33043516	The initial study confirmed the dependency of colon cancer cell lines on the expression of KRAS, CTNNB1, and BRAF, and as discussed above, the differences in the sensitivity of wild-type and mutant PIK3CA cell lines to the targeting of PIK3CA by RNAi.	('PIK3CA', 'Gene', (236, 242))	('PIK3CA', 'Gene', '5290', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BRAF', 'Gene', (109, 113))	('dependency of colon cancer', 'Disease', (32, 58))	('PIK3CA', 'Gene', '5290', (236, 242))	('BRAF', 'Gene', '673', (109, 113))	('CTNNB1', 'Gene', '1499', (97, 103))	('mutant', 'Var', (191, 197))	('sensitivity', 'MPA', (162, 173))	('PIK3CA', 'Gene', (198, 204))	('RNAi', 'biological_process', 'GO:0016246', ('246', '250'))	('KRAS', 'Gene', (91, 95))	('CTNNB1', 'Gene', (97, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (46, 58))	('KRAS', 'Gene', '3845', (91, 95))	('dependency of colon cancer', 'Disease', 'MESH:D015179', (32, 58))
54751	33043516	152  integrated gene copy number and RNAi data, identifying PAX8 as a dependency in ovarian cancer cell lines that harbor amplification of the region containing this gene.	('PAX8', 'Gene', (60, 64))	('RNAi', 'biological_process', 'GO:0016246', ('37', '41'))	('amplification', 'Var', (122, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('PAX8', 'Gene', '7849', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('dependency in ovarian cancer', 'Disease', (70, 98))	('dependency in ovarian cancer', 'Disease', 'MESH:D019966', (70, 98))
54758	33043516	130  Referred to as Project DRIVE, this study noted many of the previously defined dependencies, including cell lines harboring NRAS, BRAF, KRAS, or PIKSCA mutations.	('KRAS', 'Gene', '3845', (140, 144))	('NRAS', 'Gene', (128, 132))	('mutations', 'Var', (156, 165))	('NRAS', 'Gene', '4893', (128, 132))	('BRAF', 'Gene', '673', (134, 138))	('PIKSCA', 'Gene', (149, 155))	('BRAF', 'Gene', (134, 138))	('KRAS', 'Gene', (140, 144))
54768	33043516	112  did though, along with others (e.g., 164 ,  165 ,  166 ), spur the use of ex vivo manipulated cells that expressed a gene-specific shRNA (constitutive or inducible expression) to study the consequence of targeting the candidate gene of interest on the initiation or maintenance of tumor growth, through the reintroduction of the modified cells to mice as transplants or xenografts.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('targeting', 'Var', (209, 218))	('nts', 'Chemical', 'MESH:D009711', (368, 371))	('mice', 'Species', '10090', (352, 356))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('shRNA', 'Gene', (136, 141))
54781	33043516	175 ,  176 ,  177  This approach facilitates the genetic modification of the progenitor cells that will form the mouse epidermis and, depending on the embryo's genetic background, can enable examination of normal and oncogenic growth.	('genetic', 'Var', (49, 56))	('oncogenic growth', 'CPA', (217, 233))	('mouse', 'Species', '10090', (113, 118))
54782	33043516	One of the shRNA screens conducted in the context of a mutated HRAS demonstrated dependency of the mutant cells on the function of Ctnnb1 or Mllt6, findings the authors successfully replicated in cell line models of human squamous cell carcinoma (SCC).	('dependency', 'Reg', (81, 91))	('SCC', 'Gene', (247, 250))	('SCC', 'Phenotype', 'HP:0002860', (247, 250))	('human', 'Species', '9606', (216, 221))	('HRAS', 'Gene', (63, 67))	('mutated', 'Var', (55, 62))	('SCC', 'Gene', '6317', (247, 250))	('Ctnnb1', 'Gene', (131, 137))	('Mllt6', 'Gene', (141, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 245))	('Ctnnb1', 'Gene', '1499', (131, 137))	('squamous cell carcinoma', 'Disease', (222, 245))	('mutant', 'Var', (99, 105))	('Mllt6', 'Gene', '4302', (141, 146))	('HRAS', 'Gene', '3265', (63, 67))
54787	33043516	However, mutation of both genes results in organismal demise, or synthetic lethality.	('mutation', 'Var', (9, 17))	('results in', 'Reg', (32, 42))	('organismal demise', 'CPA', (43, 60))	('synthetic', 'Species', '2005392', (65, 74))	('synthetic lethality', 'CPA', (65, 84))
54788	33043516	178 ,  179 ,  180 ,  181  In cancer, synthetic lethality typically refers to a gene that is nonessential when depleted in a nontransformed cell, but if depleted in a transformed cell harboring a tumor-specific mutation or combination of mutations, the cancer cell dies.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Disease', (252, 258))	('synthetic', 'Species', '2005392', (37, 46))	('mutation', 'Var', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('mutations', 'Var', (237, 246))
54799	33043516	Building on this concept and other evidence, 185  several PRMT5 inhibitors (GSK3326595, JNJ-64619178, and PF-06939999) are now the subjects of current early phase clinical trials in patients with different subtypes of leukemia or lymphoma or advanced solid tumors (NCT02783300, NCT03614728, NCT03573310, and NCT03854227).	('leukemia', 'Disease', (218, 226))	('solid tumors', 'Disease', (251, 263))	('patients', 'Species', '9606', (182, 190))	('NCT03614728', 'Var', (278, 289))	('lymphoma', 'Phenotype', 'HP:0002665', (230, 238))	('solid tumors', 'Disease', 'MESH:D009369', (251, 263))	('PRMT5', 'Gene', (58, 63))	('GSK3326595', 'Var', (76, 86))	('NCT03854227', 'Var', (308, 319))	('NCT03573310', 'Var', (291, 302))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('leukemia', 'Phenotype', 'HP:0001909', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('NCT02783300', 'Var', (265, 276))	('lymphoma', 'Disease', (230, 238))	('lymphoma', 'Disease', 'MESH:D008223', (230, 238))	('GSK', 'molecular_function', 'GO:0050321', ('76', '79'))	('leukemia', 'Disease', 'MESH:D007938', (218, 226))	('PRMT5', 'Gene', '10419', (58, 63))
54801	33043516	186  Multiple cancers types exhibit mutations in ARID1A, a gene that encodes a member of the SWI/SNF chromatin-remodeling complex.	('Multiple cancers', 'Disease', 'MESH:D009369', (5, 21))	('exhibit', 'Reg', (28, 35))	('Multiple cancers', 'Disease', (5, 21))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('101', '129'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (36, 45))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('101', '121'))	('ARID1A', 'Gene', '8289', (49, 55))	('ARID1A', 'Gene', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
54802	33043516	Analysis of Project Achilles shRNA screening data showed ARID1B expression as essential for the viability of cell lines harboring ARID1A inactivating mutations.	('ARID1A', 'Gene', '8289', (130, 136))	('ARID1B', 'Gene', '57492', (57, 63))	('ARID1A', 'Gene', (130, 136))	('ARID1B', 'Gene', (57, 63))	('inactivating mutations', 'Var', (137, 159))
54803	33043516	Follow-up studies demonstrated tumor cells harboring ARID1A mutations depend on the ARID1B, a close homolog of ARID1A, for the assembly of the SWI/SNF chromatin-remodeling complexes.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('151', '171'))	('chromatin', 'cellular_component', 'GO:0000785', ('151', '160'))	('tumor', 'Disease', (31, 36))	('ARID1B', 'Gene', (84, 90))	('ARID1A', 'Gene', '8289', (111, 117))	('depend', 'Reg', (70, 76))	('ARID1A', 'Gene', (111, 117))	('mutations', 'Var', (60, 69))	('ARID1A', 'Gene', '8289', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ARID1B', 'Gene', '57492', (84, 90))	('ARID1A', 'Gene', (53, 59))
54804	33043516	In the absence of both ARID1A and ARID1B, the disruption to the generation of SWI/SNF complexes results in cell death.	('ARID1A', 'Gene', '8289', (23, 29))	('disruption', 'Var', (46, 56))	('ARID1A', 'Gene', (23, 29))	('cell death', 'biological_process', 'GO:0008219', ('107', '117'))	('ARID1B', 'Gene', '57492', (34, 40))	('cell death', 'CPA', (107, 117))	('ARID1B', 'Gene', (34, 40))
54805	33043516	186  To date, there is no published ARID1B inhibitor; however, a recent analysis of inhibitors of other epigenetic regulators revealed that inhibition of EZH2, a methyltransferase member of the polycomb repressive complex 2, has efficacy in ARID1A-mutant ovarian clear cell carcinoma cell lines in vitro and in vivo.	('ARID1B', 'Gene', '57492', (36, 42))	('EZH2', 'Gene', (154, 158))	('EZH2', 'Gene', '2146', (154, 158))	('inhibition', 'Var', (140, 150))	('ovarian clear cell carcinoma', 'Disease', (255, 283))	('ARID1A', 'Gene', '8289', (241, 247))	('ARID1A', 'Gene', (241, 247))	('ARID1B', 'Gene', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (255, 283))	('efficacy', 'PosReg', (229, 237))
54806	33043516	187  Clinical trials with EZH2 inhibitors in various cancer types are ongoing, including the recruitment of patients with tumors associated with mutations in members of the SWI/SNF complex, such as rhabdoid tumors and synovial sarcoma (NCT02601950 and NCT02601937).	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('synovial sarcoma', 'Disease', (218, 234))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (145, 154))	('rhabdoid tumors', 'Disease', (198, 213))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (198, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('synovial sarcoma', 'Disease', 'MESH:D013584', (218, 234))	('tumors', 'Disease', (207, 213))	('patients', 'Species', '9606', (108, 116))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('173', '188'))	('EZH2', 'Gene', '2146', (26, 30))	('EZH2', 'Gene', (26, 30))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (218, 234))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (122, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('SWI/SNF', 'Gene', (173, 180))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
54809	33043516	188  In this study, the silencing of genes coding for members of the BRCA family of proteins or the RAD6/RA7D18 DNA repair pathways significantly enhanced cisplatin activity.	('RAD6/RA7D18', 'Gene', (100, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('BRCA', 'Gene', (69, 73))	('enhanced', 'PosReg', (146, 154))	('DNA repair', 'biological_process', 'GO:0006281', ('112', '122'))	('cisplatin activity', 'MPA', (155, 173))	('BRCA', 'Gene', '672;675', (69, 73))	('RAD', 'biological_process', 'GO:1990116', ('100', '103'))	('silencing', 'Var', (24, 33))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
54810	33043516	The authors, Bartz et al., attributed this finding to the silenced cells' inability to mitigate cisplatin-induced DNA damage in the context of mutant TP53 and loss of BRCA1 or other members of the BRCA1/2 network.	('BRCA1', 'Gene', (197, 202))	('TP53', 'Gene', (150, 154))	('BRCA1', 'Gene', (167, 172))	('mutant', 'Var', (143, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('loss', 'NegReg', (159, 163))	('BRCA1/2', 'Gene', (197, 204))	('BRCA1/2', 'Gene', '672;675', (197, 204))	('BRCA1', 'Gene', '672', (197, 202))	('BRCA1', 'Gene', '672', (167, 172))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
54815	33043516	TOP1 inhibitors create drug-stabilized cleavage complexes that result in DNA damage, leading to their use as part of chemotherapeutic regimens to treat ovarian, lung, and colon cancers.	('TOP1', 'Gene', (0, 4))	('colon cancers', 'Disease', 'MESH:D015179', (171, 184))	('lung', 'Disease', (161, 165))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('DNA damage', 'MPA', (73, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (171, 183))	('inhibitors', 'Var', (5, 15))	('ovarian', 'Disease', 'MESH:D010049', (152, 159))	('ovarian', 'Disease', (152, 159))	('colon cancers', 'Disease', (171, 184))	('TOP1', 'Gene', '7150', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('colon cancers', 'Phenotype', 'HP:0003003', (171, 184))	('result in', 'Reg', (63, 72))
54822	33043516	Groups began testing the potential of employing RNAi effector molecules to treat human diseases within a year of the initial studies reporting its presence in mammalian cells, targeting viral pathogens, including HIV, and mutant transcripts, including those associated with neurodegenerative diseases or cancer.	('associated', 'Reg', (258, 268))	('mammalian', 'Species', '9606', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('mutant transcripts', 'Var', (222, 240))	('RNAi', 'biological_process', 'GO:0016246', ('48', '52'))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (274, 300))	('cancer', 'Disease', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('neurodegenerative diseases', 'Disease', (274, 300))	('human', 'Species', '9606', (81, 86))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (274, 300))
54828	33043516	As discussed in Section 3.4, mutations in KRAS are present in many tumors, and several early RNAi studies assessed the feasibility of selectively targeting the transcripts encoding mutant KRAS.	('mutant', 'Var', (181, 187))	('KRAS', 'Gene', (42, 46))	('RNAi', 'biological_process', 'GO:0016246', ('93', '97'))	('KRAS', 'Gene', '3845', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KRAS', 'Gene', (188, 192))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('KRAS', 'Gene', '3845', (188, 192))
54840	33043516	We are now able to effectively edit DNA directly through the application of sequence-specific guide RNAs and the Cas endonucleases (e.g., Cas9 or Cas12 and modified variants), including the ability to make increasingly precise single-nucleotide changes (please see the following recent review 224 ).	('Cas', 'cellular_component', 'GO:0005650', ('146', '149'))	('single-nucleotide changes', 'Var', (227, 252))	('modified variants', 'Var', (156, 173))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('Cas', 'cellular_component', 'GO:0005650', ('113', '116'))	('nts', 'Chemical', 'MESH:D009711', (170, 173))	('Cas', 'cellular_component', 'GO:0005650', ('138', '141'))
54878	33194653	Each row represented one sample, recording 94 features (from left to right, attenuation features, f1-f8; GLCM features at 0 degrees, f9-f28; GLCM features at 45 degrees, f29-f48; GLCM features at 90 degrees, f49-f68; GLCM features at 135 degrees, f69-f88; LBP features, f89-f94), and the target index on the last column (0 denoted adenocarcinoma and 1 NCH).	('f1-f8', 'Var', (98, 103))	('GLCM', 'Chemical', '-', (217, 221))	('adenocarcinoma', 'Disease', 'MESH:D000230', (331, 345))	('f29-f48', 'Var', (170, 177))	('f69-f88', 'Var', (247, 254))	('f9-f28', 'Var', (133, 139))	('f89-f94', 'Var', (270, 277))	('GLCM', 'Chemical', '-', (141, 145))	('GLCM', 'Chemical', '-', (105, 109))	('f49-f68', 'Var', (208, 215))	('NCH', 'Chemical', '-', (352, 355))	('GLCM', 'Chemical', '-', (179, 183))	('adenocarcinoma', 'Disease', (331, 345))
54973	32183059	In a small cohort, the expansion of anti-p53 specific CD4+ and CD8+ T cells resulted in a longer progression-free survival.	('p53', 'Gene', '7157', (41, 44))	('expansion', 'Var', (23, 32))	('progression-free survival', 'CPA', (97, 122))	('longer', 'PosReg', (90, 96))	('CD8', 'Gene', (63, 66))	('CD4', 'Gene', (54, 57))	('CD4', 'Gene', '920', (54, 57))	('CD8', 'Gene', '925', (63, 66))	('p53', 'Gene', (41, 44))
54977	32183059	In further studies undertaken in ovarian cancer patients, in vitro cytotoxicity assays (chromium release assay) using a peptide from HER2/neu induced cytotoxicity against the autologous tumour.	('tumour', 'Disease', (186, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('chromium', 'Chemical', 'MESH:D002857', (88, 96))	('peptide', 'Var', (120, 127))	('ovarian cancer', 'Disease', (33, 47))	('cytotoxicity', 'Disease', (67, 79))	('cytotoxicity', 'Disease', (150, 162))	('HER2/neu', 'Gene', '2064', (133, 141))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('HER2/neu', 'Gene', (133, 141))	('cytotoxicity', 'Disease', 'MESH:D064420', (150, 162))	('patients', 'Species', '9606', (48, 56))
55006	32183059	PARP inhibitors have been found to induce IFN-alpha anti-tumour responses and promote tumour infiltrating cells which was enhanced by the checkpoint inhibitors.	('tumour', 'Disease', (57, 63))	('enhanced', 'PosReg', (122, 130))	('promote', 'PosReg', (78, 85))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('PARP', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('inhibitors', 'Var', (5, 15))	('induce', 'PosReg', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('IFN-alpha', 'Gene', (42, 51))	('tumour', 'Disease', (86, 92))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('PARP', 'Gene', '142', (0, 4))	('IFN-alpha', 'Gene', '3439', (42, 51))
55007	32183059	Another mechanism in which PARP inhibitors and checkpoint inhibitors may work together is through the increased mutation burden, from DNA damage, which could modulate the TME to be more receptive to the anti-tumour immune response leading to beneficial outcomes of checkpoint inhibitor therapies.	('immune response', 'biological_process', 'GO:0006955', ('215', '230'))	('mutation', 'Var', (112, 120))	('tumour', 'Disease', (208, 214))	('PARP', 'Gene', (27, 31))	('beneficial', 'PosReg', (242, 252))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('modulate', 'Reg', (158, 166))	('PARP', 'Gene', '142', (27, 31))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
55009	32183059	HDAC inhibitors act by inducing tumour cell cycle arrest and tumour cell death, reducing angiogenesis and by also modulating the immune response (reviewed in).	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('tumour cell death', 'Disease', (61, 78))	('tumour', 'Disease', (61, 67))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('modulating', 'Reg', (114, 124))	('HDAC', 'Gene', '9734', (0, 4))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('39', '56'))	('immune response', 'CPA', (129, 144))	('angiogenesis', 'biological_process', 'GO:0001525', ('89', '101'))	('angiogenesis', 'CPA', (89, 101))	('tumour cell death', 'Disease', 'MESH:D003643', (61, 78))	('reducing', 'NegReg', (80, 88))	('cell death', 'biological_process', 'GO:0008219', ('68', '78'))	('HDAC', 'Gene', (0, 4))	('immune response', 'biological_process', 'GO:0006955', ('129', '144'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('inducing', 'PosReg', (23, 31))	('arrest', 'Disease', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))	('tumour', 'Disease', (32, 38))	('inhibitors', 'Var', (5, 15))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
55015	32183059	A preliminary study in ovarian cancer cell lines showed HDAC inhibitors increased the sensitivity to cisplatin, therefore suggesting a combination of HDAC inhibitors and chemotherapy may be effective in targeting aggressive tumours.	('sensitivity to cisplatin', 'MPA', (86, 110))	('inhibitors', 'Var', (61, 71))	('increased', 'PosReg', (72, 81))	('HDAC', 'Gene', (56, 60))	('aggressive tumours', 'Disease', (213, 231))	('ovarian cancer', 'Disease', (23, 37))	('HDAC', 'Gene', '9734', (56, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('HDAC', 'Gene', '9734', (150, 154))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('tumours', 'Phenotype', 'HP:0002664', (224, 231))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('HDAC', 'Gene', (150, 154))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))	('aggressive tumours', 'Disease', 'MESH:D009369', (213, 231))
55020	32183059	NK cell activity was increased in the ABMK treated patients, and negative side effects of chemotherapy were reduced.	('increased', 'PosReg', (21, 30))	('ABMK', 'Var', (38, 42))	('ABMK', 'Chemical', '-', (38, 42))	('patients', 'Species', '9606', (51, 59))	('NK cell activity', 'CPA', (0, 16))
55022	32183059	In the context of autoimmunity, epigallocatechin gallate (EGCG, from green tea) has been shown to suppress self-reactive T cells and proinflammatory cytokines, though increase protective Treg responses in peripheral tissues in rheumatoid arthritis.	('self-reactive T cells', 'MPA', (107, 128))	('rheumatoid arthritis', 'Disease', (227, 247))	('epigallocatechin', 'Var', (32, 48))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (227, 247))	('proinflammatory cytokines', 'MPA', (133, 158))	('epigallocatechin gallate', 'Chemical', 'MESH:C045651', (32, 56))	('suppress', 'NegReg', (98, 106))	('arthritis', 'Phenotype', 'HP:0001369', (238, 247))	('EGCG', 'Chemical', 'MESH:C045651', (58, 62))	('increase', 'PosReg', (167, 175))	('protective Treg responses', 'CPA', (176, 201))	('Treg', 'Chemical', '-', (187, 191))	('autoimmunity', 'Phenotype', 'HP:0002960', (18, 30))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (227, 247))
55023	32183059	Similarly, EGCG contributed to reduced Th17 cell activation and increased FoxP3+ Treg cells in a model of autoimmune arthritis.	('reduced', 'NegReg', (31, 38))	('cell activation', 'biological_process', 'GO:0001775', ('44', '59'))	('autoimmune arthritis', 'Disease', (106, 126))	('arthritis', 'Phenotype', 'HP:0001369', (117, 126))	('FoxP3', 'Gene', '50943', (74, 79))	('Treg', 'Chemical', '-', (81, 85))	('autoimmune arthritis', 'Disease', 'MESH:D001168', (106, 126))	('Th17 cell activation', 'CPA', (39, 59))	('FoxP3', 'Gene', (74, 79))	('EGCG', 'Chemical', 'MESH:C045651', (11, 15))	('increased', 'PosReg', (64, 73))	('EGCG', 'Var', (11, 15))
55040	32183059	In studies where model antigens have been administered in animal models, it has been reported that curcumin supplementation increased T follicular helper cells and germinal centre B cells as well as subsequent IgG production.	('supplementation', 'Var', (108, 123))	('increased', 'PosReg', (124, 133))	('IgG production', 'CPA', (210, 224))	('curcumin', 'Chemical', 'MESH:D003474', (99, 107))	('curcumin', 'Gene', (99, 107))
55051	32183059	EGCG was similarly able to induce apoptosis and increase the expression of the apoptosis inducer proteins Bax and caspase 3 in esophageal squamous cell carcinoma cells, and induced apoptosis in hepatocellular carcinoma cell lines.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (127, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('induce', 'PosReg', (27, 33))	('caspase 3', 'Gene', (114, 123))	('caspase 3', 'Gene', '836', (114, 123))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('Bax', 'Gene', (106, 109))	('Bax', 'Gene', '581', (106, 109))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (194, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('induced', 'Reg', (173, 180))	('esophageal squamous cell carcinoma', 'Disease', (127, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (194, 218))	('expression', 'MPA', (61, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('hepatocellular carcinoma', 'Disease', (194, 218))	('EGCG', 'Var', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))	('increase', 'PosReg', (48, 56))
55060	32183059	Though there are some positive reports of EGCG and immune modulation relating to anti-cancer responses, studies have shown a decrease in Th1 and CD8+ T cells and an increase in Tregs after administration of EGCG.	('increase', 'PosReg', (165, 173))	('Tregs', 'CPA', (177, 182))	('EGCG', 'Chemical', 'MESH:C045651', (207, 211))	('Tregs', 'Chemical', '-', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('EGCG', 'Var', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CD8', 'Gene', (145, 148))	('decrease', 'NegReg', (125, 133))	('CD8', 'Gene', '925', (145, 148))	('EGCG', 'Chemical', 'MESH:C045651', (42, 46))	('cancer', 'Disease', (86, 92))
55066	32183059	To increase the bioavailability of curcumin, studies have shown that ligating curcumin with polyetyhyleneglycol (PEG) resulted in increased CD8+ T cell activity and effector cytokine (IFN-gamma) production, as well as decreased MDSCs and Treg concentrations in an animal model of melanoma.	('Treg', 'Chemical', '-', (238, 242))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('curcumin', 'Chemical', 'MESH:D003474', (78, 86))	('melanoma', 'Disease', (280, 288))	('CD8', 'Gene', (140, 143))	('polyetyhyleneglycol', 'Var', (92, 111))	('PEG', 'Chemical', '-', (113, 116))	('CD8', 'Gene', '925', (140, 143))	('MDSCs', 'MPA', (228, 233))	('melanoma', 'Disease', 'MESH:D008545', (280, 288))	('curcumin', 'Gene', (78, 86))	('polyetyhyleneglycol', 'Chemical', '-', (92, 111))	('increased', 'PosReg', (130, 139))	('ligating', 'Var', (69, 77))	('curcumin', 'Chemical', 'MESH:D003474', (35, 43))	('decreased', 'NegReg', (218, 227))	('bioavailability', 'MPA', (16, 31))	('increase', 'PosReg', (3, 11))
55119	32183059	In an LPS-activated dendritic cell model, quercetin modulated DC activation and reduced secretion of TNF, IL-1beta, IL-6, IL-10 and IL-12p70,.	('secretion', 'biological_process', 'GO:0046903', ('88', '97'))	('IL-6', 'molecular_function', 'GO:0005138', ('116', '120'))	('IL-1beta', 'Gene', '3552', (106, 114))	('IL-10', 'molecular_function', 'GO:0005141', ('122', '127'))	('IL-12p70', 'Var', (132, 140))	('TNF', 'Gene', (101, 104))	('IL-1beta', 'Gene', (106, 114))	('IL-10', 'Gene', (122, 127))	('reduced', 'NegReg', (80, 87))	('IL-6', 'Gene', (116, 120))	('IL-6', 'Gene', '3569', (116, 120))	('quercetin', 'Chemical', 'MESH:D011794', (42, 51))	('TNF', 'Gene', '7124', (101, 104))	('IL-12', 'molecular_function', 'GO:0005143', ('132', '137'))	('activation', 'PosReg', (65, 75))	('IL-1', 'molecular_function', 'GO:0005149', ('106', '110'))	('IL-10', 'Gene', '3586', (122, 127))	('modulated', 'Reg', (52, 61))
55125	32183059	In the same study, C3G prevented tumourigenic cell transformation and reduced the tumour burden in vivo in murine studies of induced skin tumours and also xenograft implanted human lung carcinoma cells.	('C3G', 'Var', (19, 22))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('prevented', 'NegReg', (23, 32))	('human', 'Species', '9606', (175, 180))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('lung carcinoma', 'Disease', 'MESH:D008175', (181, 195))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('murine', 'Species', '10090', (107, 113))	('tumour', 'Disease', (138, 144))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('reduced', 'NegReg', (70, 77))	('skin tumours', 'Disease', 'MESH:D012878', (133, 145))	('tumour', 'Disease', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('skin tumours', 'Disease', (133, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('lung carcinoma', 'Disease', (181, 195))
55126	32183059	Whilst there is little information on its anti-tumour immunomodulatory effects, studies have shown that C3G reduced rheumatoid arthritis presentation, and concurrently increased IL-10, Tregs, and decreased IL-6, IFN-gamma and NK cell activity.	('arthritis', 'Phenotype', 'HP:0001369', (127, 136))	('decreased IL-6', 'Phenotype', 'HP:0030783', (196, 210))	('C3G', 'Var', (104, 107))	('Tregs', 'Chemical', '-', (185, 190))	('rheumatoid arthritis', 'Disease', (116, 136))	('IL-10', 'molecular_function', 'GO:0005141', ('178', '183'))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (116, 136))	('IL-6', 'Gene', '3569', (206, 210))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('increased', 'PosReg', (168, 177))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('Tregs', 'CPA', (185, 190))	('IL-10', 'Gene', '3586', (178, 183))	('decreased', 'NegReg', (196, 205))	('reduced', 'NegReg', (108, 115))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (116, 136))	('tumour', 'Disease', (47, 53))	('IL-6', 'molecular_function', 'GO:0005138', ('206', '210'))	('IL-10', 'Gene', (178, 183))	('IL-6', 'Gene', (206, 210))	('NK cell activity', 'CPA', (226, 242))
55131	32183059	Polyphenols have antioxidant and anti-inflammatory properties and can modulate autophagy pathways as well as modulate cells of the immune system.	('modulate', 'Reg', (70, 78))	('modulate', 'Reg', (109, 117))	('Polyphenols', 'Chemical', 'MESH:D059808', (0, 11))	('anti-inflammatory', 'CPA', (33, 50))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('antioxidant', 'CPA', (17, 28))	('autophagy pathways', 'CPA', (79, 97))	('cells of the immune system', 'CPA', (118, 144))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('Polyphenols', 'Var', (0, 11))
55149	32164629	Anaplastic lymphoma kinase (ALK) fusion mutations are validated molecules targeted therapy in lung cancers, where crizotinib can be used as the specific inhibitor to suppress tumor progression.	('crizotinib', 'Chemical', 'MESH:D000077547', (114, 124))	('tumor', 'Disease', (175, 180))	('fusion mutations', 'Var', (33, 49))	('lung cancers', 'Phenotype', 'HP:0100526', (94, 106))	('ALK', 'Gene', '238', (28, 31))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('Anaplastic lymphoma', 'Disease', 'MESH:D017728', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('lung cancers', 'Disease', (94, 106))	('Anaplastic lymphoma', 'Disease', (0, 19))	('mutations', 'Var', (40, 49))	('ALK', 'Gene', (28, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lung cancers', 'Disease', 'MESH:D008175', (94, 106))
55150	32164629	However, due to the less frequent occurrence of ALK mutations and the complexity for factors to determine drug responses, the genes that could alter crizotinib sensitivity are unclear.	('mutations', 'Var', (52, 61))	('ALK', 'Gene', '238', (48, 51))	('alter', 'Reg', (143, 148))	('ALK', 'Gene', (48, 51))	('crizotinib', 'Chemical', 'MESH:D000077547', (149, 159))
55157	32164629	Ectopically overexpressed NHERF1 could be a functional protein for consideration to suppress lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('lung cancers', 'Disease', (93, 105))	('suppress', 'NegReg', (84, 92))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('lung cancers', 'Disease', 'MESH:D008175', (93, 105))	('lung cancers', 'Phenotype', 'HP:0100526', (93, 105))	('Ectopically overexpressed', 'Var', (0, 25))	('NHERF1', 'Gene', (26, 32))
55162	32164629	Mutations at NHERF N-terminus within the conserved PDZ domains hampered its interaction with SYK, promoted the progression of breast cancer.	('hampered', 'NegReg', (63, 71))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('SYK', 'Gene', '6850', (93, 96))	('interaction', 'Interaction', (76, 87))	('NHERF', 'Gene', '9368', (13, 18))	('promoted', 'PosReg', (98, 106))	('breast cancer', 'Disease', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('Mutations', 'Var', (0, 9))	('SYK', 'Gene', (93, 96))	('progression', 'CPA', (111, 122))	('NHERF', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
55165	32164629	During the early stages of carcinogenesis in colorectal cancers, nuclear NHERF1 was correlated with poor prognosis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('colorectal cancers', 'Disease', 'MESH:D015179', (45, 63))	('NHERF1', 'Gene', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (27, 41))	('colorectal cancers', 'Disease', (45, 63))	('carcinogenesis', 'Disease', (27, 41))	('nuclear', 'Var', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
55176	32164629	Comparing to other drugs, genes that influenced the sensitivity of crizotinib were less reported due to the low frequency of ALK mutations in patients.	('crizotinib', 'Chemical', 'MESH:D000077547', (67, 77))	('mutations', 'Var', (129, 138))	('ALK', 'Gene', '238', (125, 128))	('patients', 'Species', '9606', (142, 150))	('ALK', 'Gene', (125, 128))
55184	32164629	The results showed that NHERF1 ectopic expression was able to increase the drug sensitivity of crizotinib treatments.	('NHERF1', 'Gene', (24, 30))	('crizotinib', 'Chemical', 'MESH:D000077547', (95, 105))	('drug sensitivity', 'Phenotype', 'HP:0020174', (75, 91))	('drug sensitivity', 'MPA', (75, 91))	('ectopic expression', 'Var', (31, 49))	('increase', 'PosReg', (62, 70))
55203	32164629	The anti-AKT, anti-p-AKT (Ser473), anti-ALK, anti-p-ALK (Tyr1604) antibodies were from Cell Signaling Technology (Danvers, MA, USA).	('Tyr1604', 'Chemical', '-', (57, 64))	('ALK', 'Gene', (40, 43))	('AKT', 'Gene', '207', (9, 12))	('Ser473', 'Var', (26, 32))	('AKT', 'Gene', (21, 24))	('ALK', 'Gene', '238', (52, 55))	('AKT', 'Gene', '207', (21, 24))	('Ser473', 'Chemical', '-', (26, 32))	('AKT', 'Gene', (9, 12))	('ALK', 'Gene', '238', (40, 43))	('Signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('ALK', 'Gene', (52, 55))
55228	32164629	By knockdown of NHERF1 expression in H3122 cells, Increased cell survival was observed from the crizotinib dose administration curve (Fig.	('Increased', 'PosReg', (50, 59))	('crizotinib', 'Chemical', 'MESH:D000077547', (96, 106))	('knockdown', 'Var', (3, 12))	('cell survival', 'CPA', (60, 73))	('NHERF1', 'Gene', (16, 22))
55229	32164629	These results indicated that the knockdown of NHERF1 could reduce the sensitivity to crizotinib in ALK-positive cells.	('NHERF1', 'Gene', (46, 52))	('knockdown', 'Var', (33, 42))	('ALK', 'Gene', (99, 102))	('crizotinib', 'Chemical', 'MESH:D000077547', (85, 95))	('reduce', 'NegReg', (59, 65))	('ALK', 'Gene', '238', (99, 102))
55230	32164629	To further examine whether NHERF1 knockdown in ALK positive cells indeed alters the ALK kinase activity thus to alter crizotinib sensitivity, we analyzed the phosphorylation of ALK and related signal molecules.	('alter', 'Reg', (112, 117))	('crizotinib', 'Chemical', 'MESH:D000077547', (118, 128))	('ALK', 'Gene', (84, 87))	('kinase activity', 'molecular_function', 'GO:0016301', ('88', '103'))	('ALK', 'Gene', '238', (177, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('ALK', 'Gene', (47, 50))	('NHERF1', 'Gene', (27, 33))	('ALK', 'Gene', (177, 180))	('activity', 'MPA', (95, 103))	('ALK', 'Gene', '238', (84, 87))	('ALK', 'Gene', '238', (47, 50))	('crizotinib sensitivity', 'MPA', (118, 140))	('knockdown', 'Var', (34, 43))	('alters', 'Reg', (73, 79))
55231	32164629	In NHERF1 knockdown H3122 cells, the levels of phosphorylated ALK were significantly increased (Fig.	('NHERF1', 'Gene', (3, 9))	('ALK', 'Gene', (62, 65))	('increased', 'PosReg', (85, 94))	('ALK', 'Gene', '238', (62, 65))	('knockdown', 'Var', (10, 19))
55236	32164629	This at least partially explained previously discovered crizotinib sensitivity loss after RNAi of NHERF1, where the accompanied increase in ALK activation is expected to require increased drug dose to achieve the same level of induction for apoptosis.	('loss', 'NegReg', (79, 83))	('increased drug dose', 'Phenotype', 'HP:0020170', (178, 197))	('increase', 'PosReg', (128, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('241', '250'))	('NHERF1', 'Gene', (98, 104))	('ALK', 'Gene', (140, 143))	('crizotinib sensitivity', 'MPA', (56, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('241', '250'))	('RNAi', 'biological_process', 'GO:0016246', ('90', '94'))	('ALK', 'Gene', '238', (140, 143))	('RNAi', 'Var', (90, 94))	('crizotinib', 'Chemical', 'MESH:D000077547', (56, 66))
55238	32164629	The results suggested that NHERF1 overexpression decreased activation of ALK and associated ERK or AKT signaling.	('overexpression', 'Var', (34, 48))	('AKT signaling', 'biological_process', 'GO:0043491', ('99', '112'))	('ALK', 'Gene', '238', (73, 76))	('AKT', 'Gene', '207', (99, 102))	('NHERF1', 'Gene', (27, 33))	('decreased', 'NegReg', (49, 58))	('ERK', 'Gene', (92, 95))	('ERK', 'Gene', '2048', (92, 95))	('AKT', 'Gene', (99, 102))	('ALK', 'Gene', (73, 76))	('ERK', 'molecular_function', 'GO:0004707', ('92', '95'))
55274	32164629	Resistance to crizotinib can occur via secondary mutations or amplification in the ALK gene.	('occur', 'Reg', (29, 34))	('ALK', 'Gene', '238', (83, 86))	('ALK', 'Gene', (83, 86))	('amplification', 'Var', (62, 75))	('crizotinib', 'Chemical', 'MESH:D000077547', (14, 24))
55287	32164629	The reduction in NHERF1 expression in cancer cells treated with crizotinib is likely to suggest acceleration of tumor progression, as well as the resistance to drugs.	('acceleration', 'PosReg', (96, 108))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('expression', 'MPA', (24, 34))	('NHERF1', 'Gene', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('crizotinib', 'Chemical', 'MESH:D000077547', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('reduction', 'NegReg', (4, 13))	('tumor', 'Disease', (112, 117))	('crizotinib', 'Var', (64, 74))
55306	32158232	Our study data suggest that DNDA inhibits cell proliferation and induces apoptosis in lung cancer cells.	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('rat', 'Species', '10116', (54, 57))	('induces', 'Reg', (65, 72))	('cell proliferation', 'CPA', (42, 60))	('DNDA', 'Chemical', '-', (28, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('apoptosis', 'CPA', (73, 82))	('lung cancer', 'Disease', (86, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('DNDA', 'Var', (28, 32))	('inhibits', 'NegReg', (33, 41))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
55313	32158232	Lung cancer arises as a result of the progressive appearance of genetic and epigenetic alterations, both in oncogenes and tumor-suppressor genes; ultimately, this leads to deregulated activation of mitogenic and survival signaling pathways.	('activation', 'PosReg', (184, 194))	('genetic', 'Var', (64, 71))	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('rat', 'Species', '10116', (91, 94))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('122', '138'))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('deregulated', 'MPA', (172, 183))	('Lung cancer', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('122', '138'))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('tumor', 'Disease', (122, 127))	('epigenetic alterations', 'Var', (76, 98))
55314	32158232	Scientists have extensively studied genetic alterations in non-small cell lung cancer (NSCLC) tumors, including oncogenic mutations in the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor 2 (HER2), mesenchymal-epithelial transition (MET), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), B-Raf proto-oncogene (BRAF), extracellular signal-regulated kinase (ERK) and Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), as well as inactivation of tumor suppressor genes like p53, Phosphatase and Tensin homolog (PTEN), retinoblastoma protein (Rb), and cyclin-dependent kinase inhibitor 2A (p16).	('anaplastic lymphoma kinase', 'Gene', (180, 206))	('B-Raf proto-oncogene', 'Gene', (352, 372))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (180, 199))	('KRAS', 'Gene', (475, 479))	('tumor', 'Phenotype', 'HP:0002664', (509, 514))	('rat', 'Species', '10116', (437, 440))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('139', '162'))	('PIK3CA', 'Gene', '5290', (343, 349))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (614, 650))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('BRAF', 'Gene', (374, 378))	('BRAF', 'Gene', '673', (374, 378))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('254', '287'))	('rat', 'Species', '10116', (48, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (191, 199))	('p16', 'Gene', (652, 655))	('sarcoma', 'Disease', 'MESH:D012509', (441, 448))	('retinoblastoma', 'Disease', 'MESH:D012175', (581, 595))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('509', '525'))	('EGFR', 'Gene', '1956', (173, 177))	('sarcoma', 'Disease', (441, 448))	('HER2', 'Gene', (247, 251))	('human', 'Species', '9606', (214, 219))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('614', '647'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('509', '525'))	('PIK3CA', 'Gene', (343, 349))	('KRAS', 'Gene', '24525', (475, 479))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '25163', (614, 650))	('tumor', 'Disease', (509, 514))	('ERK', 'Gene', '5594', (420, 423))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('protein', 'cellular_component', 'GO:0003675', ('596', '603'))	('PTEN', 'Gene', (574, 578))	('ALK', 'Gene', '238', (208, 211))	('retinoblastoma', 'Phenotype', 'HP:0009919', (581, 595))	('sarcoma', 'Phenotype', 'HP:0100242', (441, 448))	('Phosphatase and Tensin homolog', 'cellular_component', 'GO:1990455', ('542', '572'))	('epidermal growth factor receptor', 'Gene', (139, 171))	('p53', 'Gene', '301300', (537, 540))	('inactivation', 'Var', (493, 505))	('tumor', 'Disease', 'MESH:D009369', (509, 514))	('HER2', 'Gene', '2064', (247, 251))	('ERK', 'molecular_function', 'GO:0004707', ('420', '423'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('220', '243'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('extracellular signal-regulated kinase', 'Gene', (381, 418))	('non-small cell lung cancer (NSCLC) tumors', 'Disease', 'MESH:D002289', (59, 100))	('ALK', 'Gene', (208, 211))	('B-Raf proto-oncogene', 'Gene', '673', (352, 372))	('p53', 'Gene', (537, 540))	('retinoblastoma', 'Disease', (581, 595))	('epidermal growth factor receptor', 'Gene', '1956', (139, 171))	('Phosphatase', 'molecular_function', 'GO:0016791', ('542', '553'))	('ERK', 'Gene', (420, 423))	('tumor', 'Disease', (94, 99))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('631', '647'))	('anaplastic lymphoma kinase', 'Gene', '238', (180, 206))	('mutations', 'Var', (122, 131))	('extracellular signal-regulated kinase', 'Gene', '5594', (381, 418))	('p16', 'Gene', '25163', (652, 655))	('extracellular', 'cellular_component', 'GO:0005576', ('381', '394'))	('EGFR', 'Gene', (173, 177))
55326	32158232	Studied indicate that Inhibition of FAK expression reduces the migration and invasion of epidermal growth factor (EGF) stimulated human carcinoma cells.	('Inhibition', 'Var', (22, 32))	('FAK', 'molecular_function', 'GO:0004717', ('36', '39'))	('reduces', 'NegReg', (51, 58))	('FAK', 'Protein', (36, 39))	('invasion', 'CPA', (77, 85))	('carcinoma', 'Disease', 'MESH:D002277', (136, 145))	('EGF', 'molecular_function', 'GO:0005154', ('114', '117'))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('89', '112'))	('rat', 'Species', '10116', (66, 69))	('migration', 'CPA', (63, 72))	('carcinoma', 'Disease', (136, 145))	('human', 'Species', '9606', (130, 135))
55332	32158232	After integrin stimulation, Cbl recognizes the phosphorylated FAK before it degrades via the Cbl-dependent proteasomal pathway.	('FAK', 'molecular_function', 'GO:0004717', ('62', '65'))	('Cbl', 'Gene', '374038', (28, 31))	('phosphorylated', 'Var', (47, 61))	('Cbl', 'Gene', (28, 31))	('Cbl', 'Gene', '374038', (93, 96))	('Cbl', 'Gene', (93, 96))	('proteasomal pathway', 'biological_process', 'GO:0043161', ('107', '126'))	('degrades', 'NegReg', (76, 84))
55418	32158232	Since DNDA treatment of metastatic (A549 & H1299) lung cancer cells significantly reduced cell proliferation, we further used Western blot analysis and flow cytometry methods (Figure 4C-H) to investigate whether knocking down aPKCs could induce apoptosis by determining the expression levels of various apoptotic and anti-apoptotic proteins (Figure 4A and B).	('eta', 'Gene', '1909', (25, 28))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('PKC', 'Gene', '112476', (227, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('eta', 'Gene', (25, 28))	('induce', 'CPA', (238, 244))	('PKC', 'Gene', (227, 230))	('apoptosis', 'biological_process', 'GO:0097194', ('245', '254'))	('apoptosis', 'biological_process', 'GO:0006915', ('245', '254'))	('men', 'Species', '9606', (16, 19))	('rat', 'Species', '10116', (102, 105))	('could', 'PosReg', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('down', 'Gene', (221, 225))	('DNDA', 'Chemical', '-', (6, 10))	('H1299', 'CellLine', 'CVCL:0060', (43, 48))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('the expression', 'MPA', (270, 284))	('significantly', 'NegReg', (68, 81))	('lung cancer', 'Disease', (50, 61))	('reduced cell', 'CPA', (82, 94))	('whether knocking', 'Var', (204, 220))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))
55424	32158232	The Western blot data of apoptotic markers and flow cytometry analysis results suggest that inhibition of aPKCs by DNDA in metastatic lung cancer cells induced apoptosis in the current study.	('apoptosis', 'CPA', (160, 169))	('inhibition', 'Var', (92, 102))	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('PKC', 'Gene', (107, 110))	('PKC', 'Gene', '112476', (107, 110))	('eta', 'Gene', '1909', (124, 127))	('eta', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('DNDA', 'Chemical', '-', (115, 119))	('DNDA', 'Gene', (115, 119))
55428	32158232	In comparison, there was no significant reduction in phospho PKC-zeta T410 (12%) in A549 lung cancer cells.	('PKC', 'molecular_function', 'GO:0004697', ('61', '64'))	('PKC-zeta', 'Gene', (61, 69))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('T410', 'Var', (70, 74))	('reduction', 'NegReg', (40, 49))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PKC-zeta', 'Gene', '5590', (61, 69))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))
55430	32158232	These results suggest that targeting PKC-iota inhibition will decrease the FAK activity in lung cancer cells, making the DNDA an excellent candidate for lung cancer treatment.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('FAK', 'molecular_function', 'GO:0004717', ('75', '78'))	('inhibition', 'Var', (46, 56))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('iota', 'Chemical', '-', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('FAK', 'CPA', (75, 78))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('men', 'Species', '9606', (170, 173))	('lung cancer', 'Disease', (153, 164))	('decrease', 'NegReg', (62, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('PKC', 'Gene', (37, 40))	('PKC', 'Gene', '112476', (37, 40))	('DNDA', 'Chemical', '-', (121, 125))	('PKC', 'molecular_function', 'GO:0004697', ('37', '40'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', (91, 102))
55436	32158232	Interestingly, knocking down PKC-iota significantly reduced FAK expression by a figure of 34% (p < 0.01) (Figure 6C and F).	('reduced', 'NegReg', (52, 59))	('knocking down', 'Var', (15, 28))	('FAK expression', 'MPA', (60, 74))	('FAK', 'molecular_function', 'GO:0004717', ('60', '63'))	('iota', 'Chemical', '-', (33, 37))	('PKC', 'Gene', (29, 32))	('PKC', 'Gene', '112476', (29, 32))	('PKC', 'molecular_function', 'GO:0004697', ('29', '32'))
55437	32158232	On the contrary, knocking down PKC-zeta did not change the expression of FAK (Figure 6D and F).	('FAK', 'Disease', (73, 76))	('PKC-zeta', 'Gene', (31, 39))	('FAK', 'molecular_function', 'GO:0004717', ('73', '76'))	('PKC', 'molecular_function', 'GO:0004697', ('31', '34'))	('PKC-zeta', 'Gene', '5590', (31, 39))	('knocking down', 'Var', (17, 30))
55444	32158232	From the immunofluorescence images (Figure 7H), it is evident the DNDA treated cells had cleaved FAK when compared to control cells.	('FAK', 'molecular_function', 'GO:0004717', ('97', '100'))	('DNDA', 'Chemical', '-', (66, 70))	('DNDA treated', 'Var', (66, 78))	('cleaved FAK', 'CPA', (89, 100))
55450	32158232	The immunoblot showed the smear of bands when developed for the ubiquitin, and a FAK band (125 kDa) increased by 40% in the DNDA-treated lane (Figure 9A).	('increased', 'PosReg', (100, 109))	('FAK', 'molecular_function', 'GO:0004717', ('81', '84'))	('DNDA', 'Chemical', '-', (124, 128))	('ubiquitin', 'molecular_function', 'GO:0031386', ('64', '73'))	('125 kDa', 'Var', (91, 98))
55454	32158232	The Western blots data showed that PKC- iota knockdown decreased the expression of FAK by 70% in the absence of MG132.	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('PKC', 'Gene', (35, 38))	('PKC', 'Gene', '112476', (35, 38))	('FAK', 'molecular_function', 'GO:0004717', ('83', '86'))	('expression', 'MPA', (69, 79))	('decreased', 'NegReg', (55, 64))	('MG132', 'Chemical', 'MESH:C072553', (112, 117))	('iota', 'Chemical', '-', (40, 44))	('knockdown', 'Var', (45, 54))	('FAK', 'Protein', (83, 86))
55455	32158232	On the contrary, FAK expression returned with siPRKCI in the presence of MG132 by 40% (Figure 9D and E).	('returned', 'PosReg', (32, 40))	('siPRKCI', 'Chemical', '-', (46, 53))	('MG132', 'Chemical', 'MESH:C072553', (73, 78))	('FAK', 'molecular_function', 'GO:0004717', ('17', '20'))	('MG132', 'Var', (73, 78))	('FAK expression', 'MPA', (17, 31))
55456	32158232	This data implies that FAK undergoes ubiquitination and the presence of MG132 inhibited its subsequent degradation.	('inhibited', 'NegReg', (78, 87))	('degradation', 'MPA', (103, 114))	('presence', 'Var', (60, 68))	('MG132', 'Chemical', 'MESH:C072553', (72, 77))	('FAK', 'molecular_function', 'GO:0004717', ('23', '26'))	('degradation', 'biological_process', 'GO:0009056', ('103', '114'))	('ubiquitination', 'MPA', (37, 51))	('MG132', 'Gene', (72, 77))
55468	32158232	Studies have clearly identified specific oncogenic mutations and multiple signaling pathways that lead to malignant transformations in lung cancer.	('malignant transformations', 'CPA', (106, 131))	('mutations', 'Var', (51, 60))	('lead to', 'Reg', (98, 105))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
55475	32158232	Our recently published study showed that DNDA interacted with the catalytic domains of PKC- iota (amino acid residues of Asp 339, Asp 382, Leu 385 and Thr 395) and PKC-zeta (at Asp 337, Asp 380, Leu 383 and Thr 393).	('Asp 380', 'Var', (186, 193))	('DNDA', 'Chemical', '-', (41, 45))	('PKC-zeta', 'Gene', (164, 172))	('PKC', 'molecular_function', 'GO:0004697', ('87', '90'))	('Leu', 'Chemical', 'MESH:D007930', (195, 198))	('Leu', 'Chemical', 'MESH:D007930', (139, 142))	('PKC', 'Gene', '112476', (87, 90))	('Leu 383', 'Var', (195, 202))	('Leu 385', 'Var', (139, 146))	('Thr 393', 'Var', (207, 214))	('Asp', 'Chemical', 'MESH:D001224', (177, 180))	('Asp 382', 'Var', (130, 137))	('iota', 'Chemical', '-', (92, 96))	('PKC-zeta', 'Gene', '5590', (164, 172))	('Asp', 'Chemical', 'MESH:D001224', (186, 189))	('PKC', 'Gene', '112476', (164, 167))	('Thr', 'Chemical', 'MESH:D013912', (207, 210))	('interacted', 'Reg', (46, 56))	('PKC', 'molecular_function', 'GO:0004697', ('164', '167'))	('PKC', 'Gene', (87, 90))	('Asp', 'Chemical', 'MESH:D001224', (130, 133))	('Thr 395', 'Var', (151, 158))	('Thr', 'Chemical', 'MESH:D013912', (151, 154))	('Asp', 'Chemical', 'MESH:D001224', (121, 124))	('PKC', 'Gene', (164, 167))
55489	32158232	The resulting data showed that the knock down of PKC-iota resulted in a significant decrease in FAK expression.	('decrease', 'NegReg', (84, 92))	('PKC', 'molecular_function', 'GO:0004697', ('49', '52'))	('knock down', 'Var', (35, 45))	('PKC', 'Gene', (49, 52))	('PKC', 'Gene', '112476', (49, 52))	('FAK', 'molecular_function', 'GO:0004717', ('96', '99'))	('FAK expression', 'MPA', (96, 110))	('iota', 'Chemical', '-', (53, 57))
55490	32158232	On the contrary, the knock down of PKC-zeta had no effect in terms of FAK expression (Figure 6).	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('PKC-zeta', 'Gene', '5590', (35, 43))	('PKC-zeta', 'Gene', (35, 43))	('knock down', 'Var', (21, 31))	('FAK expression', 'MPA', (70, 84))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))
55505	32158232	The data showed that the knock down of PKC-iota significantly reduced the expression of FAK in the absence of MG132.	('knock down', 'Var', (25, 35))	('expression', 'MPA', (74, 84))	('iota', 'Chemical', '-', (43, 47))	('FAK', 'molecular_function', 'GO:0004717', ('88', '91'))	('FAK', 'Protein', (88, 91))	('PKC', 'Gene', (39, 42))	('MG132', 'Chemical', 'MESH:C072553', (110, 115))	('PKC', 'Gene', '112476', (39, 42))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))	('reduced', 'NegReg', (62, 69))
55506	32158232	On the contrary, there was a significant increase in FAK levels in the presence of MG132, indicating the role of PKC-iota  in FAK protein stability (Figure 9D and E).	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('FAK levels', 'MPA', (53, 63))	('FAK', 'molecular_function', 'GO:0004717', ('126', '129'))	('MG132', 'Chemical', 'MESH:C072553', (83, 88))	('PKC', 'molecular_function', 'GO:0004697', ('113', '116'))	('MG132', 'Var', (83, 88))	('iota', 'Chemical', '-', (117, 121))	('FAK', 'molecular_function', 'GO:0004717', ('53', '56'))	('PKC', 'Gene', (113, 116))	('PKC', 'Gene', '112476', (113, 116))	('increase', 'PosReg', (41, 49))
55597	32050475	This is supported by studies which have found that structural differences in O-antigen of LPS molecule are able to modulate its recognition and phagocytosis by macrophages.	('modulate', 'Reg', (115, 123))	('phagocytosis by macrophages', 'CPA', (144, 171))	('LPS', 'Gene', '21898', (90, 93))	('LPS', 'Gene', (90, 93))	('recognition', 'CPA', (128, 139))	('structural differences', 'Var', (51, 73))	('phagocytosis', 'biological_process', 'GO:0006909', ('144', '156'))
55599	32050475	This research group observed better response of A549 cells to P. aeruginosa LPS than groups which used LPS from E. coli.	('LPS', 'Gene', '21898', (103, 106))	('LPS', 'Gene', '21898', (76, 79))	('response', 'MPA', (36, 44))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('LPS', 'Gene', (103, 106))	('P. aeruginosa', 'Var', (62, 75))	('LPS', 'Gene', (76, 79))	('E. coli', 'Species', '562', (112, 119))	('better', 'PosReg', (29, 35))	('P. aeruginosa', 'Species', '287', (62, 75))
55600	32050475	They have suggested that LPS from P. aeruginosa could elicit a stronger response of lung epithelial cells than E. coli because P. aeruginosa is one of the key respiratory pathogens while E. coli is more common in the gastrointestinal and genitourinary tracts.	('LPS', 'Gene', (25, 28))	('gastrointestinal', 'Disease', 'MESH:D005767', (217, 233))	('E. coli', 'Species', '562', (111, 118))	('E. coli', 'Species', '562', (187, 194))	('P. aeruginosa', 'Var', (127, 140))	('rat', 'Species', '10116', (164, 167))	('gastrointestinal', 'Disease', (217, 233))	('P. aeruginosa', 'Species', '287', (34, 47))	('LPS', 'Gene', '21898', (25, 28))	('P. aeruginosa', 'Species', '287', (127, 140))
55624	32050475	Aside from GSH replenishment, NAC acts as a ROS scavenger and was shown to suppress NF-kappaB activation and subsequent cytokine production in cultured cells and patients with sepsis.	('patients', 'Species', '9606', (162, 170))	('cytokine production', 'MPA', (120, 139))	('NF-kappaB', 'Gene', (84, 93))	('NF-kappaB', 'Gene', '4790', (84, 93))	('NAC', 'Chemical', 'MESH:D000111', (30, 33))	('sepsis', 'Phenotype', 'HP:0100806', (176, 182))	('sepsis', 'Disease', (176, 182))	('suppress', 'NegReg', (75, 83))	('NAC', 'Var', (30, 33))	('cytokine production', 'biological_process', 'GO:0001816', ('120', '139'))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('NAC', 'cellular_component', 'GO:0005854', ('30', '33'))	('sepsis', 'Disease', 'MESH:D018805', (176, 182))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('84', '104'))	('GSH', 'Chemical', '-', (11, 14))	('activation', 'PosReg', (94, 104))
55652	32050475	As the molecular mechanism responsible for changes in SP expression, activation of the NF-kappaB pathway and the subsequent release of cytokines, has been suggested.	('changes', 'Var', (43, 50))	('NF-kappaB', 'Gene', '4790', (87, 96))	('SP', 'Chemical', '-', (54, 56))	('NF-kappaB', 'Gene', (87, 96))	('SP expression', 'MPA', (54, 67))	('activation', 'PosReg', (69, 79))
55738	32010427	In two-chamber invasion assays, KHSRP siRNA-transfected S2-013 cells were significantly less invasive than scrambled control siRNA-transfected S2-013 cells (Figure 2C).	('invasive', 'CPA', (93, 101))	('S2-013', 'CellLine', 'CVCL:B280', (56, 62))	('less', 'NegReg', (88, 92))	('KHSRP siRNA-transfected', 'Var', (32, 55))	('S2-013', 'CellLine', 'CVCL:B280', (143, 149))
55742	32010427	Moreover, KHSRP siRNA-transfected S2-013 cells did not form hepatic or lung metastases, whereas hepatic and lung metastases were seen in scrambled control siRNA-transfected S2-013 cells.	('KHSRP', 'Var', (10, 15))	('metastases', 'Disease', 'MESH:D009362', (76, 86))	('S2-013', 'CellLine', 'CVCL:B280', (173, 179))	('metastases', 'Disease', (113, 123))	('hepatic or lung metastases', 'Disease', (60, 86))	('hepatic or lung metastases', 'Disease', 'MESH:D009362', (60, 86))	('S2-013', 'CellLine', 'CVCL:B280', (34, 40))	('metastases', 'Disease', (76, 86))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
55745	32010427	To investigate whether KHSRP-containing granules were stress granules (SGs) or P-bodies, S2-013 and PANC-1 cells cultured on fibronectin were double-labeled with anti-KHSRP, anti-G3BP (a marker for SG), and anti-Ge-1/HEDLS (a marker for P-bodies) antibodies.	('HEDLS', 'Gene', '23644', (217, 222))	('PANC-1', 'CellLine', 'CVCL:0480', (100, 106))	('HEDLS', 'Gene', (217, 222))	('Ge', 'Chemical', 'MESH:D005857', (212, 214))	('G3BP', 'Gene', '10146', (179, 183))	('fibronectin', 'Gene', (125, 136))	('S2-013', 'CellLine', 'CVCL:B280', (89, 95))	('anti-KHSRP', 'Var', (162, 172))	('G3BP', 'Gene', (179, 183))	('fibronectin', 'Gene', '2335', (125, 136))
55755	32010427	SNORA18 and SNORA22 immunoprecipitated with anti-KHSRP antibody, whereas neither transcript immunoprecipitated with isotype control antibody.	('SNORA18', 'Gene', '677805', (0, 7))	('anti-KHSRP', 'Var', (44, 54))	('antibody', 'cellular_component', 'GO:0042571', ('132', '140'))	('antibody', 'cellular_component', 'GO:0042571', ('55', '63'))	('anti-KHSRP', 'Protein', (44, 54))	('SNORA22', 'Gene', '677807', (12, 19))	('SNORA18', 'Gene', (0, 7))	('antibody', 'cellular_component', 'GO:0019815', ('55', '63'))	('SNORA22', 'Gene', (12, 19))	('antibody', 'cellular_component', 'GO:0019815', ('132', '140'))	('antibody', 'cellular_component', 'GO:0019814', ('55', '63'))	('antibody', 'cellular_component', 'GO:0019814', ('132', '140'))	('antibody', 'molecular_function', 'GO:0003823', ('55', '63'))	('antibody', 'molecular_function', 'GO:0003823', ('132', '140'))
55758	32010427	Confocal microscopy showed that peripheral actin structures were less abundant in KHSRP siRNA-transfected S2-013 cells than in scrambled control siRNA-transfected S2-013 cells grown on fibronectin (Figure 5A).	('KHSRP siRNA-transfected', 'Var', (82, 105))	('fibronectin', 'Gene', (185, 196))	('S2-013', 'CellLine', 'CVCL:B280', (163, 169))	('fibronectin', 'Gene', '2335', (185, 196))	('peripheral actin structures', 'Protein', (32, 59))	('less', 'NegReg', (65, 69))	('S2-013', 'CellLine', 'CVCL:B280', (106, 112))
55761	32010427	Cell protrusions were significantly more abundant in KHSRP siRNA-transfected S2-013 cells carrying a KHSRP-rescue construct than in KHSRP siRNA-transfected S2-013 cells not carrying a KHSRP-rescue construct (Figure 5C).	('S2-013', 'CellLine', 'CVCL:B280', (156, 162))	('Cell protrusions', 'CPA', (0, 16))	('KHSRP-rescue construct', 'Var', (101, 123))	('S2-013', 'CellLine', 'CVCL:B280', (77, 83))	('more', 'PosReg', (36, 40))
55781	32010427	First, KHSRP prompts invasiveness and metastasis of PDAC cells.	('KHSRP', 'Var', (7, 12))	('PDAC', 'Phenotype', 'HP:0006725', (52, 56))	('PDAC', 'Disease', 'MESH:D021441', (52, 56))	('invasiveness', 'CPA', (21, 33))	('PDAC', 'Disease', (52, 56))	('metastasis', 'CPA', (38, 48))
55792	32010427	Deregulation of Wnt/beta-catenin signaling is implicated in PDAC and promotes cell invasion and metastasis of PDAC.	('metastasis', 'CPA', (96, 106))	('PDAC', 'Disease', 'MESH:D021441', (60, 64))	('Deregulation', 'Var', (0, 12))	('PDAC', 'Disease', (60, 64))	('implicated', 'Reg', (46, 56))	('beta-catenin', 'Gene', '1499', (20, 32))	('PDAC', 'Phenotype', 'HP:0006725', (60, 64))	('promotes', 'PosReg', (69, 77))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('PDAC', 'Disease', (110, 114))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('PDAC', 'Disease', 'MESH:D021441', (110, 114))	('cell invasion', 'CPA', (78, 91))	('beta-catenin', 'Gene', (20, 32))
55793	32010427	Suppression of DVL3 enhances basal RAS-MEK-ERK activation and activates IGF signal transduction from the IGF1 receptor to RAS.	('activation', 'MPA', (47, 57))	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('IGF signal transduction', 'MPA', (72, 95))	('Suppression', 'Var', (0, 11))	('DVL3', 'Gene', '1857', (15, 19))	('signal transduction', 'biological_process', 'GO:0007165', ('76', '95'))	('ERK', 'Gene', (43, 46))	('enhances', 'PosReg', (20, 28))	('ERK', 'Gene', '5595;5594;5595', (43, 46))	('activates', 'PosReg', (62, 71))	('DVL3', 'Gene', (15, 19))
55799	32010427	It is interesting to consider the possibility that KHSRP-bound snoRNAs post-transcriptionally regulate levels of target mRNAs, and in turn they promote invasiveness and metastasis of PDAC cells.	('KHSRP-bound', 'Var', (51, 62))	('regulate', 'Reg', (94, 102))	('invasiveness', 'CPA', (152, 164))	('snoRNA', 'Gene', '84546', (63, 69))	('metastasis', 'CPA', (169, 179))	('promote', 'PosReg', (144, 151))	('levels of target mRNAs', 'MPA', (103, 125))	('PDAC', 'Disease', 'MESH:D021441', (183, 187))	('snoRNA', 'Gene', (63, 69))	('PDAC', 'Disease', (183, 187))	('PDAC', 'Phenotype', 'HP:0006725', (183, 187))
55801	32010427	p38-mediated phosphorylation of KHSRP post-transcriptionally downregulates utrophin A mRNA in skeletal muscle and may also enhance muscle regeneration.	('enhance', 'PosReg', (123, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('KHSRP', 'Protein', (32, 37))	('downregulates', 'NegReg', (61, 74))	('regeneration', 'biological_process', 'GO:0031099', ('138', '150'))	('p38', 'Gene', '5594', (0, 3))	('phosphorylation', 'Var', (13, 28))	('muscle regeneration', 'CPA', (131, 150))	('p38', 'Gene', (0, 3))	('utrophin A mRNA in skeletal muscle', 'MPA', (75, 109))
55811	32010427	The functional importance of the association of KHSRP with snoRNAs mediated regulation of the invasiveness and metastasis in PDAC cells suggests that inhibition of KHSRP expression, binding of KHSRP with snoRNAs, or expression of KHSRP-bound snoRNAs such as SNORA18 and SNORA22 may be effective for PDAC targeted molecular therapy.	('snoRNA', 'Gene', '84546', (242, 248))	('PDAC', 'Phenotype', 'HP:0006725', (299, 303))	('snoRNA', 'Gene', (204, 210))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))	('KHSRP', 'Gene', (193, 198))	('snoRNA', 'Gene', '84546', (59, 65))	('SNORA18', 'Gene', '677805', (258, 265))	('binding', 'molecular_function', 'GO:0005488', ('182', '189'))	('SNORA18', 'Gene', (258, 265))	('snoRNA', 'Gene', (242, 248))	('inhibition', 'Var', (150, 160))	('SNORA22', 'Gene', '677807', (270, 277))	('snoRNA', 'Gene', (59, 65))	('PDAC', 'Disease', 'MESH:D021441', (299, 303))	('PDAC', 'Disease', 'MESH:D021441', (125, 129))	('PDAC', 'Disease', (299, 303))	('PDAC', 'Disease', (125, 129))	('binding', 'Interaction', (182, 189))	('KHSRP', 'Gene', (164, 169))	('snoRNA', 'Gene', '84546', (204, 210))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('invasiveness', 'CPA', (94, 106))	('SNORA22', 'Gene', (270, 277))	('association', 'Interaction', (33, 44))
55893	27739358	It was indicated that lipophilicity of the Ahx linker significantly increases the binding affinity of the LHRH peptide to the receptor.	('increases', 'PosReg', (68, 77))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('Ahx', 'Chemical', 'MESH:D000614', (43, 46))	('binding affinity', 'Interaction', (82, 98))	('lipophilicity', 'Var', (22, 35))	('LHRH peptide', 'Protein', (106, 118))
55922	27739358	The result of this study revealed that attaching LHRH peptide to DDS augmented their anticancer efficacy to an extremely high level comparable for all three types of nanocarriers.	('augmented', 'PosReg', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('attaching', 'Var', (39, 48))	('cancer', 'Disease', (89, 95))	('LHRH peptide', 'Protein', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
55930	27739358	Moreover, the tumor amount of cisplatin in mice treated with LHRH-nanogels was 23% greater than in animals injected with non-targeted nanogels.	('mice', 'Species', '10090', (43, 47))	('tumor', 'Disease', (14, 19))	('greater', 'PosReg', (83, 90))	('LHRH-nanogels', 'Var', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
56029	31124059	Clinical Modality of Resistance and Subsequent Management of Patients with Advanced Non-small Cell Lung Cancer Failing Treatment with Osimertinib The third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment for patients with pretreated EGFR-mutated non-small cell lung cancer (NSCLC) who acquire the T790M resistance mutation.	('epidermal growth factor receptor', 'Gene', '1956', (167, 199))	('NSCLC', 'Disease', 'MESH:D002289', (355, 360))	('EGFR', 'Gene', (201, 205))	('T790M', 'Mutation', 'rs121434569', (378, 383))	('Non-small Cell Lung Cancer', 'Disease', (84, 110))	('EGFR', 'Gene', (314, 318))	('cell lung cancer', 'Disease', 'MESH:D008175', (337, 353))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('167', '190'))	('T790M resistance', 'Var', (378, 394))	('NSCLC', 'Disease', (355, 360))	('Non-small Cell Lung Cancer', 'Disease', 'MESH:D002289', (84, 110))	('cell lung cancer', 'Disease', (337, 353))	('EGFR', 'molecular_function', 'GO:0005006', ('314', '318'))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('osimertinib', 'Chemical', 'MESH:C000603933', (239, 250))	('patients', 'Species', '9606', (289, 297))	('NSCLC', 'Phenotype', 'HP:0030358', (355, 360))	('Osimertinib', 'Chemical', 'MESH:C000603933', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (342, 353))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('EGFR', 'Gene', '1956', (201, 205))	('Lung Cancer', 'Phenotype', 'HP:0100526', (99, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('201', '205'))	('EGFR', 'Gene', '1956', (314, 318))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (327, 353))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (331, 353))	('small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (88, 110))	('Non-small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (84, 110))	('Patients', 'Species', '9606', (61, 69))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('216', '232'))	('epidermal growth factor receptor', 'Gene', (167, 199))
56042	31124059	Approximately 50% of Asian patients with NSCLC harbor activating epidermal growth factor receptor (EGFR) mutations.	('activating', 'PosReg', (54, 64))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('65', '88'))	('EGFR', 'Gene', (99, 103))	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('epidermal growth factor receptor', 'Gene', (65, 97))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (105, 114))	('epidermal growth factor receptor', 'Gene', '1956', (65, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', '1956', (99, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
56044	31124059	Osimertinib is an oral irreversible third-generation EGFR-TKI, which targets both activating mutations and the T790M resistance mutation, while sparing wild-type EGFR.	('activating mutations', 'MPA', (82, 102))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('EGFR', 'Gene', (162, 166))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('T790M', 'Mutation', 'rs121434569', (111, 116))	('T790M', 'Var', (111, 116))
56045	31124059	Several clinical trials have shown higher response rates (60-70%) and longer progression-free survival (PFS) for osimertinib than platinum-based chemotherapy for advanced NSCLC patients with acquired T790M-mediated resistance to prior early-generation EGFR-TKIs.	('T790M', 'Mutation', 'rs121434569', (200, 205))	('EGFR', 'Gene', (252, 256))	('osimertinib', 'Chemical', 'MESH:C000603933', (113, 124))	('T790M-mediated', 'Var', (200, 214))	('EGFR', 'molecular_function', 'GO:0005006', ('252', '256'))	('patients', 'Species', '9606', (177, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('longer', 'PosReg', (70, 76))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('NSCLC', 'Disease', (171, 176))	('EGFR', 'Gene', '1956', (252, 256))	('response', 'MPA', (42, 50))	('higher', 'PosReg', (35, 41))	('progression-free survival', 'CPA', (77, 102))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
56052	31124059	Inclusion criteria included histologically or cytologically confirmed NSCLC, advanced stage (including stage IIIB and IV), harboring the T790M mutation, receiving osimertinib as a second-line or later therapy, and developing progressive disease (PD) while on osimertinib treatment.	('NSCLC', 'Disease', (70, 75))	('T790M', 'Mutation', 'rs121434569', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('osimertinib', 'Chemical', 'MESH:C000603933', (163, 174))	('progressive disease', 'Disease', (225, 244))	('T790M', 'Var', (137, 142))	('osimertinib', 'Chemical', 'MESH:C000603933', (259, 270))	('PD', 'Disease', 'MESH:D010300', (246, 248))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('developing', 'Reg', (214, 224))
56094	31124059	T790M loss was the most common phenomenon observed in 17 patients (17/30, 56.7%), among whom eight patients (8/17, 47.1%) continued osimertinib beyond PD and showed a median TD post-progression of 3.3 months (95% CI 0.2-6.4).	('loss', 'NegReg', (6, 10))	('patients', 'Species', '9606', (57, 65))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('PD', 'Disease', 'MESH:D010300', (151, 153))	('patients', 'Species', '9606', (99, 107))	('T790M', 'Var', (0, 5))	('osimertinib', 'Chemical', 'MESH:C000603933', (132, 143))
56096	31124059	Patients who retained the T790M mutation showed a trend for longer TD post-progression than in patients with T790M loss (median 6.0 vs. 3.3 months, p = 0.811) when osimertinib was used beyond PD.	('osimertinib', 'Chemical', 'MESH:C000603933', (164, 175))	('patients', 'Species', '9606', (95, 103))	('longer', 'PosReg', (60, 66))	('T790M', 'Mutation', 'rs121434569', (26, 31))	('PD', 'Disease', 'MESH:D010300', (192, 194))	('T790M', 'Var', (26, 31))	('T790M', 'Mutation', 'rs121434569', (109, 114))	('Patients', 'Species', '9606', (0, 8))
56097	31124059	OS and pOS were not mature, as only 4 of 13 and 6 of 17 patients had died in the T790M-retained and T790M-loss populations, respectively, at the time of data cutoff.	('patients', 'Species', '9606', (56, 64))	('T790M', 'Mutation', 'rs121434569', (81, 86))	('T790M-retained', 'Var', (81, 95))	('T790M-loss', 'Var', (100, 110))	('T790M', 'Mutation', 'rs121434569', (100, 105))
56104	31124059	In the phase II, single-arm ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) study, the median OS in patients who continued erlotinib beyond PD was 33.6 (95% CI 27.3-34.3) months compared with 22.5 (95% CI 20.1-27.0) months for patients who did not continue erlotinib treatment.	('PD', 'Disease', 'MESH:D010300', (167, 169))	('patients', 'Species', '9606', (254, 262))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('ASPIRATION', 'Phenotype', 'HP:0002835', (28, 38))	('Tarceva', 'Chemical', 'MESH:D000069347', (63, 70))	('erlotinib', 'Chemical', 'MESH:D000069347', (284, 293))	('erlotinib', 'Chemical', 'MESH:D000069347', (150, 159))	('patients', 'Species', '9606', (127, 135))	('EGFR', 'Gene', '1956', (88, 92))	('mutation', 'Var', (93, 101))	('EGFR', 'Gene', (88, 92))
56121	31124059	T790M loss and T790M retention were two basic modes, which may inform strategies for subsequent treatment and predict survival.	('retention', 'biological_process', 'GO:0051235', ('21', '30'))	('T790M', 'Mutation', 'rs121434569', (15, 20))	('T790M', 'Var', (15, 20))	('T790M loss', 'Var', (0, 10))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('inform', 'Reg', (63, 69))
56122	31124059	Our study showed a longer osimertinib TD post-progression in patients who retained the T790M mutation than in those who presented T790M loss, which means T790M-retained tumors may benefit more from osimertinib continuation treatment.	('osimertinib', 'Chemical', 'MESH:C000603933', (26, 37))	('osimertinib', 'Chemical', 'MESH:C000603933', (198, 209))	('longer', 'PosReg', (19, 25))	('T790M', 'Mutation', 'rs121434569', (154, 159))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('T790M', 'Mutation', 'rs121434569', (130, 135))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('benefit', 'PosReg', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('T790M', 'Mutation', 'rs121434569', (87, 92))	('tumors', 'Disease', (169, 175))	('T790M', 'Var', (87, 92))	('osimertinib TD', 'MPA', (26, 40))
56123	31124059	Additional EGFR mutations, such as the C797S mutation, were the most common mechanisms of resistance to osimertinib, and combining EAI045 or afatinib with cetuximab could be used to treat such patients.	('patients', 'Species', '9606', (193, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('cetuximab', 'Chemical', 'MESH:D000068818', (155, 164))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('C797S', 'Var', (39, 44))	('osimertinib', 'Chemical', 'MESH:C000603933', (104, 115))	('afatinib', 'Chemical', 'MESH:D000077716', (141, 149))	('C797S', 'Mutation', 'rs1057519861', (39, 44))
56128	31124059	A study assessed the efficacy of platinum-doublet chemotherapy in NSCLC patients harboring EGFR mutations as second-line treatment and demonstrated that PFS and ORR were not different between T790M-positive and T790M-negative populations.	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('EGFR', 'Gene', (91, 95))	('T790M', 'Mutation', 'rs121434569', (211, 216))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('T790M', 'Mutation', 'rs121434569', (192, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('platinum', 'Chemical', 'MESH:D010984', (33, 41))	('EGFR', 'Gene', '1956', (91, 95))	('mutations', 'Var', (96, 105))	('patients', 'Species', '9606', (72, 80))
56134	31124059	Continued osimertinib beyond PD in the local or gradual progression population and T790M-retained patients may provide additional clinical benefit, and further study is needed regarding whether combination of continued osimertinib with chemotherapy provides further survival benefit.	('osimertinib', 'Chemical', 'MESH:C000603933', (219, 230))	('osimertinib', 'Chemical', 'MESH:C000603933', (10, 21))	('clinical benefit', 'MPA', (130, 146))	('patients', 'Species', '9606', (98, 106))	('T790M', 'Mutation', 'rs121434569', (83, 88))	('PD', 'Disease', 'MESH:D010300', (29, 31))	('T790M-retained', 'Var', (83, 97))
56238	30666125	Mutant P53 proteins accumulate in cancer cells and induce circulating P53 antibodies in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (88, 94))	('proteins', 'Protein', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('induce', 'Reg', (51, 57))	('P53', 'Gene', (7, 10))	('P53', 'Gene', '7157', (7, 10))	('cancer', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Mutant', 'Var', (0, 6))	('P53', 'Gene', (70, 73))	('P53', 'Gene', '7157', (70, 73))	('accumulate', 'PosReg', (20, 30))
56253	30666125	In our study we found that the positive rate of AAB GBU4-5 in early T, N, and M stages decreased in late stages even though the differences were not statistically different.	('decreased', 'NegReg', (87, 96))	('M stages', 'CPA', (78, 86))	('AAB', 'Chemical', '-', (48, 51))	('AAB', 'Var', (48, 51))	('GBU4-5', 'Chemical', '-', (52, 58))
56291	30464531	Inhibition of NF-kappaB abolished the effects of TRIM32 on Bcl-2.	('Bcl-2', 'molecular_function', 'GO:0015283', ('59', '64'))	('TRIM32', 'Gene', (49, 55))	('TRIM32', 'Gene', '22954', (49, 55))	('NF-kappaB', 'Gene', '4790', (14, 23))	('NF-kappaB', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))	('Bcl-2', 'Gene', (59, 64))	('Bcl-2', 'Gene', '596', (59, 64))
56315	30464531	A549 was cultured using F12K medium with 10% FBS.	('FBS', 'Disease', (45, 48))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('F12K', 'SUBSTITUTION', 'None', (24, 28))	('F12K', 'Var', (24, 28))	('FBS', 'Disease', 'MESH:D005198', (45, 48))
56345	30464531	Next we used Western blot and qRT-PCR to check TRIM32 protein and mRNA in normal bronchial epithelial HBE cell line and seven cancer cell lines including A549, H1299, H460, H358, H3255, H1975, and H2228 (Figure 3A).	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HBE', 'Gene', '3046', (102, 105))	('H358', 'CellLine', 'CVCL:1559', (173, 177))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('HBE', 'Gene', (102, 105))	('H1975', 'CellLine', 'CVCL:1511', (186, 191))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('H3255', 'CellLine', 'CVCL:6831', (179, 184))	('H3255', 'Var', (179, 184))	('H1299', 'CellLine', 'CVCL:0060', (160, 165))	('TRIM32', 'Gene', (47, 53))	('TRIM32', 'Gene', '22954', (47, 53))	('mRNA', 'MPA', (66, 70))	('H460', 'CellLine', 'CVCL:0459', (167, 171))
56358	30464531	The apoptosis rate was much lower in A549-TRIM32 cells than in control A549 cells after 24 hours of cisplatin (5 microg/mL) treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('lower', 'NegReg', (28, 33))	('apoptosis', 'biological_process', 'GO:0006915', ('4', '13'))	('apoptosis', 'biological_process', 'GO:0097194', ('4', '13'))	('A549-TRIM32', 'CellLine', 'CVCL:0023', (37, 48))	('apoptosis rate', 'CPA', (4, 18))	('A549', 'CellLine', 'CVCL:0023', (37, 41))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('A549-TRIM32', 'Var', (37, 48))
56367	30464531	Accordingly, TRIM32 depletion increased cisplatin-induced ROS accumulation in H1299-shTRIM32 cells (Figure 6B).	('TRIM32', 'Gene', (86, 92))	('TRIM32', 'Gene', '22954', (13, 19))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('H1299-shTRIM32', 'CellLine', 'CVCL:0060', (78, 92))	('TRIM32', 'Gene', (13, 19))	('TRIM32', 'Gene', '22954', (86, 92))	('depletion', 'Var', (20, 29))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('increased', 'PosReg', (30, 39))	('cisplatin-induced ROS accumulation', 'MPA', (40, 74))
56371	30464531	On the other hand, H1299-shTRIM32 showed increased level of caspase 3 cleavage and cytochrome c release, with downregulation of Bcl-2 expression (Figures 5C and 7A).	('Bcl-2', 'molecular_function', 'GO:0015283', ('128', '133'))	('caspase 3', 'Gene', '836', (60, 69))	('increased', 'PosReg', (41, 50))	('H1299-shTRIM32', 'CellLine', 'CVCL:0060', (19, 33))	('Bcl-2', 'Gene', (128, 133))	('cytochrome c', 'Gene', '54205', (83, 95))	('Bcl-2', 'Gene', '596', (128, 133))	('cytochrome c', 'molecular_function', 'GO:0009461', ('83', '95'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('83', '95'))	('caspase 3', 'Gene', (60, 69))	('downregulation', 'NegReg', (110, 124))	('H1299-shTRIM32', 'Var', (19, 33))	('cytochrome c', 'Gene', (83, 95))
56381	30464531	Our result was also supported by The Cancer Genome Atlas data, analysis of which showed that high TRIM32 levels correlated with poor prognosis in 488 cases of NSCLC patients.	('TRIM32', 'Gene', '22954', (98, 104))	('Cancer', 'Disease', 'MESH:D009369', (37, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('NSCLC', 'Disease', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('patients', 'Species', '9606', (165, 173))	('high', 'Var', (93, 97))	('TRIM32', 'Gene', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Cancer', 'Disease', (37, 43))
56394	30464531	Downregulation of MMP could trigger apoptosis through mitochondria-dependent pathway, which releases cytochrome c with increased membrane permeability.	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('MMP', 'molecular_function', 'GO:0004235', ('18', '21'))	('mitochondria-dependent pathway', 'Pathway', (54, 84))	('cytochrome c', 'Gene', (101, 113))	('apoptosis', 'CPA', (36, 45))	('membrane', 'cellular_component', 'GO:0016020', ('129', '137'))	('Downregulation', 'Var', (0, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('MMP', 'Gene', (18, 21))	('cytochrome c', 'Gene', '54205', (101, 113))	('cytochrome c', 'molecular_function', 'GO:0045155', ('101', '113'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('101', '113'))	('trigger', 'Reg', (28, 35))	('mitochondria', 'cellular_component', 'GO:0005739', ('54', '66'))	('membrane permeability', 'MPA', (129, 150))	('increased', 'PosReg', (119, 128))
56410	30464531	Blockage of TRIM32 expression and function may potentiate cisplatin responsiveness in NSCLC.	('Blockage', 'Var', (0, 8))	('expression', 'MPA', (19, 29))	('function', 'MPA', (34, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('TRIM32', 'Gene', (12, 18))	('cisplatin responsiveness', 'MPA', (58, 82))	('TRIM32', 'Gene', '22954', (12, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('potentiate', 'PosReg', (47, 57))
56453	30078843	The antibodies against beta-arrestin-1 (ARRB1) (#30036), beta-arrestin-1-2 (ARRB1-2) (#4674) and beta-arrestin-2 (ARRB2) (#3857) were obtained from Cell Signaling Technology (Beverly, MA, USA).	('ARRB2', 'Gene', '409', (114, 119))	('ARRB1', 'Gene', (40, 45))	('ARRB1', 'Gene', '408', (40, 45))	('#4674', 'Var', (86, 91))	('beta-arrestin-2', 'Gene', (97, 112))	('beta-arrestin-1', 'Gene', (57, 72))	('Signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('beta-arrestin-1-2', 'Gene', (57, 74))	('#30036', 'Var', (48, 54))	('beta-arrestin-2', 'Gene', '409', (97, 112))	('beta-arrestin-1', 'Gene', '408', (57, 72))	('ARRB1', 'Gene', (76, 81))	('beta-arrestin-1', 'Gene', (23, 38))	('ARRB1', 'Gene', '408', (76, 81))	('ARRB2', 'Gene', (114, 119))	('beta-arrestin-1-2', 'Gene', '408;409', (57, 74))	('beta-arrestin-1', 'Gene', '408', (23, 38))
56454	30078843	Anti-Thyroid Transcription Factor 1 (TTF1) (#M3575), anti-keratin 5-6 (KRT5-6) (#M7237) and anti-keratin 7 (KRT7) (#M7018) antibodies were obtained from Dako (Agilent Technologies, Mississauga, Ontario, Canada).	('TTF1', 'Gene', (37, 41))	('TTF1', 'Gene', '7270', (37, 41))	('KRT5-6', 'Gene', (71, 77))	('Anti-Thyroid Transcription Factor 1', 'Gene', '7270', (0, 35))	('keratin 7', 'Gene', '3855', (97, 106))	('Anti-Thyroid Transcription Factor 1', 'Gene', (0, 35))	('KRT7', 'Gene', '3855', (108, 112))	('#M7237', 'Var', (80, 86))	('KRT7', 'Gene', (108, 112))	('KRT5-6', 'Gene', '3852;140807', (71, 77))	('keratin 7', 'Gene', (97, 106))	('#M7018', 'Var', (115, 121))	('#M3575', 'Var', (44, 50))
56455	30078843	Antibodies against Tumour Protein p63 (p63) (#CM163C) and Napsin A (NAPSA) (#NCL-L-Napsin A) were obtained from Biocare Medical (Pacheco, CA, USA) and Leica Biosystems (Concord, ON, Canada), respectively.	('Napsin A', 'Gene', (83, 91))	('Napsin A', 'Gene', '9476', (58, 66))	('Napsin A', 'Gene', '9476', (83, 91))	('#CM163C', 'Var', (45, 52))	('p63', 'Gene', (34, 37))	('NAPSA', 'Gene', '9476', (68, 73))	('p63', 'Gene', '8626', (39, 42))	('Tumour', 'Phenotype', 'HP:0002664', (19, 25))	('NAPSA', 'Gene', (68, 73))	('p63', 'Gene', '8626', (34, 37))	('Napsin A', 'Gene', (58, 66))	('p63', 'Gene', (39, 42))
56534	30078843	In addition to this 4-protein combination, other combinations seemed to have a good performance, including the 3-protein combinations KRT7+KRT5-6+p63 (AIC = -7.583 and AUC = 1.000 in amsbio test dataset (Table 2 upper part) and AIC = -5.005 and AUC = 1.000 in the in-house test dataset (Table 2 lower part)) and beta-arrestin-1-2+KRT7+KRT5-6 (AIC = -9.216 and AUC = 0.998 in amsbio test dataset (Table 2 upper part), and AIC = -7.006 and AUC = 1.000 in the in-house test dataset (Table 2 lower part)).	('KRT7', 'Gene', '3855', (134, 138))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('KRT7', 'Gene', (134, 138))	('beta-arrestin-1-2', 'Gene', (312, 329))	('KRT5-6', 'Gene', '3852;140807', (139, 145))	('KRT5-6', 'Gene', (335, 341))	('KRT7', 'Gene', '3855', (330, 334))	('beta-arrestin-1-2', 'Gene', '408;409', (312, 329))	('AIC = -7.006', 'Var', (421, 433))	('p63', 'Gene', (146, 149))	('KRT7', 'Gene', (330, 334))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('KRT5-6', 'Gene', '3852;140807', (335, 341))	('AUC = 1.000', 'Var', (438, 449))	('KRT5-6', 'Gene', (139, 145))	('p63', 'Gene', '8626', (146, 149))
56574	30078843	Keeping this caveat in mind, our data suggest that beta-arrestin-1 would be downregulated during the squamous differentiation process and/or the mechanism of oncogenesis in SCC, similar to the loss-of-function mutations in NOTCH1 and the amplification of SOX2 and TP63.	('beta-arrestin-1', 'Gene', (51, 66))	('mutations', 'Var', (210, 219))	('oncogenesis', 'CPA', (158, 169))	('oncogenesis', 'biological_process', 'GO:0007048', ('158', '169'))	('beta-arrestin-1', 'Gene', '408', (51, 66))	('SCC', 'Gene', (173, 176))	('loss-of-function', 'NegReg', (193, 209))	('downregulated', 'NegReg', (76, 89))	('NOTCH1', 'Gene', '4851', (223, 229))	('NOTCH1', 'Gene', (223, 229))	('TP63', 'Gene', '8626', (264, 268))	('SOX2', 'Gene', (255, 259))	('SCC', 'Gene', '6317', (173, 176))	('SOX2', 'Gene', '6657', (255, 259))	('TP63', 'Gene', (264, 268))
56589	30078843	The same group made different statements in a subsequent paper, suggesting that loss of beta-arrestin-1 in both ADC and SCC was a predictor of poor survival, and that OS of ADC patients who showed beta-arrestin-1 expression in their cancer tissues was independent of its expression level.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('poor survival', 'CPA', (143, 156))	('SCC', 'Gene', '6317', (120, 123))	('patients', 'Species', '9606', (177, 185))	('loss', 'Var', (80, 84))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('beta-arrestin-1', 'Gene', (88, 103))	('beta-arrestin-1', 'Gene', (197, 212))	('beta-arrestin-1', 'Gene', '408', (197, 212))	('beta-arrestin-1', 'Gene', '408', (88, 103))	('SCC', 'Gene', (120, 123))
56606	30103780	EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors Lung adenocarcinoma with EGFR activating mutations will inevitably acquire resistance to first generation TKIs.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('T790M', 'Mutation', 'rs121434569', (5, 10))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('activating', 'PosReg', (223, 233))	('EGFR', 'molecular_function', 'GO:0005006', ('218', '222'))	('EGFR', 'Gene', (218, 222))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('EGFR', 'Gene', (161, 165))	('Lung adenocarcinoma', 'Disease', (193, 212))	('osimertinib', 'Chemical', 'MESH:C000603933', (25, 36))	('patients', 'Species', '9606', (107, 115))	('EGFR', 'Gene', (0, 4))	('acquire', 'Reg', (260, 267))	('EGFR', 'Gene', '1956', (218, 222))	('EGFR', 'Gene', '1956', (161, 165))	('mutations', 'Var', (234, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('lung adenocarcinoma', 'Disease', (87, 106))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (193, 212))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (193, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('resistance', 'MPA', (268, 278))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
56607	30103780	Acquired EGFR T790M mutation causes about 50% of these resistance cases.	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('T790M', 'Mutation', 'rs121434569', (14, 19))	('T790M', 'Var', (14, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
56611	30103780	Cobas  Mutation Test v2 kit was used to detect EGFR mutations in FFPE or plasma samples.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))
56616	30103780	Quantification of T790M after treatment decreased to very low level, but no association was observed between clinical response and T790M mutation level decrease.	('T790M', 'Var', (131, 136))	('men', 'Species', '9606', (35, 38))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('T790M', 'Mutation', 'rs121434569', (131, 136))	('Quantification', 'MPA', (0, 14))	('T790M', 'Var', (18, 23))
56618	30103780	EGFR T790M mutation level is not associated with clinical response after osimertinib treatment.	('EGFR', 'Gene', (0, 4))	('men', 'Species', '9606', (90, 93))	('T790M', 'Mutation', 'rs121434569', (5, 10))	('T790M', 'Var', (5, 10))	('osimertinib', 'Chemical', 'MESH:C000603933', (73, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
56620	30103780	Though epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved outcome of EGFR mutation positive advanced non-small cell lung cancer (NSCLC), most of these patients develop resistance to first generation EGFR TKIs after a median of 10-12 months, in which about 50-60% of these tumors harbor EGFR T790M resistance mutation.	('mutation', 'Var', (123, 131))	('EGFR', 'molecular_function', 'GO:0005006', ('248', '252'))	('epidermal growth factor receptor', 'Gene', (7, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('335', '339'))	('epidermal growth factor receptor', 'Gene', '1956', (7, 39))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (154, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('EGFR', 'Gene', (248, 252))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (150, 176))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', '1956', (118, 122))	('improved', 'PosReg', (98, 106))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('7', '30'))	('EGFR', 'Gene', (335, 339))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('non-small cell lung cancer', 'Disease', (150, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('tumors', 'Disease', (321, 327))	('NSCLC', 'Disease', (178, 183))	('EGFR', 'Gene', '1956', (248, 252))	('patients', 'Species', '9606', (200, 208))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (150, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('T790M', 'Mutation', 'rs121434569', (340, 345))	('EGFR', 'Gene', (118, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('T790M resistance', 'Var', (340, 356))	('EGFR', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (321, 327))	('EGFR', 'Gene', '1956', (335, 339))
56621	30103780	Osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR activating and T790M resistance mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'Gene', '1956', (73, 77))	('activating', 'PosReg', (78, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('EGFR', 'Gene', (73, 77))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('EGFR', 'Gene', '1956', (37, 41))	('T790M', 'Mutation', 'rs121434569', (93, 98))	('EGFR', 'Gene', (37, 41))	('T790M', 'Var', (93, 98))
56625	30103780	The use of circulating tumor DNA (ctDNA) to detect genetic alterations by various platforms known as liquid biopsy has provided a non-invasive option.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('genetic alterations', 'Var', (51, 70))
56626	30103780	The current study focuses on the efficacy of T790M detection by different platforms, as well as T790M level response after receiving osimertinib treatment.	('T790M', 'Var', (45, 50))	('osimertinib', 'Chemical', 'MESH:C000603933', (133, 144))	('T790M', 'Mutation', 'rs121434569', (45, 50))	('T790M', 'Mutation', 'rs121434569', (96, 101))	('men', 'Species', '9606', (150, 153))	('T790M', 'Var', (96, 101))
56628	30103780	ASTRIS (D5160C00022) is open label, multinational, multicenter, real world treatment study of single agent osimertinib for patients with advanced/metastatic EGFR T790M mutation positive NSCLC who have received prior therapy with an first generation EGFR-TKI.	('T790M', 'Var', (162, 167))	('EGFR', 'Gene', (157, 161))	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('249', '253'))	('NSCLC', 'Disease', (186, 191))	('patients', 'Species', '9606', (123, 131))	('men', 'Species', '9606', (80, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (249, 253))	('osimertinib', 'Chemical', 'MESH:C000603933', (107, 118))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('EGFR', 'Gene', '1956', (157, 161))	('ASTRIS', 'Chemical', '-', (0, 6))	('T790M', 'Mutation', 'rs121434569', (162, 167))
56631	30103780	EGFR T790M positive patients received osimertinib 80 mg Qd until disease progression evaluated by investigators.	('osimertinib', 'Chemical', 'MESH:C000603933', (38, 49))	('EGFR', 'Gene', (0, 4))	('T790M', 'Mutation', 'rs121434569', (5, 10))	('T790M', 'Var', (5, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('patients', 'Species', '9606', (20, 28))	('EGFR', 'Gene', '1956', (0, 4))
56634	30103780	Cobas  Mutation Test v2 kit was used to detect both EGFR activating mutation and T790M in FFPE or plasma samples.	('EGFR', 'Gene', '1956', (52, 56))	('T790M', 'Mutation', 'rs121434569', (81, 86))	('EGFR', 'Gene', (52, 56))	('T790M', 'Var', (81, 86))	('activating', 'PosReg', (57, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
56635	30103780	The Cobas is an allele-specific polymerase chain reaction assay to detect known common EGFR mutations.	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('mutations', 'Var', (92, 101))
56638	30103780	The SQI was derived from a dilution series with known copy numbers of mutated EGFR and a fixed amount of wild-type EGFR, with the wildtype DNA copy as internal control.	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))	('mutated', 'Var', (70, 77))
56647	30103780	The proportion of T790M positive cases detected by ddPCR in stage IIIB, IVA and IVB patients were 30, 47.6 and 57.1%, respectively (P = 0.176) (Fig.	('patients', 'Species', '9606', (84, 92))	('T790M positive', 'Var', (18, 32))	('IVA', 'Disease', (72, 75))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('stage IIIB', 'Disease', (60, 70))	('IVA', 'Disease', 'MESH:C538167', (72, 75))
56648	30103780	However, T790M positive defined by cobas plasma ctDNA test were significantly different in stage IIIB, IVA and IVB (Fig.	('T790M', 'Var', (9, 14))	('T790M', 'Mutation', 'rs121434569', (9, 14))	('IVA', 'Disease', (103, 106))	('IVA', 'Disease', 'MESH:C538167', (103, 106))	('different', 'Reg', (78, 87))	('IVB', 'Disease', (111, 114))	('stage IIIB', 'Disease', (91, 101))
56650	30103780	The T790M quantification by ddPCR significantly rises in stage IIIB, IVA and IVB cases (P = 0.033), while no such trend was observed in different M1a, M2b and M1c cases (P = 0.178).	('IVB', 'Disease', (77, 80))	('rises', 'PosReg', (48, 53))	('IVA', 'Disease', (69, 72))	('T790M', 'Mutation', 'rs121434569', (4, 9))	('IVA', 'Disease', 'MESH:C538167', (69, 72))	('T790M', 'Var', (4, 9))	('stage IIIB', 'Disease', (57, 67))
56651	30103780	No association was observed between T790M status and duration of first generation EGFR TKI treatment (Table 2).	('men', 'Species', '9606', (96, 99))	('EGFR', 'Gene', (82, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('T790M', 'Mutation', 'rs121434569', (36, 41))	('EGFR', 'Gene', '1956', (82, 86))	('T790M status', 'Var', (36, 48))
56654	30103780	Quantification of T790M after 6 weeks of treatment decreased to very low level, while no association was observed between response status and T790M mutation level decrease (Fig.	('T790M', 'Var', (142, 147))	('men', 'Species', '9606', (46, 49))	('decreased', 'NegReg', (51, 60))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('T790M', 'Mutation', 'rs121434569', (142, 147))	('T790M', 'Var', (18, 23))
56655	30103780	The aim of this study was to evaluate different T790M detecting methods in advanced NSCLC patients who experienced disease progression after receiving EGFR TKI treatment, as well as T790M quantification after osimertinib treatment.	('men', 'Species', '9606', (165, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('osimertinib', 'Chemical', 'MESH:C000603933', (209, 220))	('EGFR', 'Gene', (151, 155))	('NSCLC', 'Disease', (84, 89))	('T790M', 'Mutation', 'rs121434569', (48, 53))	('T790M', 'Mutation', 'rs121434569', (182, 187))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('patients', 'Species', '9606', (90, 98))	('T790M', 'Var', (182, 187))	('EGFR', 'Gene', '1956', (151, 155))	('men', 'Species', '9606', (226, 229))
56659	30103780	The overall T790M positive rate was 52.2% considering all testing methods, the ORR of T790M positive patients receiving osimertinib treatment was 60.9%.	('patients', 'Species', '9606', (101, 109))	('T790M', 'Mutation', 'rs121434569', (12, 17))	('osimertinib', 'Chemical', 'MESH:C000603933', (120, 131))	('T790M', 'Var', (12, 17))	('men', 'Species', '9606', (137, 140))	('T790M', 'Mutation', 'rs121434569', (86, 91))	('T790M', 'Var', (86, 91))
56660	30103780	Our analysis revealed a rising trend of T790M positive rates detected by ddPCR in stage IIIB, IVA and IVB patients.	('stage IIIB', 'Disease', (82, 92))	('IVB', 'Disease', (102, 105))	('T790M', 'Mutation', 'rs121434569', (40, 45))	('IVA', 'Disease', (94, 97))	('ddPCR', 'Gene', (73, 78))	('patients', 'Species', '9606', (106, 114))	('IVA', 'Disease', 'MESH:C538167', (94, 97))	('T790M positive', 'Var', (40, 54))
56661	30103780	In plasma ctDNA samples tested by cobas, T790M positive rate was significantly higher in stage IVB than stage IIIB and IVA, M1c than M1a and M1b patients.	('patients', 'Species', '9606', (145, 153))	('stage IVB', 'Disease', (89, 98))	('T790M positive', 'Var', (41, 55))	('IVA', 'Disease', 'MESH:C538167', (119, 122))	('T790M', 'Mutation', 'rs121434569', (41, 46))	('higher', 'PosReg', (79, 85))	('IVA', 'Disease', (119, 122))
56670	30103780	Previous studies dynamically monitored EGFR mutation status using plasma samples by ddPCR to evaluate response to first generation EGFR TKIs.	('mutation', 'Var', (44, 52))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('EGFR', 'Gene', (131, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
56884	29504256	showed a dose-response relationship of carcinogens in the atmosphere, especially NO, with the incidence of lung ADC.44 In addition to the regularly monitored pollutants, such as SO2, NO2, and PM10, NO and PM2.5 should also be considered air pollution factors associated with lung cancer.	('SO2', 'Chemical', 'MESH:D013458', (178, 181))	('lung ADC.44', 'Disease', (107, 118))	('lung cancer', 'Disease', (275, 286))	('PM10', 'Var', (192, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('NO2', 'Chemical', 'MESH:D009585', (183, 186))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))
56890	29504256	A retrospective study by Kligerman and White showed that as a result of factors such as high expression of CYPlA1 and P53 gene mutations, genetic susceptibility to carcinogens in tobacco smoke and air pollution is greater in women than in men.47 In addition, estrogen has been shown to promote the proliferation of lung cancer cells and the interaction between the ER and EGFR signaling pathways in lung cancer.	('EGFR', 'Gene', '1956', (372, 376))	('lung cancer', 'Disease', 'MESH:D008175', (399, 410))	('men', 'Species', '9606', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('EGFR', 'molecular_function', 'GO:0005006', ('372', '376'))	('interaction', 'Interaction', (341, 352))	('lung cancer', 'Phenotype', 'HP:0100526', (399, 410))	('lung cancer', 'Disease', (315, 326))	('tobacco', 'Species', '4097', (179, 186))	('men', 'Species', '9606', (239, 242))	('mutations', 'Var', (127, 136))	('promote', 'PosReg', (286, 293))	('signaling', 'biological_process', 'GO:0023052', ('377', '386'))	('EGFR', 'Gene', (372, 376))	('lung cancer', 'Disease', 'MESH:D008175', (315, 326))	('lung cancer', 'Disease', (399, 410))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('proliferation', 'CPA', (298, 311))	('women', 'Species', '9606', (225, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (315, 326))
56909	29581874	The name "hedgehog" comes from the spiky aspect of the embryonic cuticle observed in the mutant for this gene.	('hedgehog', 'Gene', '42737', (10, 18))	('mutant', 'Var', (89, 95))	('hedgehog', 'Gene', (10, 18))
56922	29581874	CD133+ cells represent between 0.30% and 6% of tumor cells in NSCLC and exhibit the ability to grow as spheroids in agarose culture and to differentiate to CD133- tumor cells, and show high in vivo oncogenic potential in NOD/SCID mice.	('SCID', 'Gene', '19090', (225, 229))	('NSCLC', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mice', 'Species', '10090', (230, 234))	('SCLC', 'Phenotype', 'HP:0030357', (63, 67))	('SCID', 'Gene', (225, 229))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CD133+', 'Var', (0, 6))	('agarose', 'Chemical', 'MESH:D012685', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('tumor', 'Disease', (47, 52))	('oncogenic potential', 'CPA', (198, 217))
56935	29581874	showed that CD133 was not specific enough to isolate CSCs in vitro in NSCLC cell lines, as some CD133- cells had CSC features (colony formation, self-renewal, proliferation, differentiation, and chemoresistance).	('NSCLC', 'Disease', (70, 75))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('proliferation', 'CPA', (159, 172))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('CD133- cells', 'Var', (96, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('differentiation', 'CPA', (174, 189))	('self-renewal', 'CPA', (145, 157))
56952	29581874	For example, Gorlin syndrome, which induces the formation of multiple basal cell carcinomas, rhabdomyosarcomas and medulloblastomas, is characterized by the presence of inactivating mutations of PTCH that result in constant activation of Smo.	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('multiple basal cell carcinomas', 'Disease', 'MESH:C537656', (61, 91))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (70, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('medulloblastomas', 'Disease', (115, 131))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (13, 28))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (70, 90))	('PTCH', 'Gene', '5727', (195, 199))	('inactivating mutations', 'Var', (169, 191))	('Gorlin syndrome', 'Disease', (13, 28))	('activation', 'PosReg', (224, 234))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (93, 110))	('rhabdomyosarcomas', 'Disease', (93, 110))	('medulloblastomas', 'Disease', 'MESH:D008527', (115, 131))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (93, 110))	('Smo', 'Gene', '6608', (238, 241))	('PTCH', 'Gene', (195, 199))	('multiple basal cell carcinomas', 'Disease', (61, 91))	('Smo', 'Gene', (238, 241))
56953	29581874	SUFU mutations have also been described in sporadic cases of medulloblastomas.	('SUFU', 'Gene', (0, 4))	('SUFU', 'Gene', '51684', (0, 4))	('medulloblastomas', 'Disease', (61, 77))	('mutations', 'Var', (5, 14))	('medulloblastomas', 'Disease', 'MESH:D008527', (61, 77))	('described', 'Reg', (30, 39))
56954	29581874	In sporadic basal cell carcinomas, approximately 70% of cases present a mutation of Shh pathway-related genes (inactivating mutation of PTCH or activating mutation of SMO).	('Shh pathway-related genes', 'Gene', (84, 109))	('activating', 'PosReg', (144, 154))	('sporadic basal cell carcinomas', 'Disease', (3, 33))	('mutation', 'Reg', (72, 80))	('PTCH', 'Gene', '5727', (136, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('PTCH', 'Gene', (136, 140))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (12, 32))	('inactivating mutation', 'Var', (111, 132))	('sporadic basal cell carcinomas', 'Disease', 'MESH:D002280', (3, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (12, 33))	('SMO', 'Gene', '6608', (167, 170))	('SMO', 'Gene', (167, 170))
56965	29581874	In another work on lung cancer cell lines (HCC and H1339), inhibition of the Shh pathway by a pharmacological Smo-inhibitor (vismodegib) resulted in a decrease of the population of CSCs measured by the ability of efflux of Hoechst 33342 (SP+ cells) using flow cytometry analysis.	('Smo', 'Gene', (110, 113))	('vismodegib', 'Chemical', 'MESH:C538724', (125, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('efflux', 'biological_process', 'GO:0140115', ('213', '219'))	('efflux', 'biological_process', 'GO:0140352', ('213', '219'))	('SP+', 'Chemical', '-', (238, 241))	('decrease', 'NegReg', (151, 159))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (223, 236))	('Smo', 'Gene', '6608', (110, 113))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('ability', 'MPA', (202, 209))	('inhibition', 'Var', (59, 69))	('Shh pathway', 'Pathway', (77, 88))	('lung cancer', 'Disease', (19, 30))
56968	29581874	In gallbladder cancer, CSCs isolated by Fluorescence-activated cell sorting (FACS) (through CD44 and aberrantly glycosylated integrin alpha3beta1 staining) showed high level of Shh pathway activation, which was required for CSC renewal.	('aberrantly', 'Var', (101, 111))	('CD44', 'Gene', (92, 96))	('Shh pathway', 'Pathway', (177, 188))	('activation', 'PosReg', (189, 199))	('CD44', 'Gene', '960', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('gallbladder cancer', 'Disease', (3, 21))	('gallbladder cancer', 'Disease', 'MESH:D005706', (3, 21))
56971	29581874	Inhibition of the Shh pathway prevented the tobacco-induced tumor phenotype.	('tobacco', 'Species', '4097', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Inhibition', 'Var', (0, 10))	('Shh pathway', 'Pathway', (18, 29))	('tumor', 'Disease', (60, 65))
56991	29581874	performed analyses using the A549M NSCLC cell line, in which A549 cells were made resistant to cisplatin and erlotinib by treatment with TGFbeta and acquisition of a mesenchymal phenotype.	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('A549', 'CellLine', 'CVCL:0023', (61, 65))	('NSCLC', 'Disease', (35, 40))	('TGFbeta', 'Gene', (137, 144))	('SCLC', 'Phenotype', 'HP:0030357', (36, 40))	('erlotinib', 'Chemical', 'MESH:D000069347', (109, 118))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('mesenchymal phenotype', 'CPA', (166, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('TGFbeta', 'Gene', '7040', (137, 144))	('A549M', 'SUBSTITUTION', 'None', (29, 34))	('A549M', 'Var', (29, 34))
56992	29581874	The IC50 values of cisplatin and erlotinib in A549M cells were significantly lower with pretreatment by vismodegib or anti-Shh siRNA.	('lower', 'NegReg', (77, 82))	('IC50 values', 'MPA', (4, 15))	('erlotinib', 'Chemical', 'MESH:D000069347', (33, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('erlotinib', 'Gene', (33, 42))	('A549M', 'SUBSTITUTION', 'None', (46, 51))	('A549M', 'Var', (46, 51))	('vismodegib', 'Chemical', 'MESH:C538724', (104, 114))
56995	29581874	NSCLC with early tumor progression with first-line platinum-based chemotherapy) showed overexpression of Gli2 compared with chemosensitive NSCLC and that inhibition of Shh pathway had a synergistic effect with cisplatin in the most chemoresistant cell lines in vitro.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('platinum', 'Chemical', 'MESH:D010984', (51, 59))	('Gli2', 'Gene', (105, 109))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('tumor', 'Disease', (17, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('Shh pathway', 'Pathway', (168, 179))	('inhibition', 'Var', (154, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (210, 219))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('overexpression', 'PosReg', (87, 101))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('Gli2', 'Gene', '2736', (105, 109))	('NSCLC', 'Disease', (0, 5))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))
56997	29581874	showed a correlation between the expression of Shh-related proteins and the presence of EGFR mutation in surgically resected lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (125, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('EGFR', 'Gene', '1956', (88, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('expression', 'MPA', (33, 43))	('mutation', 'Var', (93, 101))	('EGFR', 'Gene', (88, 92))
57010	29581874	These results were confirmed in transgenic mouse models with deletion of RB1 (retinoblastoma 1) and TRP53 (transformation related protein 53).	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('transformation related protein 53', 'Gene', (107, 140))	('retinoblastoma', 'Phenotype', 'HP:0009919', (78, 92))	('transformation related protein 53', 'Gene', '22059', (107, 140))	('TRP53', 'Gene', (100, 105))	('RB1', 'Gene', (73, 76))	('deletion', 'Var', (61, 69))	('retinoblastoma 1', 'Gene', (78, 94))	('retinoblastoma 1', 'Gene', '19645', (78, 94))	('RB1', 'Gene', '19645', (73, 76))	('mouse', 'Species', '10090', (43, 48))	('TRP53', 'Gene', '22059', (100, 105))
57011	29581874	Tumor growth was inhibited by deletion of Smo in these models and treatment with pharmacological inhibitors of the Shh pathway.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Smo', 'Gene', '6608', (42, 45))	('Tumor growth', 'CPA', (0, 12))	('deletion', 'Var', (30, 38))	('inhibited', 'NegReg', (17, 26))	('Smo', 'Gene', (42, 45))
57018	29581874	Interestingly, one patient experienced a prolonged progression free survival (27 months), with a tumor showing amplification of SOX2, a CSC-related gene.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('amplification', 'Var', (111, 124))	('patient', 'Species', '9606', (19, 26))	('SOX2', 'Gene', '6657', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SOX2', 'Gene', (128, 132))	('tumor', 'Disease', (97, 102))
57060	29495918	MicroRNAs have been associated with various types of cancer, which involved in many important biological and pathological processes, including growth, differentiation, and tumorigenesis.	('MicroRNAs', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('associated', 'Reg', (20, 30))	('growth', 'CPA', (143, 149))	('differentiation', 'CPA', (151, 166))	('involved', 'Reg', (67, 75))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
57069	29495918	Thus, NRAS silencing may be an efficient therapeutic strategy in tumors.	('silencing', 'Var', (11, 20))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('NRAS', 'Gene', (6, 10))	('NRAS', 'Gene', '4893', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
57094	29495918	To generate a construct containing the mutant miR-29a binding site, 2 nucleotides corresponding to the 5'-seeding region of the miR-29a binding site on the wild-type fragment were substituted.	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('miR-29a', 'Gene', '407021', (128, 135))	('miR-29a', 'Gene', (46, 53))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('miR-29a', 'Gene', (128, 135))	('mutant', 'Var', (39, 45))	('miR-29a', 'Gene', '407021', (46, 53))
57111	29495918	To confirm whether NRAS was the direct target of miR-29a, human NRAS 3'-UTR, containing either wild-type or mutant miR-29a binding sequence, then was cloned downstream of the firefly luciferase reporter gene in the pMIR-reporter vector.	('binding', 'molecular_function', 'GO:0005488', ('123', '130'))	('human', 'Species', '9606', (58, 63))	('NRAS', 'Gene', (19, 23))	('miR-29a', 'Gene', (49, 56))	('miR-29a', 'Gene', '407021', (49, 56))	('mutant', 'Var', (108, 114))	('NRAS', 'Gene', (64, 68))	('NRAS', 'Gene', '4893', (19, 23))	('miR-29a', 'Gene', (115, 122))	('miR-29a', 'Gene', '407021', (115, 122))	('NRAS', 'Gene', '4893', (64, 68))
57128	29495918	Moreover, we investigated that compared to miR-29a or cisplatin treatment alone, the activities of caspase-3, which acts as a key executor of cell apoptosis, were significantly upregulated upon treatment of miR-29a and cisplatin, whereas forced expression of NRAS attenuated the activation of caspase-3 (Figure 4D).	('upregulated', 'PosReg', (177, 188))	('miR-29a', 'Gene', (43, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('NRAS', 'Gene', (259, 263))	('caspase-3', 'Gene', (293, 302))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('NRAS', 'Gene', '4893', (259, 263))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('caspase-3', 'Gene', '836', (99, 108))	('caspase-3', 'Gene', (99, 108))	('miR-29a', 'Gene', (207, 214))	('cisplatin', 'Var', (219, 228))	('miR-29a', 'Gene', '407021', (207, 214))	('caspase-3', 'Gene', '836', (293, 302))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('miR-29a', 'Gene', '407021', (43, 50))	('activities', 'MPA', (85, 95))
57148	29495918	Resistance to chemotherapy is a complex process, which results from a lot of factors including individual differences in patients or genetic or epigenetic changes in tumors.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('genetic', 'Var', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('epigenetic changes', 'Var', (144, 162))	('results from', 'Reg', (55, 67))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('patients', 'Species', '9606', (121, 129))
57159	28489825	In small cell lung cancer (SCLC), an aggressive NE lung cancer, loss-of-function NOTCH mutations and the inhibitory effects of ectopic Notch activation indicate that Notch signaling is tumor suppressive.	('aggressive NE lung cancer', 'Disease', (37, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (3, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Notch', 'Gene', '31293', (166, 171))	('mutations', 'Var', (87, 96))	('tumor', 'Disease', (185, 190))	('Notch', 'Gene', '31293', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('SCLC', 'Gene', '7864', (27, 31))	('loss-of-function', 'NegReg', (64, 80))	('SCLC', 'Gene', (27, 31))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('Notch', 'Gene', (166, 171))	('NOTCH', 'Gene', '31293', (81, 86))	('aggressive NE lung cancer', 'Disease', 'MESH:D008175', (37, 62))	('Notch', 'Gene', (135, 140))	('small cell lung cancer', 'Disease', 'MESH:D055752', (3, 25))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('small cell lung cancer', 'Disease', (3, 25))	('NOTCH', 'Gene', (81, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))
57197	28489825	Cells that express both Notch ligands and receptors are also present in human SCLC cell lines, and Dll4 induced HES1 in these lines (Extended Data Fig.	('Notch', 'Gene', (24, 29))	('HES1', 'Gene', (112, 116))	('human', 'Species', '9606', (72, 77))	('Dll4', 'Var', (99, 103))	('HES1', 'Gene', '3280', (112, 116))	('Notch', 'Gene', '31293', (24, 29))	('SCLC', 'Gene', (78, 82))	('SCLC', 'Gene', '7864', (78, 82))
57202	28489825	SCLC cells with intermediate levels of GFP expression (GFPint cells) displayed intermediate activation of the Notch pathway, as expected, but clustered mostly with GFPneg cells and away from GFPhigh cells (Extended Data Fig.	('Notch', 'Gene', '31293', (110, 115))	('SCLC', 'Gene', '7864', (0, 4))	('activation', 'PosReg', (92, 102))	('Notch', 'Gene', (110, 115))	('GFP expression', 'Var', (39, 53))	('SCLC', 'Gene', (0, 4))
57214	28489825	Epigenetic remodeling involving repressor complexes containing Rest (reviewed in ) may contribute to the irreversibility of the Notch-driven NE to non-NE switch in SCLC cells.	('SCLC', 'Gene', '7864', (164, 168))	('SCLC', 'Gene', (164, 168))	('Notch', 'Gene', '31293', (128, 133))	('Epigenetic', 'Var', (0, 10))	('Notch', 'Gene', (128, 133))
57231	28489825	In a cohort of SCLC patients, we found a trend for HES1 positivity in tumors as a negative prognostic factor for overall and progression-free survival (Extended Data Fig.	('HES1', 'Gene', '3280', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('positivity', 'Var', (56, 66))	('progression-free survival', 'CPA', (125, 150))	('tumors', 'Disease', (70, 76))	('HES1', 'Gene', (51, 55))	('SCLC', 'Gene', (15, 19))	('SCLC', 'Gene', '7864', (15, 19))	('patients', 'Species', '9606', (20, 28))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('negative', 'NegReg', (82, 90))
57242	28489825	Furthermore, although Notch1 is also expressed and active in SCLC, blockade of just Notch2/3 was sufficient to suppress tumor growth and the generation of non-NE cells.	('blockade', 'Var', (67, 75))	('suppress', 'NegReg', (111, 119))	('Notch1', 'Gene', '18128', (22, 28))	('Notch2/3', 'Gene', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Notch1', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SCLC', 'Gene', '7864', (61, 65))	('SCLC', 'Gene', (61, 65))	('rat', 'Species', '10116', (145, 148))	('tumor', 'Disease', (120, 125))
57248	28489825	Second, although most of the loss-of-function NOTCH mutations in human SCLC tumors are heterozygous, they might be sufficient to lower signaling from Notch receptors in NE SCLC cells and impair the NE to non-NE switch in response to ligands.	('human', 'Species', '9606', (65, 70))	('NOTCH', 'Gene', (46, 51))	('response to ligands', 'MPA', (221, 240))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('SCLC', 'Gene', (71, 75))	('SCLC tumors', 'Disease', (71, 82))	('SCLC', 'Gene', '7864', (71, 75))	('lower', 'NegReg', (129, 134))	('Notch', 'Gene', '31293', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('impair', 'NegReg', (187, 193))	('signaling', 'MPA', (135, 144))	('SCLC', 'Gene', (172, 176))	('SCLC', 'Gene', '7864', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('NOTCH', 'Gene', '31293', (46, 51))	('mutations', 'Var', (52, 61))	('Notch', 'Gene', (150, 155))	('NE to non-NE switch', 'MPA', (198, 217))	('SCLC tumors', 'Disease', 'MESH:D018288', (71, 82))	('loss-of-function', 'NegReg', (29, 45))
57258	28489825	The triple-knockout (TKO) SCLC mouse model bearing deletions in p53, Rb, and p130 has been described.	('p53', 'Gene', (64, 67))	('p130', 'Gene', '70769', (77, 81))	('mouse', 'Species', '10090', (31, 36))	('deletions', 'Var', (51, 60))	('p53', 'Gene', '22059', (64, 67))	('SCLC', 'Gene', '7864', (26, 30))	('SCLC', 'Gene', (26, 30))	('p130', 'Gene', (77, 81))
57261	28489825	We also bred in the Rosa26lox-stop-lox-tdTomato and Rosa26lox-stop-lox-luciferase Cre-reporter alleles to the TKO model to label tumor cells with tdTomato and luciferase respectively.	('Rosa26lox-stop-lox-luciferase', 'Var', (52, 81))	('Tomato', 'Species', '4081', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('Tomato', 'Species', '4081', (41, 47))
57262	28489825	SCLC tumors were induced in 7 to 10 weeks old mice (with no discrimination by sex of mice) by intratracheal instillation with 4x107 PFU of Adeno-CMV-Cre (Baylor College of Medicine, Houston, TX) or Adeno-CGRP-Cre (University of Iowa).	('mice', 'Species', '10090', (85, 89))	('rat', 'Species', '10116', (97, 100))	('CGRP', 'Gene', '12310', (204, 208))	('SCLC tumors', 'Disease', 'MESH:D018288', (0, 11))	('CGRP', 'Gene', (204, 208))	('SCLC tumors', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('induced', 'Reg', (17, 24))	('mice', 'Species', '10090', (46, 50))	('Adeno-CMV-Cre', 'Var', (139, 152))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
57263	28489825	Tumors were collected for analysis after around 5-7 months for Ad-CMV-Cre or 7-8 months for Ad-CGRP-Cre, unless otherwise stated.	('Ad-CMV-Cre', 'Var', (63, 73))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CGRP', 'Gene', '12310', (95, 99))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CGRP', 'Gene', (95, 99))
57291	28489825	The extracellular domain of rat Dll4 containing affinity-enhancing G28S, F107L, L206P N118I, I143F, H194Y and K215E mutations (named Dll4E12 or Dll4 in the manuscript) was cloned into the pAcGp67A vector and modified with a C-terminal 8xHis tag.	('G28S', 'Mutation', 'rs1373760209', (67, 71))	('L206P', 'SUBSTITUTION', 'None', (80, 85))	('F107L', 'Var', (73, 78))	('I143F', 'Var', (93, 98))	('F107L', 'Mutation', 'p.F107L', (73, 78))	('affinity-enhancing', 'PosReg', (48, 66))	('K215E', 'Var', (110, 115))	('K215E', 'Mutation', 'p.K215E', (110, 115))	('N118I', 'Var', (86, 91))	('H194Y', 'Var', (100, 105))	('H194Y', 'Mutation', 'p.H194Y', (100, 105))	('G28S', 'Var', (67, 71))	('extracellular', 'cellular_component', 'GO:0005576', ('4', '17'))	('N118I', 'SUBSTITUTION', 'None', (86, 91))	('rat', 'Species', '10116', (28, 31))	('L206P', 'Var', (80, 85))	('I143F', 'Mutation', 'p.I143F', (93, 98))
57304	28489825	For acute analysis of gene expression changes, RNA was isolated from GFPhigh cells FACS-sorted 48 hours after transfection with MigR1-N1ICD or Rest-IRES-GFP or the empty vector control.	('FACS', 'Gene', (83, 87))	('FACS', 'Gene', '14081', (83, 87))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))	('MigR1-N1ICD', 'Var', (128, 139))
57323	28489825	The following recombinant proteins were used: Midkine (OriGene TP723299, 50ng/ml), Betacellulin (BioLegend 551302, 5ng/ml), Gdf15 (MyBioSource MBS205834, 25ng/ml), Bmp4 (BioLegend 595301, 50ng/ml), Ephrin A1 (BioLegend 755002, 50ng/ml), SCF (BioLegend 579702, 50ng/ml), Fstl1 (R&D Systems 1738-FN-050, 200ng/ml).	('Betacellulin', 'Gene', (83, 95))	('Gdf15', 'Gene', (124, 129))	('Bmp4', 'Gene', '12159', (164, 168))	('SCF', 'Gene', (237, 240))	('Fstl1', 'Gene', '14314', (270, 275))	('Midkine', 'Gene', '17242', (46, 53))	('Ephrin A1', 'Gene', (198, 207))	('BioLegend 595301', 'Var', (170, 186))	('Ephrin A1', 'Gene', '13636', (198, 207))	('Ephrin', 'molecular_function', 'GO:0046875', ('198', '204'))	('BioLegend 755002', 'Var', (209, 225))	('Betacellulin', 'Gene', '12223', (83, 95))	('Midkine', 'Gene', (46, 53))	('SCF', 'Gene', '17311', (237, 240))	('Gdf15', 'Gene', '23886', (124, 129))	('SCF', 'molecular_function', 'GO:0005173', ('237', '240'))	('BioLegend 579702', 'Var', (242, 258))	('Fstl1', 'Gene', (270, 275))	('Bmp4', 'Gene', (164, 168))	('Ephrin', 'molecular_function', 'GO:0005106', ('198', '204'))
57329	28489825	The primary antibodies used were: Hes1 (CST 11988, 1:200), Notch2 (CST 5732, 1:200), GFP (Invitrogen A-11122, 1:400), cleaved caspase-3 (CST 9664, 1:200), Ki-67 (BD Biosciences 550609, 1:200), Ascl1/Mash1 (BD Biosciences, 556604, 1:200).	('Ki-67', 'Gene', '17345', (155, 160))	('CST 11988', 'Var', (40, 49))	('cleaved caspase-3', 'Gene', (118, 135))	('cleaved caspase-3', 'Gene', '12367', (118, 135))	('Ki-67', 'Gene', (155, 160))	('Mash1', 'Gene', '17172', (199, 204))	('Ascl1', 'Gene', '17172', (193, 198))	('Mash1', 'Gene', (199, 204))	('Ascl1', 'Gene', (193, 198))	('CST 9664', 'Var', (137, 145))
57355	28489825	The antibodies used were Notch1 (Cell Signaling Technology (CST) 4380), cleaved Notch1 (CST 4147), Notch2 (CST 5732), Hes1 (CST 11988), GFP (Invitrogen A-11122), Rest (Abcam 21635), alpha-tubulin (Sigma T9026) and HSP90 (CST 4877).	('Sigma T9026', 'Var', (197, 208))	('cleaved', 'Var', (72, 79))	('Signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('Notch1', 'Gene', (25, 31))	('Notch1', 'Gene', '18128', (25, 31))	('Notch1', 'Gene', (80, 86))	('Notch1', 'Gene', '18128', (80, 86))	('CST 11988', 'Var', (124, 133))	('HSP90', 'Protein', (214, 219))	('alpha-tubulin', 'Protein', (182, 195))
57375	28489825	The antibodies used were Notch1 (CST 3608), rabbit IgG (CST 2729) and Rest (Millipore 17-641).	('Notch1', 'Gene', (25, 31))	('Notch1', 'Gene', '18128', (25, 31))	('CST 3608', 'Var', (33, 41))	('rabbit', 'Species', '9986', (44, 50))	('CST', 'Var', (56, 59))
57380	29163842	Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma We evaluated the real-world efficacy and side effects of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma.	('afatinib', 'Chemical', 'MESH:D000077716', (25, 33))	('EGFR', 'Gene', '1956', (217, 221))	('afatinib', 'Chemical', 'MESH:D000077716', (171, 179))	('EGFR', 'Gene', (217, 221))	('lung adenocarcinoma', 'Disease', (240, 259))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (240, 259))	('mutation-positive', 'Var', (222, 239))	('lung adenocarcinoma', 'Disease', (94, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('EGFR', 'Gene', '1956', (71, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (240, 259))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('mutation-positive', 'Var', (76, 93))	('EGFR', 'Gene', (71, 75))
57382	29163842	Rebiopsy tissue was collected for EGFR mutation and MET amplification analyses.	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'Gene', '1956', (34, 38))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))
57391	29163842	Mutations in the EGFR kinase domain could activate downstream signaling pathways and cause cancer cells to proliferate, metastasize, and invade other tissues, or become resistant to apoptosis.	('invade', 'CPA', (137, 143))	('cancer', 'Disease', (91, 97))	('cause', 'Reg', (85, 90))	('activate', 'PosReg', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('metastasize', 'CPA', (120, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('downstream signaling pathways', 'Pathway', (51, 80))	('EGFR', 'Gene', (17, 21))
57392	29163842	Two major EGFR mutations, exon 19 deletions and exon 21 p.L858R point mutation, account for approximately 90.0% of EGFR mutations.	('EGFR', 'Gene', '1956', (10, 14))	('p.L858R point mutation', 'Var', (56, 78))	('EGFR', 'Gene', (10, 14))	('EGFR', 'Gene', '1956', (115, 119))	('deletions', 'Var', (34, 43))	('p.L858R', 'Mutation', 'rs121434568', (56, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))
57393	29163842	These are referred to as "classical" EGFR mutations and are well documented for effectively responding to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('104', '127'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('146', '162'))	('EGFR', 'Gene', '1956', (166, 170))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))	('EGFR', 'Gene', (166, 170))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))	('epidermal growth factor receptor', 'Gene', (106, 138))
57394	29163842	Notably, the use of first-generation EGFR-TKIs (e.g., gefitinib or erlotinib) as a first-line therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma has been associated with a higher objective response rate (ORR) and longer progression-free survival (PFS) than platinum-based doublet chemotherapy.	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('mutation-positive', 'Var', (134, 151))	('erlotinib', 'Chemical', 'MESH:D000069347', (67, 76))	('higher', 'PosReg', (199, 205))	('objective response', 'CPA', (206, 224))	('EGFR', 'Gene', (129, 133))	('lung adenocarcinoma', 'Disease', (152, 171))	('progression-free', 'Disease', (247, 263))	('longer', 'PosReg', (240, 246))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', '1956', (129, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (152, 171))	('gefitinib', 'Chemical', 'MESH:D000077156', (54, 63))	('patients', 'Species', '9606', (106, 114))	('EGFR', 'Gene', (37, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))
57395	29163842	Afatinib, an irreversible second-generation EGFR-TKI and member of the ErbB family, has activity against not only "classical" EGFR mutations, but also rare EGFR mutations, including the exon 18 p.G719X and exon 21 p.L861Q point mutations.	('exon', 'Var', (206, 210))	('activity', 'MPA', (88, 96))	('ErbB', 'Gene', '1956;2064', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('p.L861Q', 'Var', (214, 221))	('EGFR', 'Gene', '1956', (126, 130))	('EGFR', 'Gene', '1956', (156, 160))	('p.G719X', 'Mutation', 'p.G719X', (194, 201))	('EGFR', 'Gene', '1956', (44, 48))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('p.L861Q', 'Mutation', 'rs121913444', (214, 221))	('ErbB', 'Gene', (71, 75))	('p.G719X', 'Var', (194, 201))	('has activity', 'molecular_function', 'GO:0050501', ('84', '96'))	('EGFR', 'molecular_function', 'GO:0005006', ('154', '158'))	('mutations', 'Var', (131, 140))	('EGFR', 'Gene', (126, 130))	('EGFR', 'Gene', (156, 160))	('EGFR', 'Gene', (44, 48))
57397	29163842	In these phase III trials afatinib was associated with a significantly prolonged PFS compared to first-line chemotherapy with cisplatin and pemetrexed or cisplatin and gemcitabine, respectively.	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('afatinib', 'Chemical', 'MESH:D000077716', (26, 34))	('pemetrexed', 'Chemical', 'MESH:D000068437', (140, 150))	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('afatinib', 'Var', (26, 34))	('prolonged', 'PosReg', (71, 80))	('PFS', 'MPA', (81, 84))
57409	29163842	Patients were stratified into three groups according to their EGFR mutation status: Group 1, "classical" mutation; Group 2, complex mutation with classical mutation; and Group 3, rare mutation with or without complex mutation (Table 1).	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('complex mutation', 'Var', (124, 140))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))
57430	29163842	However, EGFR mutation patterns were not clinically associated with brain metastases.	('associated', 'Reg', (52, 62))	('EGFR', 'Gene', '1956', (9, 13))	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', (9, 13))	('brain metastases', 'Disease', 'MESH:D009362', (68, 84))	('brain metastases', 'Disease', (68, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
57434	29163842	Among the EGFR mutation subgroups, Group 1 and Group 2 patients were associated with favorable ORRs of 70.4% and 66.7%, respectively (Supplementary Table 3), while Group 3 patients were associated with a lower ORR of 53.9% (P > 0.05).	('EGFR', 'Gene', '1956', (10, 14))	('mutation', 'Var', (15, 23))	('EGFR', 'Gene', (10, 14))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (55, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))
57435	29163842	For the 5 patients with a primary p.T790M mutation (p.T790M and p.L858R [n = 4] and p.T790M and p.G719A [n = 1]), the ORR was 60.0%.	('p.T790M', 'Var', (84, 91))	('p.L858R', 'Mutation', 'rs121434568', (64, 71))	('p.T790M', 'Mutation', 'rs121434569', (34, 41))	('p.L858R', 'Var', (64, 71))	('p.T790M', 'Mutation', 'rs121434569', (52, 59))	('p.T790M', 'Var', (34, 41))	('p.T790M', 'Mutation', 'rs121434569', (84, 91))	('patients', 'Species', '9606', (10, 18))	('p.G719A', 'Mutation', 'rs121913428', (96, 103))	('p.G719A', 'Var', (96, 103))
57436	29163842	For the 4 patients with an exon 20 insertion, the ORR was 25.0% (partial response [n = 1], stable disease [n = 2], and progressive disease [n = 1]).	('stable', 'Disease', (91, 97))	('progressive', 'Disease', (119, 130))	('insertion', 'Var', (35, 44))	('patients', 'Species', '9606', (10, 18))	('exon 20', 'Gene', (27, 34))
57438	29163842	The tumors of patients with exon 20 insertions were well known to be resistant to EGFR-TKI treatment.	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('exon', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EGFR', 'Gene', '1956', (82, 86))	('patients', 'Species', '9606', (14, 22))	('insertions', 'Var', (36, 46))
57440	29163842	There was also no significant difference in the median PFS between the 81 patients with exon 19 deletions and the 24 patients with p.L858R point mutations (12.2 vs. 10.3 months, respectively; P > 0.05 [Figure 5]) (HR: 0.66 [95.0% CI: 0.36-1.20]).	('patients', 'Species', '9606', (74, 82))	('exon 19 deletions', 'Var', (88, 105))	('deletions', 'Var', (96, 105))	('p.L858R', 'Mutation', 'rs121434568', (131, 138))	('patients', 'Species', '9606', (117, 125))
57445	29163842	Of the 28 patients who underwent rebiopsy, 9 patients (32.1%) had a p.T790M mutation (6 from tumor tissues, 2 from pleural effusions, and one from liquid biopsy).	('p.T790M', 'Var', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('pleural effusion', 'Phenotype', 'HP:0002202', (115, 131))	('patients', 'Species', '9606', (45, 53))	('pleural effusions', 'Phenotype', 'HP:0002202', (115, 132))	('pleural effusions', 'Disease', (115, 132))	('patients', 'Species', '9606', (10, 18))	('pleural effusions', 'Disease', 'MESH:D010996', (115, 132))	('p.T790M', 'Mutation', 'rs121434569', (68, 75))
57446	29163842	Patients who gained a p.T790M mutation after acquiring resistance to afatinib exhibited a trend towards a longer median PFS compared to those who had not (9.3 vs. 7.3 months, respectively; P > 0.05) (HR: 0.57 [95.0% CI: 0.24-1.33]).	('p.T790M', 'Var', (22, 29))	('gained', 'PosReg', (13, 19))	('PFS', 'MPA', (120, 123))	('afatinib', 'Chemical', 'MESH:D000077716', (69, 77))	('Patients', 'Species', '9606', (0, 8))	('p.T790M', 'Mutation', 'rs121434569', (22, 29))
57465	29163842	Subgroup analyses of the LUX-Lung 3 and LUX-Lung 6 trials have demonstrated that lung adenocarcinoma patients harboring exon 19 deletions have a favorable PFS compared to patients harboring p.L858R point mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (101, 109))	('PFS', 'MPA', (155, 158))	('exon 19 deletions', 'Var', (120, 137))	('patients', 'Species', '9606', (171, 179))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('p.L858R', 'Mutation', 'rs121434568', (190, 197))	('deletions', 'Var', (128, 137))
57466	29163842	In a molecular epidemiology study focusing on EGFR mutations across 7 Asian regions, including Taiwan, the proportion of patients with exon 19 deletions and p.L858R point mutations were found to be comparable (22.1% vs. 20.9% of 1,450 patients, respectively).	('mutations', 'Var', (51, 60))	('p.L858R', 'Mutation', 'rs121434568', (157, 164))	('patients', 'Species', '9606', (235, 243))	('EGFR', 'Gene', '1956', (46, 50))	('p.L858R point mutations', 'Var', (157, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('patients', 'Species', '9606', (121, 129))
57467	29163842	In our real-world cohort study, 81 patients (57.9%) with exon 19 deletions and 24 patients (17.1%) with p.L858R point mutations were enrolled, which differed from the proportions of patients in the Asian epidemiological report.	('patients', 'Species', '9606', (82, 90))	('exon 19 deletions', 'Var', (57, 74))	('p.L858R', 'Mutation', 'rs121434568', (104, 111))	('deletions', 'Var', (65, 74))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (35, 43))
57469	29163842	In our study, we were unable to represent and reproduce the significantly superior OS outcome in exon 19 deletion patients compared to p.L858R point mutation patients owing to the disproportionate patients enrolled and limited follow-up (maximum duration, 28.0 months).	('deletion', 'Var', (105, 113))	('patients', 'Species', '9606', (197, 205))	('superior', 'PosReg', (74, 82))	('OS', 'Chemical', '-', (83, 85))	('exon 19', 'Gene', (97, 104))	('patients', 'Species', '9606', (158, 166))	('p.L858R', 'Mutation', 'rs121434568', (135, 142))	('patients', 'Species', '9606', (114, 122))
57470	29163842	Therefore, further clinical studies may be required to determine whether exon 19 deletion patients have a superior PFS outcome after afatinib treatment compared to those harboring the p.L858R point mutation.	('exon 19', 'Gene', (73, 80))	('PFS', 'Disease', (115, 118))	('deletion', 'Var', (81, 89))	('p.L858R', 'Mutation', 'rs121434568', (184, 191))	('patients', 'Species', '9606', (90, 98))	('afatinib', 'Chemical', 'MESH:D000077716', (133, 141))
57471	29163842	Patients harboring mutations of de novo p.T790M mutations and exon 20 insertions, have demonstrated a reduced benefit in clinical outcomes compared to other mutations (e.g., p.G719X, p.L861Q, and p.S768I).	('p.S768I', 'Mutation', 'rs121913465', (196, 203))	('p.L861Q', 'Var', (183, 190))	('p.S768I', 'Var', (196, 203))	('p.G719X', 'Var', (174, 181))	('Patients', 'Species', '9606', (0, 8))	('p.G719X', 'Mutation', 'p.G719X', (174, 181))	('p.T790M', 'Mutation', 'rs121434569', (40, 47))	('p.L861Q', 'Mutation', 'rs121913444', (183, 190))	('p.T790M', 'Var', (40, 47))
57472	29163842	In our real-world cohort study, ORRs of 25.0% and 60.0% were observed for patients with exon 20 insertions or complex mutations and de novo p.T790M mutations, respectively.	('p.T790M', 'Mutation', 'rs121434569', (140, 147))	('complex mutations', 'Var', (110, 127))	('exon', 'Gene', (88, 92))	('p.T790M', 'Var', (140, 147))	('patients', 'Species', '9606', (74, 82))	('insertions', 'Var', (96, 106))
57473	29163842	These 5 de novo p.T790M were detected by the method of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and had concomitant p.L858R or p.G719A mutation.	('p.L858R', 'Mutation', 'rs121434568', (167, 174))	('p.L858R', 'Var', (167, 174))	('p.G719A', 'Mutation', 'rs121913428', (178, 185))	('flight', 'biological_process', 'GO:0060361', ('107', '113'))	('p.T790M', 'Mutation', 'rs121434569', (16, 23))	('p.T790M', 'Var', (16, 23))	('p.G719A', 'Var', (178, 185))
57479	29163842	The concomitant use of erlotinib and whole brain radiotherapy followed by erlotinib maintenance therapy could be advantageous in terms of PFS or OS outcomes in EGFR mutation-positive patients.	('PFS', 'Disease', (138, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('160', '164'))	('OS', 'Chemical', '-', (145, 147))	('EGFR', 'Gene', '1956', (160, 164))	('erlotinib', 'Chemical', 'MESH:D000069347', (23, 32))	('erlotinib', 'Chemical', 'MESH:D000069347', (74, 83))	('mutation-positive', 'Var', (165, 182))	('EGFR', 'Gene', (160, 164))	('patients', 'Species', '9606', (183, 191))
57480	29163842	The Afatinib Compassionate Use Consortium has stated that a greater cerebral response to afatinib treatment was observed in 11 (35.5%) of 31 EGFR mutation-positive patients compared to those in the chemotherapy group.	('cerebral', 'CPA', (68, 76))	('EGFR', 'Gene', '1956', (141, 145))	('afatinib', 'Chemical', 'MESH:D000077716', (89, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('EGFR', 'Gene', (141, 145))	('patients', 'Species', '9606', (164, 172))	('Afatinib', 'Chemical', 'MESH:D000077716', (4, 12))	('greater', 'PosReg', (60, 67))	('mutation-positive', 'Var', (146, 163))
57484	29163842	The most common mechanism of acquired resistance to first-generation EGFR-TKIs is the p.T790M mutation that accounts for 50.0-63.0% of cases.	('EGFR', 'Gene', '1956', (69, 73))	('p.T790M', 'Mutation', 'rs121434569', (86, 93))	('EGFR', 'Gene', (69, 73))	('p.T790M', 'Var', (86, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))
57486	29163842	Our findings confirmed that the p.T790M mutation was the main mechanism of acquired resistance, followed by MET amplifications.	('p.T790M', 'Mutation', 'rs121434569', (32, 39))	('acquired resistance', 'MPA', (75, 94))	('p.T790M', 'Var', (32, 39))
57487	29163842	Patients with p.T790M mutation-positive acquired resistance had a significantly longer post-progression survival and more indolent progression of the lung adenocarcinoma than p.T790M mutation-negative patients.	('patients', 'Species', '9606', (201, 209))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('p.T790M', 'Mutation', 'rs121434569', (14, 21))	('post-progression', 'CPA', (87, 103))	('Patients', 'Species', '9606', (0, 8))	('p.T790M', 'Mutation', 'rs121434569', (175, 182))	('longer', 'PosReg', (80, 86))	('lung adenocarcinoma', 'Disease', (150, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 169))	('p.T790M mutation-positive', 'Var', (14, 39))	('acquired', 'CPA', (40, 48))
57488	29163842	The limited availability of rebiopsy tissue and shorter follow-up intervals (maximum duration, 28.0 months) has led to a reduction in the incidence of the p.T790M mutation compared to previous studies.	('p.T790M', 'Var', (155, 162))	('p.T790M', 'Mutation', 'rs121434569', (155, 162))	('reduction', 'NegReg', (121, 130))
57495	29163842	The p.T790M mutation is the most common mechanism of acquired resistance to afatinib.	('p.T790M', 'Var', (4, 11))	('acquired resistance', 'MPA', (53, 72))	('p.T790M', 'Mutation', 'rs121434569', (4, 11))	('afatinib', 'Chemical', 'MESH:D000077716', (76, 84))
57498	29163842	Patients were excluded because (1) their EGFR mutation status was unknown, (2) they were administered afatinib for < 30 days, (3) they were treated with combination immunotherapy, or (4) they had received palliative chemotherapy prior to afatinib treatment.	('EGFR', 'Gene', (41, 45))	('afatinib', 'Chemical', 'MESH:D000077716', (238, 246))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('EGFR', 'Gene', '1956', (41, 45))	('mutation', 'Var', (46, 54))	('afatinib', 'Chemical', 'MESH:D000077716', (102, 110))
57515	29163842	We retrospectively collected the records of the EGFR mutation status of patients from formal pathology reports and referral data from other hospitals.	('EGFR', 'Gene', '1956', (48, 52))	('mutation', 'Var', (53, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('patients', 'Species', '9606', (72, 80))
57530	28934120	In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857, p = 0.0235).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('docetaxel', 'Chemical', 'MESH:D000077143', (127, 136))	('patients', 'Species', '9606', (74, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('ramucirumab', 'Chemical', 'MESH:C543333', (20, 31))	('ramucirumab', 'Var', (20, 31))	('docetaxel', 'Chemical', 'MESH:D000077143', (37, 46))	('OS', 'Chemical', '-', (68, 70))	('NSCLC', 'Disease', (102, 107))	('prolonged', 'PosReg', (47, 56))
57538	28934120	The vascular endothelial growth factor (VEGF) family, including different VEGF isoforms generated through the alternative splicing of VEGF mRNA and placenta-derived growth factor (PDGF), has a key role in this process.	('VEGF', 'Gene', '7422', (74, 78))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('4', '38'))	('VEGF', 'Gene', '7422', (134, 138))	('vascular endothelial growth factor', 'Gene', (4, 38))	('VEGF', 'Gene', (40, 44))	('VEGF', 'Gene', (74, 78))	('vascular endothelial growth factor', 'Gene', '7422', (4, 38))	('VEGF', 'Gene', (134, 138))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('VEGF', 'Gene', '7422', (40, 44))	('alternative splicing', 'Var', (110, 130))	('PDGF', 'molecular_function', 'GO:0005161', ('180', '184'))
57571	28934120	A subsequent Japanese randomized phase II trial investigated the combination of erlotinib and bevacizumab in the first-line treatment of patients with activating epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC.	('EGFR', 'Gene', (196, 200))	('epidermal growth factor receptor', 'Gene', '1956', (162, 194))	('erlotinib', 'Chemical', 'MESH:D000069347', (80, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('162', '185'))	('EGFR', 'molecular_function', 'GO:0005006', ('196', '200'))	('activating', 'PosReg', (151, 161))	('patients', 'Species', '9606', (137, 145))	('NSCLC', 'Disease', (229, 234))	('epidermal growth factor receptor', 'Gene', (162, 194))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('EGFR', 'Gene', '1956', (196, 200))	('mutation-positive', 'Var', (202, 219))	('bevacizumab', 'Chemical', 'MESH:D000068258', (94, 105))
57577	28934120	Also, intriguing data emerged for patients with de novo T790 EGFR mutation: in this subgroup of 60 patients, the one-year PFS rate was 60.2%, and median PFS was 15.4 months.	('T790 EGFR', 'Mutation', 'c.790T>EGFR', (56, 65))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (34, 42))	('T790', 'Var', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('PFS', 'Disease', (122, 125))
57578	28934120	Based on this evidence, a randomized, open-label, phase III trial combining first-line erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harboring EGFR mutations is ongoing.	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('EGFR', 'Gene', '1956', (169, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('169', '173'))	('NSCLC', 'Disease', (153, 158))	('bevacizumab', 'Chemical', 'MESH:D000068258', (102, 113))	('EGFR', 'Gene', (169, 173))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('mutations', 'Var', (174, 183))	('patients', 'Species', '9606', (117, 125))	('erlotinib', 'Chemical', 'MESH:D000069347', (87, 96))
57585	28934120	Overall response rate (ORR) and disease control rate (DCR) were slightly higher in the bevacizumab arm versus the SOC arm (ORR 9.7% vs. 6.7%; DCR 86.2% vs. 79.3%, respectively).	('bevacizumab', 'Var', (87, 98))	('higher', 'PosReg', (73, 79))	('SOC', 'biological_process', 'GO:0031578', ('114', '117'))	('disease control', 'CPA', (32, 47))	('Overall response', 'CPA', (0, 16))	('bevacizumab', 'Chemical', 'MESH:D000068258', (87, 98))
57600	28934120	Among grade >=3 adverse events, rash (9% vs. 1%), neutropenia (29% vs. 24%), leukopenia (14% vs. 11%), and febrile neutropenia (9% vs. 7%) were more common with vandetanib plus docetaxel than with placebo plus docetaxel.	('neutropenia', 'Phenotype', 'HP:0001875', (115, 126))	('rash', 'Disease', (32, 36))	('rash', 'Phenotype', 'HP:0000988', (32, 36))	('leukopenia', 'Phenotype', 'HP:0001882', (77, 87))	('docetaxel', 'Chemical', 'MESH:D000077143', (210, 219))	('vandetanib', 'Var', (161, 171))	('vandetanib', 'Chemical', 'MESH:C452423', (161, 171))	('neutropenia', 'Disease', (50, 61))	('febrile neutropenia', 'Disease', (107, 126))	('neutropenia', 'Disease', (115, 126))	('leukopenia', 'Disease', (77, 87))	('febrile neutropenia', 'Disease', 'MESH:D009503', (107, 126))	('docetaxel', 'Chemical', 'MESH:D000077143', (177, 186))	('leukopenia', 'Disease', 'MESH:D007970', (77, 87))	('neutropenia', 'Disease', 'MESH:D009503', (50, 61))	('neutropenia', 'Disease', 'MESH:D009503', (115, 126))	('rash', 'Disease', 'MESH:D005076', (32, 36))	('neutropenia', 'Phenotype', 'HP:0001875', (50, 61))
57635	28934120	Among the 89 patients with EGFR mutations, OS (13.9 vs. 6.5 months, HR 0.48, 95% CI: 0.30-0.76, p = 0.002) and PFS (2.7 vs. 1.4 months, HR 0.27, 95% CI: 0.16-0.46, p < 0.001) were significantly longer with sorafenib than placebo.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('sorafenib', 'Chemical', 'MESH:D000077157', (206, 215))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (32, 41))	('OS', 'Chemical', '-', (43, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))
57636	28934120	PFS was significantly longer with sorafenib than placebo also in patients with either wild-type or mutated KRAS, but OS was similar.	('sorafenib', 'Chemical', 'MESH:D000077157', (34, 43))	('OS', 'Chemical', '-', (117, 119))	('longer', 'PosReg', (22, 28))	('KRAS', 'Gene', (107, 111))	('PFS', 'MPA', (0, 3))	('KRAS', 'Gene', '3845', (107, 111))	('mutated', 'Var', (99, 106))	('patients', 'Species', '9606', (65, 73))
57700	28934120	Disease control rate was also significantly increased in the nintedanib arm (61 vs. 53%, odds ratio 1.37, p = 0.039).	('increased', 'PosReg', (44, 53))	('nintedanib', 'Var', (61, 71))	('nintedanib', 'Chemical', 'MESH:C530716', (61, 71))	('Disease control', 'CPA', (0, 15))
57747	28934120	The BEVERLY randomized phase III trial that is currently ongoing will verify the efficacy of the combination of erlotinib and bevacizumab in Caucasian patients with advanced NSCLC and activating EGFR mutations (Clinicaltrial.gov ID: NCT02633189).	('EGFR', 'molecular_function', 'GO:0005006', ('195', '199'))	('EGFR', 'Gene', (195, 199))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('mutations', 'Var', (200, 209))	('patients', 'Species', '9606', (151, 159))	('activating', 'PosReg', (184, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('erlotinib', 'Chemical', 'MESH:D000069347', (112, 121))	('bevacizumab', 'Chemical', 'MESH:D000068258', (126, 137))	('EGFR', 'Gene', '1956', (195, 199))	('NSCLC', 'Disease', (174, 179))
57764	28811966	While the role of secreted variants of CEACAM1 is poorly understood, they are capable of inhibiting intercellular homophilic adhesion by acting as decoy receptors, and may be useful as serum or urine biomarkers for several malignancies.	('variants', 'Var', (27, 35))	('intercellular homophilic adhesion', 'MPA', (100, 133))	('decoy', 'MPA', (147, 152))	('inhibiting', 'NegReg', (89, 99))	('malignancies', 'Disease', 'MESH:D009369', (223, 235))	('CEACAM1', 'Gene', (39, 46))	('malignancies', 'Disease', (223, 235))
57772	28811966	CEACAM1 expression is mostly excluded from resting (naive) T cells and is expressed at high levels on T cells activated by stimulation with IL-2 or anti-CD3 antibodies via induced transcription and the recruitment of intracellular CEACAM1 to the cell surface.	('IL-2', 'Gene', '3558', (140, 144))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('IL-2', 'Gene', (140, 144))	('cell surface', 'cellular_component', 'GO:0009986', ('246', '258'))	('anti-CD3', 'Var', (148, 156))	('transcription', 'MPA', (180, 193))	('intracellular', 'cellular_component', 'GO:0005622', ('217', '230'))	('CEACAM1', 'Gene', (0, 7))	('recruitment', 'MPA', (202, 213))	('IL-2', 'molecular_function', 'GO:0005134', ('140', '144'))
57777	28811966	CEACAM1 in T cells can also suppress mitogen activated protein kinases ERK and JNK and their downstream pathways.	('suppress', 'NegReg', (28, 36))	('JNK', 'Gene', '5599', (79, 82))	('ERK', 'Gene', '5595;5594;5595', (71, 74))	('JNK', 'molecular_function', 'GO:0004705', ('79', '82'))	('ERK', 'Gene', (71, 74))	('ERK', 'molecular_function', 'GO:0004707', ('71', '74'))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('CEACAM1', 'Var', (0, 7))	('JNK', 'Gene', (79, 82))
57780	28811966	This suggests that CEACAM1 blockade will promote polarization toward the Th1 profile and restore IFNgamma production in situations where CEACAM1 suppression is operative in highly active T cells.	('restore', 'PosReg', (89, 96))	('IFNgamma', 'Gene', '3458', (97, 105))	('polarization toward the Th1 profile', 'MPA', (49, 84))	('blockade', 'Var', (27, 35))	('promote', 'PosReg', (41, 48))	('CEACAM1', 'Gene', (19, 26))	('IFNgamma', 'Gene', (97, 105))
57781	28811966	Thus, inhibition of CEACAM1-L signaling would relieve proximal inhibition of TCR/CD3 complex signaling and restore cytotoxicity and IFNgamma secretion, whereas inhibition of CEACAM1-S signaling would reverse the expansion of unique regulatory populations such as CD4+LAP (latency associated peptide)+ T cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('secretion', 'biological_process', 'GO:0046903', ('141', '150'))	('IFNgamma', 'Gene', (132, 140))	('IFNgamma', 'Gene', '3458', (132, 140))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('latency associated peptide', 'Gene', '7040', (272, 298))	('TCR/CD3 complex signaling', 'MPA', (77, 102))	('latency associated peptide', 'Gene', (272, 298))	('LAP', 'Gene', '7939', (267, 270))	('LAP', 'Gene', (267, 270))	('TCR', 'cellular_component', 'GO:0042101', ('77', '80'))	('restore', 'PosReg', (107, 114))	('TCR', 'biological_process', 'GO:0006283', ('77', '80'))	('CD4', 'Gene', '920', (263, 266))	('proximal inhibition', 'MPA', (54, 73))	('inhibition', 'Var', (6, 16))	('CD4', 'Gene', (263, 266))	('cytotoxicity', 'Disease', (115, 127))	('signaling', 'biological_process', 'GO:0023052', ('184', '193'))
57784	28811966	This suggests that CEACAM1 inhibition might lead to intestinal inflammation as observed with other checkpoint inhibitors.	('lead to', 'Reg', (44, 51))	('inflammation', 'biological_process', 'GO:0006954', ('63', '75'))	('intestinal inflammation', 'Disease', 'MESH:D007249', (52, 75))	('CEACAM1', 'Gene', (19, 26))	('inhibition', 'Var', (27, 37))	('intestinal inflammation', 'Disease', (52, 75))
57790	28811966	CEACAM1-mediated inhibition of T cell cytotoxicity is enhanced by CEACAM1 cross-linking and blocked by CEACAM1 blockade.	('cross-linking', 'Var', (74, 87))	('CEACAM1', 'Protein', (66, 73))	('cytotoxicity', 'Disease', (38, 50))	('enhanced', 'PosReg', (54, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (38, 50))
57796	28811966	Therefore, heterophilic engagement of CEACAM1 with TIM-3 mediates T cell inhibition, with both of these cell surface receptors regulating autoimmunity and antitumor immunity.	('autoimmunity', 'Disease', 'MESH:D001327', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('TIM-3', 'Gene', (51, 56))	('heterophilic', 'Var', (11, 23))	('tumor', 'Disease', (159, 164))	('cell surface', 'cellular_component', 'GO:0009986', ('104', '116'))	('autoimmunity', 'Phenotype', 'HP:0002960', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('autoimmunity', 'Disease', (138, 150))	('T cell inhibition', 'CPA', (66, 83))
57797	28811966	examined circulating and tumor-infiltrating CD8+ T lymphocytes of CRC patients and showed maximal T cell exhaustion upon TIM-3 and CEACAM1 co-expression, as was observed in mouse CRC models.	('CD8', 'Gene', (44, 47))	('patients', 'Species', '9606', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('CD8', 'Gene', '925', (44, 47))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('tumor', 'Disease', (25, 30))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (98, 115))	('T cell', 'CPA', (98, 104))	('mouse', 'Species', '10090', (173, 178))	('co-expression', 'Var', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('CRC', 'Disease', (66, 69))
57816	28811966	CEACAM1 silencing in mouse and human cancer cells upregulated NK cell activating ligands on their surface, while overexpression of CEACAM1-3S and -3L in CRC cell lines caused sequestration of MICA/B intracellularly, preventing it from activating NK cells.	('sequestration', 'MPA', (175, 188))	('activating', 'MPA', (235, 245))	('upregulated', 'PosReg', (50, 61))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('mouse', 'Species', '10090', (21, 26))	('silencing', 'Var', (8, 17))	('human', 'Species', '9606', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('MICA/B', 'Gene', (192, 198))	('CRC', 'Phenotype', 'HP:0003003', (153, 156))	('CEACAM1', 'Gene', (0, 7))
57818	28811966	Furthermore, CEACAM1 forms a complex with NKG2D whereupon CEACAM1 recruits SHP-1 involved in dephosphorylation of the guanine nucleotide exchange factor Vav1, subsequently blocking initiation of cytolysis.	('blocking', 'NegReg', (172, 180))	('SHP-1', 'Gene', (75, 80))	('dephosphorylation', 'MPA', (93, 110))	('cytolysis', 'biological_process', 'GO:0019835', ('195', '204'))	('Vav1', 'Gene', '7409', (153, 157))	('initiation of cytolysis', 'MPA', (181, 204))	('dephosphorylation', 'biological_process', 'GO:0016311', ('93', '110'))	('CEACAM1', 'Var', (58, 65))	('recruits', 'PosReg', (66, 74))	('Vav1', 'Gene', (153, 157))
57820	28811966	While more preclinical and clinical data are still required, particularly to elucidate the CEACAM1 splice variant functions, inhibition of CEACAM1 on NK cells offers an additional advantage that is exploitable by CEACAM1 immunotherapy in advanced cancer treatments.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('CEACAM1', 'Gene', (139, 146))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('inhibition', 'Var', (125, 135))	('advantage', 'PosReg', (180, 189))
57821	28811966	The principle that modulating NK cell function in a cancer setting can lead to improved outcomes has been established in vivo.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('outcomes', 'MPA', (88, 96))	('improved', 'PosReg', (79, 87))	('modulating', 'Var', (19, 29))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
57822	28811966	Unlike currently approved T-cell targeted PD-1 and CTLA4 inhibitors, whose functions in NK cells are debated, targeting CEACAM1 for cancer immunotherapy can offer a second mechanism of action to promote tumor killing by immune surveillance.	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('CTLA4', 'Gene', '1493', (51, 56))	('PD-1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PD-1', 'Gene', '5133', (42, 46))	('promote', 'PosReg', (195, 202))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('CTLA4', 'Gene', (51, 56))	('CEACAM1', 'Gene', (120, 127))	('targeting', 'Var', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
57825	28811966	On the other hand, it has been shown that cross-linking CEACAM1 on mouse B cells with either antibodies or CEACAM1 transfectants, but only in the presence of B cell receptor (BCR) cross-linking, promotes B cell activation but not immunoglobulin isotype switching.	('immunoglobulin', 'molecular_function', 'GO:0003823', ('230', '244'))	('promotes', 'PosReg', (195, 203))	('cross-linking', 'Var', (42, 55))	('isotype switching', 'biological_process', 'GO:0045190', ('245', '262'))	('mouse', 'Species', '10090', (67, 72))	('B cell activation', 'CPA', (204, 221))	('B cell activation', 'biological_process', 'GO:0042113', ('204', '221'))
57826	28811966	Consistent with the latter observations, it has recently been demonstrated using Ceacam1-/- mice that CEACAM1 is a critical regulator of B cell survival, influencing B-cell number and protective antiviral antibody responses.	('antibody', 'molecular_function', 'GO:0003823', ('205', '213'))	('protective antiviral antibody responses', 'CPA', (184, 223))	('antibody', 'cellular_component', 'GO:0042571', ('205', '213'))	('B-cell number', 'CPA', (166, 179))	('CEACAM1', 'Var', (102, 109))	('antibody', 'cellular_component', 'GO:0019814', ('205', '213'))	('antibody', 'cellular_component', 'GO:0019815', ('205', '213'))	('influencing', 'Reg', (154, 165))	('mice', 'Species', '10090', (92, 96))
57828	28811966	While CEACAM1 had little effect on the proliferation of newly formed B cells, the number of mature B cells is reduced significantly in Ceacam1-/- mouse lymph nodes and forced expression of CEACAM1 in T cells leads to increased IgA production in mucosal tissues.	('IgA production', 'MPA', (227, 241))	('reduced', 'NegReg', (110, 117))	('Ceacam1-/-', 'Var', (135, 145))	('mouse', 'Species', '10090', (146, 151))	('increased IgA', 'Phenotype', 'HP:0003261', (217, 230))	('CEACAM1', 'Gene', (189, 196))	('increased', 'PosReg', (217, 226))
57844	28811966	Therefore, inhibition of CEACAM1 could prevent development of circulating monocytes into tumor-associated macrophages, thereby preventing M2 infiltration or persistence in advanced tumors.	('prevent', 'NegReg', (39, 46))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('preventing', 'NegReg', (127, 137))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inhibition', 'Var', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('persistence', 'CPA', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('CEACAM1', 'Gene', (25, 32))
57847	28811966	This suggests that CEACAM1 inhibition may be beneficial to patients whose tumors are characterized by high degrees of fibrosis by halting the establishment of a microenvironmental niche capable of driving tumor progression locally or at distant sites.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('halting', 'NegReg', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CEACAM1', 'Gene', (19, 26))	('fibrosis', 'Disease', 'MESH:D005355', (118, 126))	('inhibition', 'Var', (27, 37))	('fibrosis', 'Disease', (118, 126))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (74, 79))	('patients', 'Species', '9606', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('establishment of a microenvironmental niche', 'MPA', (142, 185))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
57861	28811966	In addition, CEACAM1 activation has been reported to delay Fas ligand-induced apoptosis of human neutrophils using SHP1, ERK1/2 and caspase 3-mediated pathways, which suggests that CEACAM1 inhibition on neutrophils may promote neutrophil apoptosis.	('ERK1/2', 'Gene', (121, 127))	('ERK1/2', 'Gene', '5595;5594', (121, 127))	('neutrophil apoptosis', 'biological_process', 'GO:0001781', ('227', '247'))	('SHP1', 'Gene', (115, 119))	('ERK1', 'molecular_function', 'GO:0004707', ('121', '125'))	('neutrophil apoptosis', 'CPA', (227, 247))	('Fas ligand', 'Gene', '356', (59, 69))	('SHP1', 'Gene', '5777', (115, 119))	('Fas ligand', 'Gene', (59, 69))	('ligand', 'molecular_function', 'GO:0005488', ('63', '69'))	('promote', 'PosReg', (219, 226))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('CEACAM1', 'Gene', (181, 188))	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('caspase 3', 'Gene', (132, 141))	('inhibition', 'Var', (189, 199))	('caspase 3', 'Gene', '836', (132, 141))	('delay', 'NegReg', (53, 58))	('human', 'Species', '9606', (91, 96))
57873	28811966	In addition, WT tumor-bearing mice treated with a CEACAM1-blocking antibody exhibited significantly reduced tumor growth and angiogenesis with reduced levels of CD11b+Gr1+ MDSCs in spleen and blood in a CRC model.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('angiogenesis', 'CPA', (125, 137))	('levels of CD11b+Gr1+ MDSCs', 'MPA', (151, 177))	('mice', 'Species', '10090', (30, 34))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('reduced', 'NegReg', (100, 107))	('CRC', 'Phenotype', 'HP:0003003', (203, 206))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('CEACAM1-blocking', 'Var', (50, 66))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (16, 21))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('angiogenesis', 'biological_process', 'GO:0001525', ('125', '137'))	('reduced', 'NegReg', (143, 150))
57875	28811966	These findings suggest a mechanism whereby pharmacological inhibition of CEACAM1 might result in decreased MDSC infiltration into tumors and, potentially, neutrophilia depending on the balance in humans between production and removal.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('neutrophilia', 'Phenotype', 'HP:0011897', (155, 167))	('neutrophilia', 'Disease', (155, 167))	('CEACAM1', 'Gene', (73, 80))	('pharmacological inhibition', 'Var', (43, 69))	('decreased', 'NegReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('humans', 'Species', '9606', (196, 202))	('neutrophilia', 'Disease', 'MESH:C563010', (155, 167))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
57886	28811966	It is thus possible that in the context of CEACAM1 inhibition, Shc stabilization can lead to cancer promoting effects, a phenomenon that should be closely monitored in preclinical and clinical studies.	('Shc', 'Gene', '6464', (63, 66))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('lead to', 'Reg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Shc', 'Gene', (63, 66))	('CEACAM1', 'Gene', (43, 50))	('inhibition', 'Var', (51, 61))	('stabilization', 'NegReg', (67, 80))
57887	28811966	These initial findings suggested that CEACAM1 plays an important role in insulin internalization and that inhibition of CEACAM1 would result in hyperinsulinemia which was demonstrated with the creation of the LSACC mouse expressing a Ser phosphorylation-defective CEACAM1 (S503A) exclusively in the liver.	('insulin', 'Gene', '3630', (73, 80))	('Ser', 'Chemical', 'MESH:D012694', (234, 237))	('insulin', 'Gene', '3630', (149, 156))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (144, 160))	('Ser', 'cellular_component', 'GO:0005790', ('234', '237'))	('hyperinsulinemia', 'Disease', (144, 160))	('S503A', 'Var', (273, 278))	('inhibition', 'Var', (106, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('238', '253'))	('result in', 'Reg', (134, 143))	('insulin', 'molecular_function', 'GO:0016088', ('73', '80'))	('CEACAM1', 'Gene', (120, 127))	('mouse', 'Species', '10090', (215, 220))	('insulin', 'Gene', (73, 80))	('insulin', 'Gene', (149, 156))	('S503A', 'Mutation', 'p.S503A', (273, 278))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (144, 160))
57888	28811966	CEACAM1 Ser503 phosphorylation is required for Tyr488 phosphorylation by the insulin receptor and prevention of Tyr488 phosphorylation leads to mice developing hyperinsulinemia secondary to impaired insulin clearance, impaired glucose tolerance and random hyperglycemia.	('hyperinsulinemia secondary to impaired insulin', 'Disease', 'MESH:D006946', (160, 206))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (160, 176))	('impaired glucose tolerance', 'Disease', (218, 244))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('Tyr488', 'Var', (112, 118))	('prevention', 'Var', (98, 108))	('hyperglycemia', 'Phenotype', 'HP:0003074', (256, 269))	('hyperinsulinemia secondary to impaired insulin', 'Disease', (160, 206))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (218, 244))	('Tyr488', 'Chemical', '-', (112, 118))	('Ser', 'cellular_component', 'GO:0005790', ('8', '11'))	('hyperglycemia', 'Disease', (256, 269))	('insulin', 'molecular_function', 'GO:0016088', ('77', '84'))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('Tyr488', 'Chemical', '-', (47, 53))	('hyperglycemia', 'Disease', 'MESH:D006943', (256, 269))	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (218, 244))	('mice', 'Species', '10090', (144, 148))	('insulin', 'molecular_function', 'GO:0016088', ('199', '206'))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('Ser503', 'Chemical', '-', (8, 14))
57894	28811966	Interestingly, upon insulin stimulation and subsequent to internalization, CEACAM1 also interacts with and reduces the activity of hepatic FAS, an enzyme that catabolizes fatty acid synthesis.	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('171', '191'))	('insulin', 'molecular_function', 'GO:0016088', ('20', '27'))	('interacts', 'Interaction', (88, 97))	('CEACAM1', 'Var', (75, 82))	('FAS', 'Gene', (139, 142))	('reduces', 'NegReg', (107, 114))	('fatty acid', 'Chemical', 'MESH:D005227', (171, 181))	('insulin', 'Gene', (20, 27))	('FAS', 'Gene', '2194', (139, 142))	('activity', 'MPA', (119, 127))	('insulin', 'Gene', '3630', (20, 27))
57898	28811966	In the context of a monoclonal antibody binding to CEACAM1 on the surface of hepatocytes, internalization of CEACAM1 may be induced, resulting in increased interaction, and therefore FAS inhibition.	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('FAS', 'Gene', (183, 186))	('inhibition', 'NegReg', (187, 197))	('increased', 'PosReg', (146, 155))	('FAS', 'Gene', '2194', (183, 186))	('internalization', 'MPA', (90, 105))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('CEACAM1', 'Var', (109, 116))	('interaction', 'Interaction', (156, 167))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))
57900	28811966	Further validating CEACAM1's role in insulin clearance, removal of SHP-1, a tyrosine phosphatase dephosphorylating CEACAM1, displayed markedly increased insulin clearance in both cultured hepatocytes or mice deficient for a functional SHP-1.	('increased', 'PosReg', (143, 152))	('insulin', 'molecular_function', 'GO:0016088', ('153', '160'))	('phosphatase', 'molecular_function', 'GO:0016791', ('85', '96'))	('SHP-1', 'Gene', (67, 72))	('insulin', 'Gene', (37, 44))	('mice', 'Species', '10090', (203, 207))	('tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('insulin', 'Gene', '3630', (37, 44))	('removal', 'Var', (56, 63))	('insulin', 'molecular_function', 'GO:0016088', ('37', '44'))	('insulin', 'Gene', (153, 160))	('insulin', 'Gene', '3630', (153, 160))
57906	28811966	Other than diet and age studies performed in mouse Ceacam1 mutants, other contributing factors such as hormonal disturbances, human leukocyte antigen type and genetic polymorphisms have not yet been investigated in the context of CEACAM1 inhibition.	('mouse', 'Species', '10090', (45, 50))	('mutants', 'Var', (59, 66))	('Ceacam1', 'Gene', (51, 58))	('human', 'Species', '9606', (126, 131))
57907	28811966	Short term inhibition of CEACAM1 as a cancer therapeutic may, however, prove beneficial in maintaining weight of cancer patients having cachexia.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cachexia', 'Phenotype', 'HP:0004326', (136, 144))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('inhibition', 'Var', (11, 21))	('cachexia', 'Disease', 'MESH:D002100', (136, 144))	('weight', 'Disease', (103, 109))	('cancer', 'Disease', (38, 44))	('patients', 'Species', '9606', (120, 128))	('cachexia', 'Disease', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CEACAM1', 'Gene', (25, 32))
57911	28811966	We suggest that diabetic patients and those with liver disease should be carefully monitored and/or considered for exclusion from early trials of CEACAM1 inhibitors in cancer because of the distinct possibility of worsening these conditions due to CEACAM1's function in insulin clearance and preventing NASH.	('diabetic', 'Disease', 'MESH:D003920', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('insulin', 'molecular_function', 'GO:0016088', ('270', '277'))	('insulin', 'Gene', (270, 277))	('CEACAM1', 'Var', (248, 255))	('liver disease', 'Phenotype', 'HP:0001392', (49, 62))	('liver disease', 'Disease', (49, 62))	('NASH', 'MPA', (303, 307))	('diabetic', 'Disease', (16, 24))	('insulin', 'Gene', '3630', (270, 277))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('preventing NASH', 'Phenotype', 'HP:0100596', (292, 307))	('liver disease', 'Disease', 'MESH:D008107', (49, 62))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Disease', (168, 174))
57913	28811966	CEACAM1 also plays an important role in vascular endothelial lumen formation, given its function as a mediator of VEGF-induced vasculogenesis and angiogenesis, particularly in the context of cancer development In addition, Ceacam1-/- mice develop endothelial dysfunction with these mice demonstrating impaired endothelial integrity with fat deposition and aortic plaque-like lesions in the aorta due to insulin's regulation of altered nitric oxide production in aortic endothelial cells with CEACAM1 abolishment.	('endothelial dysfunction', 'Disease', (247, 270))	('angiogenesis', 'biological_process', 'GO:0001525', ('146', '158'))	('regulation', 'biological_process', 'GO:0065007', ('413', '423'))	('insulin', 'molecular_function', 'GO:0016088', ('403', '410'))	('cancer', 'Disease', (191, 197))	('mice', 'Species', '10090', (234, 238))	('mice', 'Species', '10090', (282, 286))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('CEACAM1', 'Gene', (492, 499))	('insulin', 'Gene', '3630', (403, 410))	('aortic plaque', 'Phenotype', 'HP:0012397', (356, 369))	('vasculogenesis', 'biological_process', 'GO:0001570', ('127', '141'))	('nitric oxide production', 'MPA', (435, 458))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Ceacam1-/-', 'Var', (223, 233))	('nitric oxide', 'Chemical', 'MESH:D009569', (435, 447))	('endothelial dysfunction', 'Disease', 'MESH:C536439', (247, 270))	('insulin', 'Gene', (403, 410))
57917	28811966	CEACAM1 inhibitors may act as anti-angiogenic compounds, similar to the class of VEGF inhibitors approved for cancer therapy.	('cancer', 'Disease', (110, 116))	('anti-angiogenic', 'CPA', (30, 45))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CEACAM1', 'Gene', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('inhibitors', 'Var', (8, 18))
57918	28811966	Since CEACAM1 inhibition will be used in the context of metastatic patients, this negates the risk posed by the possibility of increased vessel leakiness promoting metastasis.	('vessel leakiness', 'Disease', 'MESH:C535298', (137, 153))	('patients', 'Species', '9606', (67, 75))	('CEACAM1', 'Enzyme', (6, 13))	('vessel leakiness', 'Disease', (137, 153))	('increased vessel leakiness', 'Phenotype', 'HP:0030005', (127, 153))	('metastasis', 'CPA', (164, 174))	('inhibition', 'Var', (14, 24))
57920	28811966	Under these conditions, Ceacam1-/- mice exhibited lower mortality, improved cardiac function and lower myocardial expression of pro-apoptotic genes compared with wild-type littermates.	('lower', 'NegReg', (50, 55))	('improved cardiac function', 'Phenotype', 'HP:0001635', (67, 92))	('Ceacam1-/-', 'Var', (24, 34))	('myocardial expression of pro-apoptotic', 'MPA', (103, 141))	('cardiac', 'MPA', (76, 83))	('mice', 'Species', '10090', (35, 39))	('lower', 'NegReg', (97, 102))	('improved', 'PosReg', (67, 75))
57925	28811966	Thus, high-fat feeding of Ceacam1 mutants stimulates a NASH-like condition as seen in human patients, progressive fibrosis and renal dysfunctions.	('mutants', 'Var', (34, 41))	('progressive', 'Disease', (102, 113))	('renal dysfunctions', 'Phenotype', 'HP:0000083', (127, 145))	('human', 'Species', '9606', (86, 91))	('patients', 'Species', '9606', (92, 100))	('fibrosis', 'Disease', (114, 122))	('NASH-like', 'MPA', (55, 64))	('stimulates', 'PosReg', (42, 52))	('renal dysfunctions', 'Disease', (127, 145))	('fibrosis', 'Disease', 'MESH:D005355', (114, 122))	('renal dysfunctions', 'Disease', 'MESH:D007674', (127, 145))	('Ceacam1', 'Gene', (26, 33))
57934	28811966	This function has been confined to the overwhelming expression of CEACAM1-L rather than CEACAM1-S on melanoma cells (Fig.	('melanoma', 'Disease', (101, 109))	('CEACAM1-L', 'Var', (66, 75))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))
57937	28811966	The relationship of CEACAM1 with cells of the immune compartment has been studied in depth in melanoma; a high percentage of circulating NK and CD8+ T lymphocytes are CEACAM1+ in melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('CD8', 'Gene', (144, 147))	('patients', 'Species', '9606', (188, 196))	('CEACAM1+', 'Var', (167, 175))	('CD8', 'Gene', '925', (144, 147))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))
57947	28811966	This might depend on the inherent genetic mutations of the murine cell lines used as xenografts or on intrinsic modulation of the transformative properties of CEA and CEACAM6 on the human cell lines used in these studies, which could inhibit cell differentiation or promote anoikis when engaged at the cell surface by CEACAM1 on the human CRC cells.	('promote', 'PosReg', (266, 273))	('CEACAM6', 'Gene', '4680', (167, 174))	('anoikis', 'biological_process', 'GO:0043276', ('274', '281'))	('human', 'Species', '9606', (182, 187))	('cell differentiation', 'CPA', (242, 262))	('CRC', 'Phenotype', 'HP:0003003', (339, 342))	('cell surface', 'cellular_component', 'GO:0009986', ('302', '314'))	('CEACAM6', 'Gene', (167, 174))	('human', 'Species', '9606', (333, 338))	('inhibit', 'NegReg', (234, 241))	('cell differentiation', 'biological_process', 'GO:0030154', ('242', '262'))	('murine', 'Species', '10090', (59, 65))	('mutations', 'Var', (42, 51))	('anoikis', 'CPA', (274, 281))
57962	28811966	Knockdown of CEACAM1 in human PaCa5061 pancreatic cancer cells resulted in prolonged overall survival in mice subjected to subcutaneous injection of tumor cells, suggesting CEACAM1 increases the aggressiveness of the xenograft.	('aggressiveness', 'Disease', 'MESH:D001523', (195, 209))	('mice', 'Species', '10090', (105, 109))	('PaCa5061', 'CellLine', 'CVCL:C886', (30, 38))	('prolonged', 'PosReg', (75, 84))	('CEACAM1', 'Var', (173, 180))	('aggressiveness', 'Disease', (195, 209))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('human', 'Species', '9606', (24, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('aggressiveness', 'Phenotype', 'HP:0000718', (195, 209))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))	('tumor', 'Disease', (149, 154))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('overall survival', 'CPA', (85, 101))	('increases', 'PosReg', (181, 190))
57963	28811966	Although this was not examined attentively, it remains possible that this occurs through signal responses whereby CEACAM1 silencing leads to significant changes in chemokine/cytokine secretion from tumor cells thus influencing immune cell infiltration, as seen with metastatic CRC.	('CRC', 'Phenotype', 'HP:0003003', (277, 280))	('CEACAM1', 'Gene', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cytokine secretion', 'biological_process', 'GO:0050663', ('174', '192'))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('metastatic CRC', 'Disease', (266, 280))	('chemokine/cytokine secretion from', 'MPA', (164, 197))	('tumor', 'Disease', (198, 203))	('silencing', 'Var', (122, 131))	('influencing', 'Reg', (215, 226))	('immune cell infiltration', 'CPA', (227, 251))	('changes', 'Reg', (153, 160))
57964	28811966	Although no information is yet available relative to CEACAM1 expression in immune cells infiltrating pancreatic tumors, immune activation in general and high TIM-3 expression on circulating CD4+ T lymphocytes in particular correlates with improved overall survival of pancreatic cancer patients.	('TIM-3', 'Gene', (158, 163))	('pancreatic tumors', 'Disease', 'MESH:D010190', (101, 118))	('overall', 'MPA', (248, 255))	('CEACAM1', 'Gene', (53, 60))	('pancreatic cancer', 'Disease', (268, 285))	('CD4', 'Gene', '920', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('pancreatic cancer', 'Disease', 'MESH:D010190', (268, 285))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('pancreatic tumors', 'Disease', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD4', 'Gene', (190, 193))	('activation', 'PosReg', (127, 137))	('improved', 'PosReg', (239, 247))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (268, 285))	('high', 'Var', (153, 157))	('patients', 'Species', '9606', (286, 294))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (101, 118))
57968	28811966	In invasive bladder cancers (pT2-T4), endothelial cells of immature blood vessels become CEACAM1+ whereas epithelial cells remain negative but correlate with high VEGF-C and -D. Overexpression of CEACAM1 in several bladder cancer cell lines results in repressed growth on one hand, while silencing results in increased VEGF expression and enhanced blood vessel formation.	('Overexpression', 'PosReg', (178, 192))	('invasive bladder', 'Phenotype', 'HP:0100645', (3, 19))	('VEGF-C and -D', 'Gene', '7424;2277', (163, 176))	('VEGF', 'Protein', (319, 323))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('bladder cancer', 'Disease', 'MESH:D001749', (215, 229))	('blood vessel formation', 'CPA', (348, 370))	('invasive bladder cancers', 'Disease', (3, 27))	('bladder cancer', 'Disease', (215, 229))	('repressed growth', 'MPA', (252, 268))	('bladder cancer', 'Phenotype', 'HP:0009725', (215, 229))	('formation', 'biological_process', 'GO:0009058', ('361', '370'))	('increased', 'PosReg', (309, 318))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (3, 27))	('enhanced', 'PosReg', (339, 347))	('increased VEGF expression', 'Phenotype', 'HP:0030269', (309, 334))	('bladder cancers', 'Phenotype', 'HP:0009725', (12, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('silencing', 'Var', (288, 297))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))
58015	28494807	The neoplastic cells were diffusely positive for CK7, CA-125, and AMACR; focally positive for CK20, P53, and CEA; and negative for thyroid transcription factor 1 (TTF-1) (Fig.	('transcription factor', 'molecular_function', 'GO:0000981', ('139', '159'))	('P53', 'Var', (100, 103))	('positive', 'Reg', (81, 89))	('CK7', 'Var', (49, 52))	('TTF-1', 'Gene', '7080', (163, 168))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('CA-125', 'Var', (54, 60))	('TTF-1', 'Gene', (163, 168))	('positive', 'Reg', (36, 44))	('CK20', 'Var', (94, 98))
58042	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))
58045	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))
58047	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))
58058	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))
58059	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))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('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))
58063	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))
58066	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))	('plasma cfDNA', 'Disease', (103, 115))
58067	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))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('275', '279'))	('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))
58070	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))
58071	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))	('genetic aberrations', 'Var', (110, 129))	('tumor', 'Disease', (25, 30))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
58074	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))
58075	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))
58081	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))
58082	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))	('NSCLC', 'Disease', (54, 59))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('variants', 'Var', (143, 151))
58092	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))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('detected', 'Reg', (26, 34))	('EGFR', 'Gene', '1956', (89, 93))	('T790M', 'Var', (83, 88))
58094	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))
58096	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))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('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))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('TMEFF2', 'Gene', (11, 17))	('TMEFF2', 'Gene', (55, 61))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))	('TMEFF2', 'Gene', '23671', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
58098	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))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('methylated', 'Var', (184, 194))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('patients', 'Species', '9606', (125, 133))
58103	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))
58107	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))
58123	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))
58124	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', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', (67, 73))	('GS', 'Disease', 'MESH:D011125', (156, 158))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GS', 'Disease', 'MESH:D011125', (38, 40))	('mutations', 'Var', (13, 22))	('Shannon entropy level', 'MPA', (97, 118))
58127	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))
58128	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))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('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))
58133	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))	('EGFR', 'Gene', '1956', (429, 433))	('PTEN', 'Gene', '5728', (293, 297))	('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', 'molecular_function', 'GO:0005006', ('130', '134'))	('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))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('429', '433'))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('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))
58134	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))	('EGFR', 'molecular_function', 'GO:0005006', ('351', '355'))	('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))	('PI3K-mTOR pathway', 'Pathway', (567, 584))	('CCNE1', 'Gene', (237, 242))	('NKX2-1', 'Gene', '7080', (200, 206))	('adenocarcinoma', 'Disease', 'MESH:D000230', (516, 530))	('adenocarcinoma', 'Disease', 'MESH:D000230', (49, 63))	('TERC', 'Gene', '7012', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('CCND3', 'Gene', (264, 269))	('p53', 'Gene', (590, 593))	('ERBB2', 'Gene', (363, 368))	('EGFR', 'molecular_function', 'GO:0005006', ('226', '230'))	('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))	('NKX2-1', 'Gene', (200, 206))	('EGFR', 'Gene', (351, 355))	('TERC', 'Gene', (251, 255))	('MET', 'Gene', (374, 377))	('CCNE1', 'Gene', '898', (237, 242))	('mutations', 'Var', (332, 341))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (132, 151))	('PI3K', 'molecular_function', 'GO:0016303', ('567', '571'))	('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))	('adenocarcinoma', 'Disease', (137, 151))	('MDM2', 'Gene', (214, 218))	('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))
58137	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))	('PTEN', 'Gene', (226, 230))	('associated', 'Reg', (128, 138))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (19, 24))	('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))	('JAK', 'molecular_function', 'GO:0004713', ('166', '169'))	('AC', 'Phenotype', 'HP:0030446', (27, 29))	('tumor', 'Disease', (153, 158))	('SMAD4', 'Gene', (260, 265))	('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))	('KIT', 'molecular_function', 'GO:0005020', ('221', '224'))	('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))	('FGFR2', 'Gene', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('NRAS', 'Gene', (172, 176))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))	('tumors', 'Disease', (74, 80))
58138	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))
58140	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))
58141	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))
58142	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.	('NRAS', 'Gene', '4893', (103, 107))	('EGFR', 'Gene', (83, 87))	('PIK3CA', 'Gene', '5290', (89, 95))	('CTNNB1', 'Gene', (115, 121))	('TP53', 'Gene', (77, 81))	('found', 'Reg', (35, 40))	('JAK3', 'Gene', (109, 113))	('JAK', 'molecular_function', 'GO:0004713', ('109', '112'))	('BRAF', 'Gene', (97, 101))	('NRAS', 'Gene', (103, 107))	('EGFR', 'Gene', '1956', (83, 87))	('PIK3CA', 'Gene', (89, 95))	('JAK3', 'Gene', '3718', (109, 113))	('TP53', 'Gene', '7157', (77, 81))	('mutations', 'Var', (20, 29))	('CTNNB1', 'Gene', '1499', (115, 121))	('KRAS', 'Gene', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('CKDN2A', 'Gene', (127, 133))	('BRAF', 'Gene', '673', (97, 101))
58143	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))
58147	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))
58148	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))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('solid tumor', 'Disease', 'MESH:D009369', (50, 61))	('FGFR3', 'Gene', (13, 18))	('reverse transcription', 'biological_process', 'GO:0001171', ('154', '175'))	('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))
58149	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))
58150	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))	('PDE4DIP', 'Gene', '9659', (143, 150))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('SCLC', 'Phenotype', 'HP:0030357', (204, 208))	('PDE', 'molecular_function', 'GO:0004114', ('143', '146'))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('lung cancer', 'Disease', (91, 102))
58151	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))	('patients', 'Species', '9606', (155, 163))	('GS', 'Disease', 'MESH:D011125', (64, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('GS', 'Disease', 'MESH:D011125', (127, 129))	('lung cancer', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('lung cancer', 'Disease', (91, 102))
58155	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))
58158	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))
58162	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))
58166	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))	('rearrangements', 'Var', (60, 74))	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (76, 80))	('BRAF', 'Gene', '673', (133, 137))	('RET', 'Gene', '5979', (56, 59))	('ALK', 'Gene', (41, 44))	('BRAF', 'Gene', (133, 137))	('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))
58168	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', 'molecular_function', 'GO:0005006', ('136', '140'))	('double deletion in', 'Var', (106, 124))	('cfDNA', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('patient', 'Species', '9606', (148, 155))	('GS', 'Disease', 'MESH:D011125', (96, 98))	('EGFR', 'Gene', '1956', (136, 140))	('MET amplification', 'MPA', (175, 192))	('EGFR', 'Gene', (136, 140))
58169	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))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutations', 'Var', (76, 85))	('PIK3CA', 'Gene', '5290', (252, 258))	('EGFR', 'Gene', (240, 244))	('TP53', 'Gene', '7157', (264, 268))	('EGFR', 'molecular_function', 'GO:0005006', ('240', '244'))	('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))
58170	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))
58173	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))
58174	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))
58175	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))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('mutations', 'Var', (68, 77))	('mutations', 'Var', (119, 128))
58176	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))
58177	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))	('EGFR', 'molecular_function', 'GO:0005006', ('202', '206'))	('NSCLC', 'Disease', (56, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('240', '244'))	('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))
58178	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))
58190	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))
58194	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))
58198	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))	('DNA', 'cellular_component', 'GO:0005574', ('271', '274'))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))
58215	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
58216	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))
58217	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))	('EGFR', 'Gene', '1956', (214, 218))	('clinical', 'Species', '191496', (194, 202))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('EGFR', 'Gene', (214, 218))	('mutations', 'Var', (219, 228))
58219	27589834	compared mutations found in inherited cardiac disease patients on the Illumina MiSeq and the Ion Torrent  PGM platforms.	('cardiac disease', 'Disease', 'MESH:D006331', (38, 53))	('PGM', 'molecular_function', 'GO:0004619', ('106', '109'))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (9, 18))	('cardiac disease', 'Disease', (38, 53))
58223	27589834	In addition, targeted NGS identified eight EGFR indels and SNVs that were not detected by the real-time PCR method used.	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('EGFR', 'Gene', '1956', (43, 47))	('indels', 'Var', (48, 54))	('GS', 'Disease', 'MESH:D011125', (23, 25))	('EGFR', 'Gene', (43, 47))
58224	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))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('GS', 'Disease', 'MESH:D011125', (47, 49))	('tumor', 'Disease', (118, 123))	('DNA', 'cellular_component', 'GO:0005574', ('269', '272'))	('EGFR', 'Gene', '1956', (312, 316))	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'molecular_function', 'GO:0005006', ('312', '316'))	('EGFR', 'Gene', (312, 316))
58225	27589834	However, it is noteworthy that the specificity of IHC using mutated EGFR antibodies is excellent (98.0%).	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (68, 72))	('mutated', 'Var', (60, 67))
58226	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.	('GS', 'Disease', 'MESH:D011125', (138, 140))	('genomic alterations', 'Var', (161, 180))	('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))
58227	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))	('mutations', 'Var', (74, 83))	('lung tumors', 'Disease', 'MESH:D008175', (87, 98))	('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))
58230	27589834	Mutations in EGFR result in abnormal receptor activity leading to increased signaling.	('increased', 'PosReg', (66, 75))	('receptor activity', 'molecular_function', 'GO:0038024', ('37', '54'))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('activity', 'MPA', (46, 54))	('receptor', 'Protein', (37, 45))	('receptor activity', 'molecular_function', 'GO:0038023', ('37', '54'))	('Mutations', 'Var', (0, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('signaling', 'MPA', (76, 85))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
58231	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))
58232	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', 'molecular_function', 'GO:0005006', ('17', '21'))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('patients', 'Species', '9606', (3, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (33, 37))	('gefitinib', 'Chemical', 'MESH:D000077156', (102, 111))	('EGFR', 'Gene', (17, 21))
58233	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', 'molecular_function', 'GO:0005006', ('93', '97'))	('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))
58234	27589834	In personalized medicine, detecting EGFR-activating mutations and monitoring for resistance mutations enable physicians to prescribe treatments and modify them as necessary.	('EGFR', 'Gene', (36, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (36, 40))
58235	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.	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('GS', 'Disease', 'MESH:D011125', (144, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
58236	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))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('mutations', 'Var', (75, 84))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('EGFR', 'Gene', '1956', (59, 63))
58237	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))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('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))
58238	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))	('EGFR', 'molecular_function', 'GO:0005006', ('464', '468'))	('Nucleic Acid', 'cellular_component', 'GO:0005561', ('189', '201'))	('tumor', 'Disease', 'MESH:D009369', (525, 530))	('tumor', 'Phenotype', 'HP:0002664', (525, 530))
58239	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))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
58240	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))	('patients', 'Species', '9606', (221, 229))	('L858R', 'Mutation', 'rs121434568', (239, 244))	('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))
58241	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.	('EGFR', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
58242	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))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('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))
58244	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))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
58245	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%.	('patients', 'Species', '9606', (13, 21))	('mutation', 'Var', (121, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
58247	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.	('cfDNA', 'Disease', (109, 114))	('mutation', 'Var', (82, 90))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))
58248	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))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumors', 'Disease', (313, 319))	('increased', 'PosReg', (208, 217))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('patients', 'Species', '9606', (277, 285))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('tumor', 'Disease', (134, 139))	('patients', 'Species', '9606', (242, 250))
58251	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.	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('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))
58252	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))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))
58254	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))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (9, 14))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', '1956', (34, 38))
58256	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))
58257	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))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('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))
58258	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))	('patients', 'Species', '9606', (138, 146))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (23, 31))	('higher', 'PosReg', (122, 128))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('170', '174'))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('EGFR', 'Gene', (170, 174))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))
58259	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))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('T790M', 'Mutation', 'rs121434569', (93, 98))	('L858R', 'Var', (82, 87))	('T790M', 'Var', (93, 98))	('EGFR', 'Gene', '1956', (59, 63))	('deletion', 'Var', (72, 80))
58260	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))	('EGFR', 'Gene', '1956', (66, 70))	('T790M', 'Mutation', 'rs121434569', (167, 172))	('EGFR', 'Gene', (66, 70))	('T790M', 'Var', (105, 110))	('AZD9291', 'Chemical', 'MESH:C000596361', (189, 196))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('T790M-potent', 'Var', (167, 179))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
58262	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', 'molecular_function', 'GO:0005006', ('194', '198'))	('EGFR', 'molecular_function', 'GO:0005006', ('230', '234'))	('EGFR', 'Gene', '1956', (194, 198))	('mutations', 'Var', (298, 307))	('EGFR', 'Gene', (194, 198))	('EGFR', 'molecular_function', 'GO:0005006', ('281', '285'))	('EGFR', 'Gene', '1956', (281, 285))	('EGFR', 'Gene', (281, 285))
58263	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))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
58264	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))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
58266	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))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
58267	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', 'molecular_function', 'GO:0005006', ('108', '112'))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('C797S', 'Mutation', 'rs1057519861', (64, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('C797S', 'Var', (64, 69))	('drug binding', 'molecular_function', 'GO:0008144', ('92', '104'))	('drug', 'MPA', (92, 96))	('EGFR', 'Gene', '1956', (59, 63))
58268	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))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('patients', 'Species', '9606', (114, 122))	('EGFR', 'Gene', '1956', (96, 100))
58269	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', 'molecular_function', 'GO:0005006', ('106', '110'))	('EGFR', 'Gene', '1956', (106, 110))	('patient', 'Species', '9606', (55, 62))	('EGFR', 'Gene', (106, 110))
58270	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))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('T790M', 'Var', (68, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutations', 'Var', (119, 128))	('EGFR', 'Gene', '1956', (151, 155))	('patients', 'Species', '9606', (86, 94))
58271	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))	('KIT', 'molecular_function', 'GO:0005020', ('123', '126'))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('acquired resistance', 'MPA', (54, 73))	('EGFR', 'Gene', (141, 145))	('T790M', 'Mutation', 'rs121434569', (20, 25))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('mutations', 'Var', (95, 104))	('KIT', 'Gene', (123, 126))	('KDR', 'Gene', '3791', (114, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))
58272	27589834	more than one mutation in the EGFR tyrosine kinase domain).	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))
58273	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))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', (38, 42))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (43, 52))	('lower', 'NegReg', (74, 79))
58274	27589834	Additionally, to determine if EGFR mutations could be found in other sample types, Liu et al.	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
58275	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))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('pleural effusion', 'Phenotype', 'HP:0002202', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('NSCLC', 'Disease', (120, 125))	('patients', 'Species', '9606', (97, 105))
58276	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', 'molecular_function', 'GO:0005006', ('105', '109'))	('EGFR', 'Gene', (105, 109))
58277	27589834	demonstrated that deep sequencing of plasma cfDNA is highly specific for the detection of EGFR mutations, including T790M.	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('T790M', 'Var', (116, 121))	('EGFR', 'Gene', (90, 94))
58278	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
58280	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))	('EGFR', 'molecular_function', 'GO:0005006', ('203', '207'))	('NSCLC', 'Disease', (172, 177))	('tumor', 'Disease', (70, 75))	('EGFR', 'Gene', (203, 207))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('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))
58283	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', 'molecular_function', 'GO:0005006', ('96', '100'))	('EGFR', 'Gene', '1956', (96, 100))
58284	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))	('EGFR', 'molecular_function', 'GO:0005006', ('228', '232'))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
58286	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', 'molecular_function', 'GO:0005006', ('148', '152'))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('239', '243'))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (239, 243))	('mutations', 'Var', (244, 253))	('EGFR', 'Gene', (239, 243))
58287	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', 'molecular_function', 'GO:0005006', ('11', '15'))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
58290	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', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))
58292	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))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('GS', 'Disease', 'MESH:D011125', (56, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))
58293	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))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('T790M', 'Mutation', 'rs121434569', (140, 145))	('EGFR', 'Gene', (83, 87))	('T790M', 'Var', (140, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('EGFR', 'Gene', '1956', (30, 34))
58294	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))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('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))
58295	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))
58301	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.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('4', '37'))	('phosphatase', 'molecular_function', 'GO:0016791', ('189', '200'))	('oncogenesis', 'biological_process', 'GO:0007048', ('281', '292'))	('receptor tyrosine kinase', 'Gene', (68, 92))	('lung tumors', 'Disease', 'MESH:D008175', (325, 336))	('PI3K', 'molecular_function', 'GO:0016303', ('211', '215'))	('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))	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('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))
58302	27589834	In several cases, MET amplification has been associated with resistance to EGFR-TKI therapy.	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('MET amplification', 'Var', (18, 35))	('associated', 'Reg', (45, 55))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))
58303	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))
58308	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.	('MET exon 14', 'Gene', (66, 77))	('detected', 'Reg', (93, 101))	('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))	('tumors', 'Disease', (236, 242))	('lung tumor', 'Disease', (269, 279))	('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))
58309	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))	('MET exon', 'Var', (56, 64))	('c-MET', 'Gene', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('SCLC', 'Phenotype', 'HP:0030357', (19, 23))	('c-MET', 'Gene', '4233', (139, 144))	('tumors', 'Disease', (39, 45))
58311	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.	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('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))	('splicing', 'biological_process', 'GO:0045292', ('23', '31'))	('MET exon 14 splicing alterations', 'Var', (11, 43))	('CDK4', 'Gene', (121, 125))
58312	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))
58313	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))	('decrease', 'NegReg', (260, 268))	('tumor', 'Disease', (272, 277))	('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))
58315	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))
58317	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))
58319	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))
58320	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))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))
58321	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))
58324	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))
58331	27842505	The 76 (31 %) patients who were CA 19-9+ had shorter overall survival (OS) than CA 19-9- group (12.5 vs 26.2 months, P = 0.005).	('shorter', 'NegReg', (45, 52))	('overall survival', 'MPA', (53, 69))	('OS', 'Chemical', '-', (71, 73))	('CA 19-9+', 'Var', (32, 40))	('patients', 'Species', '9606', (14, 22))
58332	27842505	Cox's multivariate regression analysis identified Eastern Cooperative Oncology Group Performance Status 0 or 1 (P < 0.001), mutated epidermal growth factor receptor (EGFR) status (P < 0.001), stage IIIB (P < 0.001), CYFRA 21-1- (P < 0.001), CA 19-9- (P = 0.005) and use of platinum doublet therapy (P = 0.034) as independent predictors of longer OS.	('mutated', 'Var', (124, 131))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('132', '155'))	('EGFR', 'Gene', '1956', (166, 170))	('epidermal growth factor receptor', 'Gene', (132, 164))	('EGFR', 'Gene', (166, 170))	('platinum', 'Chemical', 'MESH:D010984', (273, 281))	('OS', 'Chemical', '-', (346, 348))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('epidermal growth factor receptor', 'Gene', '1956', (132, 164))	('Oncology', 'Phenotype', 'HP:0002664', (70, 78))
58333	27842505	We stratified patients by CA 19-9 and CYFRA 21-1 as double positive (CA 19-9+/CYFRA 21-1+, n = 59), single positive (either CA19-9+ or CYFRA 21-1+, n = 113), or double negative (CA 19-9-/CYFRA 21-1-, n = 74).	('CA19-9+', 'Var', (124, 131))	('CA 19-9+/CYFRA', 'Var', (69, 83))	('patients', 'Species', '9606', (14, 22))	('CYFRA 21-1+', 'Var', (135, 146))
58355	27842505	We isolated tumor DNA from various specimens and analyzed epidermal growth factor receptor gene (EGFR) mutation status at exons 18-21, using the peptide nucleic acid-locked nucleic acid PCR clamp methods, as described previously.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('58', '81'))	('epidermal growth factor receptor', 'Gene', (58, 90))	('EGFR', 'Gene', '1956', (97, 101))	('nucleic acid', 'cellular_component', 'GO:0005561', ('153', '165'))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('nucleic acid', 'cellular_component', 'GO:0005561', ('173', '185'))	('EGFR', 'Gene', (97, 101))	('epidermal growth factor receptor', 'Gene', '1956', (58, 90))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('mutation', 'Var', (103, 111))	('tumor', 'Disease', (12, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
58373	27842505	Of the 246 patients, 100 (41 %) had EGFR mutations in their specimens, and 22 (9 %) had chronic lung inflammatory diseases (16 with interstitial pneumonia, 3 with NTM infection, and 3 with bronchiectasis).	('mutations', 'Var', (41, 50))	('lung inflammatory diseases', 'Disease', 'MESH:D008171', (96, 122))	('pneumonia', 'Phenotype', 'HP:0002090', (145, 154))	('NTM infection', 'Disease', 'MESH:D007239', (163, 176))	('bronchiectasis', 'Phenotype', 'HP:0002110', (189, 203))	('lung inflammatory diseases', 'Disease', (96, 122))	('bronchiectasis', 'Disease', (189, 203))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('interstitial pneumonia', 'Disease', (132, 154))	('EGFR', 'Gene', '1956', (36, 40))	('interstitial pneumonia', 'Disease', 'MESH:D017563', (132, 154))	('EGFR', 'Gene', (36, 40))	('patients', 'Species', '9606', (11, 19))	('had', 'Reg', (84, 87))	('NTM infection', 'Disease', (163, 176))
58376	27842505	Comparison of clinical profiles of CA 19-9- and CA 19-9+ patients showed the CA 19-9- group included a significantly higher percentage of patients with ECOG PS 0 or 1 status (P < 0.001), serum CYFRA 21-1- (P = 0.002), and platinum doublet therapy administration (P = 0.007).	('CA 19-9-', 'Var', (77, 85))	('serum CYFRA 21-1-', 'MPA', (187, 204))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (57, 65))	('platinum', 'Chemical', 'MESH:D010984', (222, 230))	('higher', 'PosReg', (117, 123))	('platinum doublet therapy', 'CPA', (222, 246))
58379	27842505	The CYFRA 21-1- group had a significantly higher percentage of patients with ECOG PS 0 or 1 status (P = 0.002), inflammatory lung disease (P = 0.020), serum CA 19-9- (P = 0.002), and platinum doublet therapy administration (P = 0.046).	('platinum', 'Chemical', 'MESH:D010984', (183, 191))	('lung disease', 'Phenotype', 'HP:0002088', (125, 137))	('serum CA 19-9-', 'MPA', (151, 165))	('inflammatory lung disease', 'Disease', 'MESH:D008171', (112, 137))	('higher', 'PosReg', (42, 48))	('patients', 'Species', '9606', (63, 71))	('CYFRA 21-1-', 'Var', (4, 15))	('inflammatory lung disease', 'Disease', (112, 137))
58387	27842505	To clarify the relationships of chemotherapy regimens to OS, we analyzed the platinum doublet subcohorts with regard to OS; we found that CA 19-9- independently predicted longer OS (HR: 0.54, CI:0.35 - 0.84, P = 0.007).	('CA 19-9-', 'Var', (138, 146))	('OS', 'Chemical', '-', (57, 59))	('longer OS', 'Disease', (171, 180))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('OS', 'Chemical', '-', (120, 122))	('OS', 'Chemical', '-', (178, 180))
58391	27842505	Comparison of clinical profiles of CA 19-9+ and CA 19-9- patients showed the CA 19-9+ group to include significantly higher proportions of patients with vessel invasion (P = 0.032), pleural invasion (P = 0.023), cancer invasive factors (P = 0.005) and positive PAS stain (P = 0.001).	('pleural invasion', 'Disease', (182, 198))	('patients', 'Species', '9606', (139, 147))	('PAS', 'Chemical', 'MESH:D011478', (261, 264))	('patients', 'Species', '9606', (57, 65))	('PAS', 'cellular_component', 'GO:0000407', ('261', '264'))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('pleural invasion', 'Disease', 'MESH:D010995', (182, 198))	('vessel invasion', 'CPA', (153, 168))	('higher', 'PosReg', (117, 123))	('positive PAS stain', 'CPA', (252, 270))	('CA 19-9+', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
58393	27842505	We also investigated the association between EGFR status and survival in the 116 patients with stage I lung adenocarcinoma; for whom 110 (95 %) had EGFR mutation analyses available, which showed 61 (53 %) to have EGFR mutations.	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', (213, 217))	('mutations', 'Var', (218, 227))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('patients', 'Species', '9606', (81, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('stage I lung adenocarcinoma', 'Disease', (95, 122))	('stage I lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('EGFR', 'Gene', '1956', (213, 217))
58405	27842505	Consequently, we divided patients into three groups as well; 24 % double positive (CA 19-9+/CYFRA 21-1+), 46 % single positive (either CA 19-9+ or CYFRA 21-1+), and 30 % double negative (CA 19-9-/CYFRA 21-1-).	('CA 19-9-/CYFRA 21-1-', 'Var', (187, 207))	('patients', 'Species', '9606', (25, 33))	('CYFRA 21-1+', 'Var', (147, 158))	('CA 19-9+', 'Var', (135, 143))	('CA 19-9+/CYFRA 21-1+', 'Var', (83, 103))
58413	27842505	In our pathological analysis of clinical stage I patients, CA 19-9 positive lung adenocarcinoma had more histologically malignant features (P = 0.005) and shorter recurrence-free survival (P = 0.030) than CA 19-9 negative lung adenocarcinoma (Fig.	('CA 19-9 positive', 'Var', (59, 75))	('lung adenocarcinoma', 'Disease', (76, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (222, 241))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('shorter', 'NegReg', (155, 162))	('lung adenocarcinoma', 'Disease', (222, 241))	('more', 'PosReg', (100, 104))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('patients', 'Species', '9606', (49, 57))	('histologically malignant features', 'CPA', (105, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (222, 241))	('recurrence-free survival', 'CPA', (163, 187))
58449	33804894	This approach provided the opportunity to understand the extent of the genomic heterogeneity among A. baumannii isolates, in terms of insertions, deletions, inversions and single nucleotide polymorphisms.	('A. baumannii', 'Species', '470', (99, 111))	('deletions', 'Var', (146, 155))	('single nucleotide polymorphisms', 'Var', (172, 203))	('insertions', 'Var', (134, 144))
58474	33804894	The polysaccharides composing the capsule act as water retainers that shield the bacterial body against desiccation; however, although mutant strains within the K locus displayed lower resistance, the heterogeneous behavior of encapsulated bacteria in relation to desiccation led to the conclusion that the capsule plays a minor role.	('lower', 'NegReg', (179, 184))	('capsule', 'cellular_component', 'GO:0042603', ('34', '41'))	('capsule', 'cellular_component', 'GO:0042603', ('307', '314'))	('mutant', 'Var', (135, 141))	('resistance', 'MPA', (185, 195))	('heterogeneous', 'MPA', (201, 214))	('water', 'Chemical', 'MESH:D014867', (49, 54))	('polysaccharides', 'Chemical', 'MESH:D011134', (4, 19))
58486	33804894	Moreover, DNA damages as consequence of water stress, as well as other environmental stresses in clinical settings, generate base-pair substitutions in a number of different bacterial targets, thereby contributing to the acquisition of additional antibiotic resistances in A. baumannii (i.e., rifampin-resistance).	('rifampin', 'Chemical', 'MESH:D012293', (293, 301))	('environmental', 'Species', '1275957', (71, 84))	('base-pair substitutions', 'Var', (125, 148))	('water', 'Chemical', 'MESH:D014867', (40, 45))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('antibiotic resistances', 'MPA', (247, 269))	('A. baumannii', 'Species', '470', (273, 285))	('acquisition', 'Reg', (221, 232))
58505	33804894	Although the precise mechanism of surface-associated motility remains to be elucidated, the signaling network of cyclic-di-GMP, the second messenger molecule involved in adaptation to various stress responses, was shown to upregulate biofilm formation and downregulate surface associated motility.	('cyclic-di-GMP', 'Chemical', 'MESH:C062025', (113, 126))	('downregulate', 'NegReg', (256, 268))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('biofilm formation', 'biological_process', 'GO:0042710', ('234', '251'))	('surface associated motility', 'CPA', (269, 296))	('upregulate', 'PosReg', (223, 233))	('cyclic-di-GMP', 'Var', (113, 126))	('biofilm formation', 'CPA', (234, 251))
58510	33804894	The amino acid sequence of this protein is highly conserved among A. baumannii clinical isolates; its involvement in antibiotic-resistance was revealed by the use of ompA mutants.	('A. baumannii', 'Species', '470', (66, 78))	('antibiotic-resistance', 'MPA', (117, 138))	('involvement', 'Reg', (102, 113))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('mutants', 'Var', (171, 178))
58524	33804894	Another important Omp in A. baumannii is Omp33-36 kDa or Omp34 or Omp33.	('A. baumannii', 'Species', '470', (25, 37))	('Omp33', 'Var', (66, 71))	('Omp34', 'Var', (57, 62))
58528	33804894	To acquire free iron, A. baumannii produces and secretes siderophores, low molecular weight iron scavengers (400-1000 kDa) able to chelate it at high affinity.	('siderophores', 'MPA', (57, 69))	('400-1000', 'Var', (109, 117))	('iron', 'Chemical', 'MESH:D007501', (16, 20))	('A. baumannii', 'Species', '470', (22, 34))	('iron', 'Chemical', 'MESH:D007501', (92, 96))
58543	33804894	Interestingly, it was recently reported that PstS plays an important role in A. baumannii virulence during microaerobic conditions; indeed, the pstS deletion mutant showed reduced adhesion to and invasion of human alveolar type II cells (A549 cell line, see below), whereas its overexpression enhances pathogenesis.	('reduced', 'NegReg', (172, 179))	('invasion', 'CPA', (196, 204))	('virulence', 'biological_process', 'GO:0016032', ('90', '99'))	('overexpression enhances', 'PosReg', (278, 301))	('virulence', 'biological_process', 'GO:0009406', ('90', '99'))	('A549', 'CellLine', 'CVCL:0023', (238, 242))	('A. baumannii', 'Species', '470', (77, 89))	('virulence', 'biological_process', 'GO:0009405', ('90', '99'))	('human', 'Species', '9606', (208, 213))	('pstS', 'Gene', (144, 148))	('adhesion to', 'CPA', (180, 191))	('pathogenesis', 'biological_process', 'GO:0009405', ('302', '314'))	('deletion mutant', 'Var', (149, 164))
58546	33804894	To date, five secretion systems have been identified in A. baumannii, comprising type 1 secretion system (T1SS), T2SS, T4SS, T5SS, and T6SS.	('T2SS', 'Var', (113, 117))	('secretion', 'biological_process', 'GO:0046903', ('88', '97'))	('A. baumannii', 'Species', '470', (56, 68))	('T4SS', 'Var', (119, 123))	('secretion', 'biological_process', 'GO:0046903', ('14', '23'))
58550	33804894	The 16-stranded beta barrel AbFhaC protein recognizes and translocates to the cell surface its partner protein, AbFhaB, via two specific periplasmic polypeptide transport-associated domains; AbFhaB has the arginine-glycine-aspartic acid (RGD) motif that was shown to be associated with eukaryotic integrin and fibronectin attachment.	('AbFhaB', 'Var', (191, 197))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('arginine', 'Chemical', 'MESH:D001120', (206, 214))	('aspartic acid', 'Chemical', 'MESH:D001224', (223, 236))	('RGD', 'Chemical', 'MESH:C047981', (238, 241))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('glycine', 'Chemical', 'MESH:D005998', (215, 222))	('cell surface', 'cellular_component', 'GO:0009986', ('78', '90'))	('transport', 'biological_process', 'GO:0006810', ('161', '170'))	('translocates', 'MPA', (58, 70))
58570	33804894	Indeed, ata mutants displayed an attenuated virulent phenotype in in vivo models.	('attenuated', 'NegReg', (33, 43))	('virulent phenotype', 'MPA', (44, 62))	('mutants', 'Var', (12, 19))	('ata', 'Chemical', 'MESH:D000640', (8, 11))
58571	33804894	Interestingly, the A. baumannii T5bSS FhaB protein binds both host integrins and fibronectins, having a RGD motif.	('binds', 'Interaction', (51, 56))	('A. baumannii', 'Species', '470', (19, 31))	('RGD', 'Chemical', 'MESH:C047981', (104, 107))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('T5bSS', 'Var', (32, 37))
58589	33804894	TFEB leads to upregulation of several autophagic genes (up to 79), including LC3BII which in cooperation with p62 induces the autophagosome-lysosome system that A. baumannii exploits to traffic intracellularly and persist within lung cells, possibly due to reduced lysosome acidification.	('autophagic genes', 'Gene', (38, 54))	('autophagosome-lysosome system', 'CPA', (126, 155))	('LC3BII', 'Gene', (77, 83))	('lysosome', 'cellular_component', 'GO:0005764', ('265', '273'))	('TFEB', 'Var', (0, 4))	('A. baumannii', 'Species', '470', (161, 173))	('autophagosome', 'cellular_component', 'GO:0005776', ('126', '139'))	('lysosome', 'cellular_component', 'GO:0005764', ('140', '148'))	('induces', 'Reg', (114, 121))	('acidification', 'biological_process', 'GO:0045851', ('274', '287'))	('LC3', 'Chemical', '-', (77, 80))	('upregulation', 'PosReg', (14, 26))
58590	33804894	More recently, it was reported that A. baumannii ChoP-PAFR-mediated entry of human bronchial epithelial cells can also elicit the Janus kinase (Jak)-signal transducer and the activator of transcription (STAT) pathway, as well as intracellular oxidative stress and apoptosis as a response to the bacterial infections.	('ChoP-PAFR-mediated', 'Var', (49, 67))	('oxidative stress', 'Phenotype', 'HP:0025464', (243, 259))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('elicit', 'Reg', (119, 125))	('bacterial infections', 'Disease', 'MESH:D001424', (295, 315))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('intracellular', 'cellular_component', 'GO:0005622', ('229', '242'))	('A. baumannii', 'Species', '470', (36, 48))	('intracellular', 'MPA', (229, 242))	('Jak', 'molecular_function', 'GO:0004713', ('144', '147'))	('apoptosis', 'CPA', (264, 273))	('A. baumannii ChoP-PAFR-mediated', 'Var', (36, 67))	('bacterial infections', 'Disease', (295, 315))	('bacterial infections', 'Phenotype', 'HP:0002718', (295, 315))	('human', 'Species', '9606', (77, 82))
58609	33804894	As mentioned earlier, by detoxifying H2O2 into water and oxygen, KatG and KatE are able to attenuate the neutrophil-mediated oxidative injury.	('attenuate', 'NegReg', (91, 100))	('detoxifying', 'Var', (25, 36))	('water', 'Chemical', 'MESH:D014867', (47, 52))	('H2O2', 'Chemical', 'MESH:D006861', (37, 41))	('neutrophil-mediated oxidative injury', 'MPA', (105, 141))	('oxygen', 'Chemical', 'MESH:D010100', (57, 63))
58642	33839455	Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88.	('T88', 'Var', (196, 199))	('e', 'Gene', '2069', (164, 165))	('antibody', 'cellular_component', 'GO:0019815', ('6', '14'))	('e', 'Gene', '2069', (172, 173))	('e', 'Gene', '2069', (155, 156))	('e', 'Gene', '2069', (108, 109))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (60, 61))	('e', 'Gene', '2069', (91, 92))	('e', 'Gene', '2069', (185, 186))	('e', 'Gene', '2069', (68, 69))	('extracellular region', 'cellular_component', 'GO:0005576', ('149', '169'))	('e', 'Gene', '2069', (176, 177))	('antibody', 'cellular_component', 'GO:0019814', ('6', '14'))	('degradation', 'biological_process', 'GO:0009056', ('46', '57'))	('e', 'Gene', '2069', (175, 176))	('e', 'Gene', '2069', (87, 88))	('e', 'Gene', '2069', (96, 97))	('antibody', 'molecular_function', 'GO:0003823', ('6', '14'))	('e', 'Gene', '2069', (32, 33))	('antibody', 'cellular_component', 'GO:0042571', ('6', '14'))	('e', 'Gene', '2069', (47, 48))	('Trop-2', 'Gene', (77, 83))	('E', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (70, 71))	('e', 'Gene', '2069', (149, 150))	('e', 'Gene', '2069', (180, 181))	('e', 'Gene', '2069', (101, 102))
58647	33839455	We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease.	('pro', 'Chemical', 'MESH:D011392', (62, 65))	('pro', 'Chemical', 'MESH:D011392', (127, 130))	('ADAM10', 'Gene', '102', (13, 19))	('e', 'Gene', '2069', (60, 61))	('ADAM10', 'Gene', (105, 111))	('e', 'Gene', '2069', (134, 135))	('inhibitors', 'Var', (20, 30))	('ADAM10', 'Gene', (13, 19))	('e', 'Gene', '2069', (66, 67))	('e', 'Gene', '2069', (97, 98))	('abolish', 'NegReg', (50, 57))	('ADAM10', 'Gene', '102', (105, 111))	('e', 'Gene', '2069', (1, 2))	('e', 'Gene', '2069', (121, 122))	('e', 'Gene', '2069', (131, 132))	('Trop-2', 'Gene', (76, 82))	('e', 'Gene', '2069', (118, 119))
58648	33839455	Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('e', 'Gene', '2069', (47, 48))	('Trop-2', 'Gene', (15, 21))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (4, 5))	('R87-T88', 'Var', (25, 32))	('e', 'Gene', '2069', (38, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('Proteolysis', 'biological_process', 'GO:0006508', ('0', '11'))	('e', 'Gene', '2069', (51, 52))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))
58649	33839455	A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination.	('colon cancer', 'Disease', (59, 71))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (78, 79))	('e', 'Gene', '2069', (36, 37))	('e', 'Gene', '2069', (130, 131))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('R87A-T88A', 'Var', (80, 89))	('e', 'Gene', '2069', (144, 145))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('e', 'Gene', '2069', (6, 7))	('e', 'Gene', '2069', (111, 112))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('e', 'Gene', '2069', (115, 116))	('e', 'Gene', '2069', (49, 50))	('e', 'Gene', '2069', (69, 70))	('T88A', 'Mutation', 'c.88T>A', (85, 89))	('R87A', 'Mutation', 'p.R87A', (80, 84))	('Trop-2', 'Gene', (90, 96))
58663	33839455	showed that regulated intramembrane proteolysis (RIP) is responsible for the cleavage of Trop-2 that is mediated by ADAM17/TACE at the A187-V188 site, followed by gamma-secretase processing at G285-V286.	('e', 'Gene', '2069', (110, 111))	('e', 'Gene', '2069', (173, 174))	('e', 'Gene', '2069', (4, 5))	('e', 'Gene', '2069', (13, 14))	('e', 'Gene', '2069', (133, 134))	('e', 'Gene', '2069', (28, 29))	('pro', 'Chemical', 'MESH:D011392', (36, 39))	('e', 'Gene', '2069', (170, 171))	('TACE', 'Gene', (123, 127))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (67, 68))	('e', 'Gene', '2069', (148, 149))	('pro', 'Chemical', 'MESH:D011392', (179, 182))	('e', 'Gene', '2069', (75, 76))	('e', 'Gene', '2069', (34, 35))	('e', 'Gene', '2069', (58, 59))	('Trop-2', 'Gene', (89, 95))	('ADAM17', 'Gene', '6868', (116, 122))	('e', 'Gene', '2069', (177, 178))	('e', 'Gene', '2069', (105, 106))	('ADAM17', 'Gene', (116, 122))	('proteolysis', 'biological_process', 'GO:0006508', ('36', '47'))	('e', 'Gene', '2069', (79, 80))	('TACE', 'Gene', '6868', (123, 127))	('e', 'Gene', '2069', (183, 184))	('G285-V286', 'Var', (193, 202))	('e', 'Gene', '2069', (157, 158))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (84, 85))
58667	33839455	ADAM10 is shown to cleave Trop-2 at R87-T88 in cancer cells, to activate Trop-2, and to induce cancer cell growth.	('e', 'Gene', '2069', (21, 22))	('Trop-2', 'Gene', (26, 32))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (95, 101))	('e', 'Gene', '2069', (99, 100))	('ADAM10', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('e', 'Gene', '2069', (51, 52))	('Trop-2', 'Gene', (73, 79))	('ADAM10', 'Gene', '102', (0, 6))	('e', 'Gene', '2069', (24, 25))	('e', 'Gene', '2069', (103, 104))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('e', 'Gene', '2069', (71, 72))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('e', 'Gene', '2069', (93, 94))	('e', 'Gene', '2069', (55, 56))	('R87-T88', 'Var', (36, 43))
58668	33839455	Using tumor xenografts of human colon cancer cells that express the R87A-T88A Trop-2 mutant (designated as A87-A88 Trop-2), we demonstrate that Trop-2 proteolytic processing by ADAM10 correspondingly drives metastatic dissemination.	('ADAM10', 'Gene', (177, 183))	('e', 'Gene', '2069', (46, 47))	('T88A', 'Mutation', 'c.88T>A', (73, 77))	('e', 'Gene', '2069', (188, 189))	('e', 'Gene', '2069', (13, 14))	('pro', 'Chemical', 'MESH:D011392', (163, 166))	('ADAM10', 'Gene', '102', (177, 183))	('e', 'Gene', '2069', (155, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('human', 'Species', '9606', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('e', 'Gene', '2069', (60, 61))	('e', 'Gene', '2069', (42, 43))	('e', 'Gene', '2069', (66, 67))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))	('e', 'Gene', '2069', (208, 209))	('R87A-T88A', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('e', 'Gene', '2069', (167, 168))	('e', 'Gene', '2069', (137, 138))	('e', 'Gene', '2069', (56, 57))	('e', 'Gene', '2069', (128, 129))	('tumor', 'Disease', (6, 11))	('pro', 'Chemical', 'MESH:D011392', (151, 154))	('colon cancer', 'Disease', (32, 44))	('R87A', 'Mutation', 'p.R87A', (68, 72))	('e', 'Gene', '2069', (222, 223))	('Trop-2', 'Gene', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('e', 'Gene', '2069', (94, 95))	('e', 'Gene', '2069', (125, 126))	('e', 'Gene', '2069', (204, 205))	('e', 'Gene', '2069', (101, 102))
58686	33839455	The AF650 polyclonal goat anti-Trop-2 antibody was from R&D Systems; the rabbit polyclonal anti-ADAM10 antibody was from Merck-Millipore (AB19026); and the goat polyclonal anti-ADAM10 antibody (sc-31853) was from Santa Cruz Biotechnology.	('ADAM10', 'Gene', (177, 183))	('e', 'Gene', '2069', (228, 229))	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('antibody', 'cellular_component', 'GO:0042571', ('184', '192'))	('antibody', 'cellular_component', 'GO:0042571', ('103', '111'))	('ADAM10', 'Gene', (96, 102))	('ADAM10', 'Gene', '102', (177, 183))	('e', 'Gene', '2069', (122, 123))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('e', 'Gene', '2069', (154, 155))	('ADAM10', 'Gene', '102', (96, 102))	('antibody', 'cellular_component', 'GO:0019815', ('184', '192'))	('antibody', 'cellular_component', 'GO:0019815', ('103', '111'))	('e', 'Gene', '2069', (2, 3))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('antibody', 'cellular_component', 'GO:0019814', ('184', '192'))	('e', 'Gene', '2069', (135, 136))	('antibody', 'cellular_component', 'GO:0019814', ('103', '111'))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))	('e', 'Gene', '2069', (71, 72))	('e', 'Gene', '2069', (64, 65))	('AF650', 'Var', (4, 9))	('antibody', 'molecular_function', 'GO:0003823', ('184', '192'))	('antibody', 'molecular_function', 'GO:0003823', ('103', '111'))
58688	33839455	The GM6001 metalloprotease family inhibitor (Calbiochem) was dissolved in dimethylsulfoxide and used at 6.5 microM to 13 microM for 24 h. The GI254023X ADAM10 and MMP-9 inhibitor was kindly provided by A. Ludwig and was dissolved in dimethylsulfoxide.	('MMP-9', 'molecular_function', 'GO:0004229', ('163', '168'))	('e', 'Gene', '2069', (22, 23))	('e', 'Gene', '2069', (53, 54))	('e', 'Gene', '2069', (77, 78))	('e', 'Gene', '2069', (236, 237))	('GI254023X', 'Var', (142, 151))	('e', 'Gene', '2069', (140, 141))	('e', 'Gene', '2069', (196, 197))	('e', 'Gene', '2069', (227, 228))	('dimethylsulfoxide', 'Chemical', 'MESH:D004121', (74, 91))	('e', 'Gene', '2069', (249, 250))	('ADAM10', 'Gene', (152, 158))	('e', 'Gene', '2069', (98, 99))	('e', 'Gene', '2069', (12, 13))	('dimethylsulfoxide', 'Chemical', 'MESH:D004121', (233, 250))	('e', 'Gene', '2069', (68, 69))	('MMP-9', 'Gene', (163, 168))	('MMP-9', 'Gene', '4318', (163, 168))	('ADAM10', 'Gene', '102', (152, 158))	('e', 'Gene', '2069', (90, 91))	('GI254023X', 'Chemical', 'MESH:C555398', (142, 151))	('e', 'Gene', '2069', (2, 3))	('pro', 'Chemical', 'MESH:D011392', (18, 21))	('e', 'Gene', '2069', (25, 26))	('pro', 'Chemical', 'MESH:D011392', (190, 193))
58693	33839455	The cells were permeabilized and blocked in 10% fetal bovine serum, 0.1% saponin, and then stained with the 162-46.2, T16, E1 anti-Trop-2, and anti-ADAM10 antibodies.	('e', 'Gene', '2069', (13, 14))	('saponin', 'Chemical', 'MESH:D012503', (73, 80))	('e', 'Gene', '2069', (59, 60))	('e', 'Gene', '2069', (163, 164))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (5, 6))	('e', 'Gene', '2069', (106, 107))	('E', 'Gene', '2069', (123, 124))	('e', 'Gene', '2069', (11, 12))	('e', 'Gene', '2069', (88, 89))	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (26, 27))	('e', 'Gene', '2069', (96, 97))	('e', 'Gene', '2069', (49, 50))	('ADAM10', 'Gene', (148, 154))	('e', 'Gene', '2069', (16, 17))	('e', 'Gene', '2069', (62, 63))	('ADAM10', 'Gene', '102', (148, 154))	('e', 'Gene', '2069', (38, 39))	('T16', 'Var', (118, 121))
58715	33839455	We have previously shown that Trop-1 undergoes activator cleavage at R80-R81.	('R80-R81', 'Var', (69, 76))	('e', 'Gene', '2069', (44, 45))	('e', 'Gene', '2069', (64, 65))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (10, 11))	('e', 'Gene', '2069', (6, 7))	('e', 'Gene', '2069', (59, 60))	('Trop-1', 'Gene', (30, 36))	('Trop-1', 'Gene', '4072', (30, 36))	('e', 'Gene', '2069', (1, 2))
58727	33839455	Mapping using Trop-2 deletion mutants identified this immunodominant epitope in the extracellular region spanning D146-R178.	('e', 'Gene', '2069', (22, 23))	('Trop-2', 'Gene', (14, 20))	('e', 'Gene', '2069', (46, 47))	('e', 'Gene', '2069', (82, 83))	('e', 'Gene', '2069', (75, 76))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (99, 100))	('D146-R178', 'Var', (114, 123))	('e', 'Gene', '2069', (24, 25))	('extracellular region', 'cellular_component', 'GO:0005576', ('84', '104'))	('mutants', 'Var', (30, 37))	('e', 'Gene', '2069', (90, 91))	('e', 'Gene', '2069', (69, 70))	('e', 'Gene', '2069', (84, 85))
58733	33839455	1C, top), which first indicated a potential, endogenous cleavage of Trop-2 between R87 and T88 in the thyroglobulin domain.	('e', 'Gene', '2069', (50, 51))	('R87', 'Var', (83, 86))	('e', 'Gene', '2069', (37, 38))	('Trop-2', 'Gene', (68, 74))	('e', 'Gene', '2069', (79, 80))	('e', 'Gene', '2069', (63, 64))	('e', 'Gene', '2069', (100, 101))	('e', 'Gene', '2069', (58, 59))	('e', 'Gene', '2069', (45, 46))	('e', 'Gene', '2069', (76, 77))	('e', 'Gene', '2069', (80, 81))	('T88', 'Var', (91, 94))	('e', 'Gene', '2069', (29, 30))
58735	33839455	Post-translational cleavage at R87-T88 was expected to result in a large conformational rearrangement, leading to the generation of a two-chain molecule with a ~10-kDa fragment bound to the ~40-kDa membrane-bound segment by a single disulfide bridge between Cys73 and Cys108 (Fig.	('disulfide', 'Chemical', 'MESH:D004220', (233, 242))	('e', 'Gene', '2069', (173, 174))	('e', 'Gene', '2069', (46, 47))	('e', 'Gene', '2069', (205, 206))	('e', 'Gene', '2069', (116, 117))	('Cys108', 'Chemical', '-', (268, 274))	('membrane', 'cellular_component', 'GO:0016020', ('198', '206'))	('e', 'Gene', '2069', (188, 189))	('e', 'Gene', '2069', (251, 252))	('e', 'Gene', '2069', (21, 22))	('e', 'Gene', '2069', (98, 99))	('e', 'Gene', '2069', (43, 44))	('Cys73', 'Var', (258, 263))	('e', 'Gene', '2069', (217, 218))	('e', 'Gene', '2069', (248, 249))	('e', 'Gene', '2069', (241, 242))	('e', 'Gene', '2069', (147, 148))	('e', 'Gene', '2069', (121, 122))	('e', 'Gene', '2069', (231, 232))	('e', 'Gene', '2069', (26, 27))	('e', 'Gene', '2069', (199, 200))	('e', 'Gene', '2069', (89, 90))	('e', 'Gene', '2069', (254, 255))	('R87-T88', 'Var', (31, 38))	('e', 'Gene', '2069', (255, 256))	('e', 'Gene', '2069', (56, 57))	('e', 'Gene', '2069', (104, 105))	('e', 'Gene', '2069', (96, 97))	('e', 'Gene', '2069', (49, 50))	('e', 'Gene', '2069', (214, 215))	('e', 'Gene', '2069', (71, 72))	('e', 'Gene', '2069', (119, 120))	('Cys108', 'Var', (268, 274))	('e', 'Gene', '2069', (151, 152))	('Cys73', 'Chemical', '-', (258, 263))
58742	33839455	Of note, the R87-T88 Trop-2 cleavage site shows exact correspondence to the activator cleavage site of the paralogous Trop-1 molecule (Fig.	('e', 'Gene', '2069', (30, 31))	('e', 'Gene', '2069', (132, 133))	('e', 'Gene', '2069', (74, 75))	('e', 'Gene', '2069', (67, 68))	('e', 'Gene', '2069', (98, 99))	('Trop-1', 'Gene', (118, 124))	('e', 'Gene', '2069', (58, 59))	('e', 'Gene', '2069', (11, 12))	('e', 'Gene', '2069', (35, 36))	('e', 'Gene', '2069', (88, 89))	('e', 'Gene', '2069', (105, 106))	('Trop-1', 'Gene', '4072', (118, 124))	('e', 'Gene', '2069', (48, 49))	('e', 'Gene', '2069', (128, 129))	('R87-T88', 'Var', (13, 20))	('e', 'Gene', '2069', (64, 65))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (6, 7))	('e', 'Gene', '2069', (93, 94))
58763	33839455	Peptide library screening combined with crystal structure analysis of known ADAM10 substrates revealed preference for Pro at P5 (Calsyntenin, proTGFalpha, TNFalpha, cleaved peptides), Arg at P1 (EGF, N-Cadherin, CD23), and Thr at P1' (amyloid beta/A4 protein, HB-EGF) in target site subsets (Fig.	('EGF', 'Gene', (263, 266))	('pro', 'Chemical', 'MESH:D011392', (251, 254))	('e', 'Gene', '2069', (109, 110))	('e', 'Gene', '2069', (20, 21))	('e', 'Gene', '2069', (179, 180))	('HB-EGF', 'Gene', '1839', (260, 266))	('e', 'Gene', '2069', (100, 101))	('TNFalpha', 'Gene', '7124', (155, 163))	('N-Cadherin', 'Gene', (200, 210))	('e', 'Gene', '2069', (107, 108))	('e', 'Gene', '2069', (275, 276))	('N-Cadherin', 'Gene', '1000', (200, 210))	('e', 'Gene', '2069', (170, 171))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('EGF', 'Gene', '1950', (195, 198))	('e', 'Gene', '2069', (19, 20))	('Arg at P1', 'Var', (184, 193))	('e', 'Gene', '2069', (91, 92))	('e', 'Gene', '2069', (281, 282))	('Arg', 'Chemical', 'MESH:D001120', (184, 187))	('e', 'Gene', '2069', (97, 98))	('e', 'Gene', '2069', (1, 2))	('HB-EGF', 'Gene', (260, 266))	('e', 'Gene', '2069', (287, 288))	('e', 'Gene', '2069', (112, 113))	('e', 'Gene', '2069', (105, 106))	('e', 'Gene', '2069', (136, 137))	('e', 'Gene', '2069', (167, 168))	('TNFalpha', 'Gene', (155, 163))	('EGF', 'molecular_function', 'GO:0005154', ('263', '266'))	('EGF', 'Gene', '1950', (263, 266))	('EGF', 'Gene', (195, 198))	('e', 'Gene', '2069', (255, 256))	('e', 'Gene', '2069', (56, 57))	('Cadherin', 'molecular_function', 'GO:0008014', ('202', '210'))	('ADAM10', 'Gene', (76, 82))	('CD23', 'Gene', (212, 216))	('e', 'Gene', '2069', (32, 33))	('e', 'Gene', '2069', (95, 96))	('pro', 'Chemical', 'MESH:D011392', (142, 145))	('e', 'Gene', '2069', (174, 175))	('ADAM10', 'Gene', '102', (76, 82))	('e', 'Gene', '2069', (6, 7))	('CD23', 'Gene', '2208', (212, 216))	("P1' (amyloid beta/A4 protein", 'Gene', '351', (230, 258))	('e', 'Gene', '2069', (244, 245))	('Thr', 'Chemical', 'MESH:D013912', (223, 226))	('e', 'Gene', '2069', (206, 207))	('EGF', 'molecular_function', 'GO:0005154', ('195', '198'))	('Pro', 'Chemical', 'MESH:D011392', (118, 121))
58780	33839455	We further showed that expression and membrane localization of Trop-2 were not affected by ADAM10 inhibition (Fig.	('Trop-2', 'Gene', (63, 69))	('inhibition', 'Var', (98, 108))	('e', 'Gene', '2069', (8, 9))	('e', 'Gene', '2069', (39, 40))	('e', 'Gene', '2069', (23, 24))	('e', 'Gene', '2069', (71, 72))	('e', 'Gene', '2069', (82, 83))	('e', 'Gene', '2069', (85, 86))	('ADAM10', 'Gene', (91, 97))	('membrane', 'cellular_component', 'GO:0016020', ('38', '46'))	('e', 'Gene', '2069', (27, 28))	('localization', 'biological_process', 'GO:0051179', ('47', '59'))	('e', 'Gene', '2069', (15, 16))	('e', 'Gene', '2069', (45, 46))	('ADAM10', 'Gene', '102', (91, 97))	('e', 'Gene', '2069', (73, 74))	('e', 'Gene', '2069', (1, 2))
58783	33839455	Treatment of Trop-2 expressing BxPC3 pancreatic cancer cells or MTE4-14/Trop-2 transfectants with the ADAM10 inhibitor GI254023X led to a strong reduction in the 40-kD cleavage band, while parallel treatment with nonspecific protease inhibitors had no such effect (Fig.	('e', 'Gene', '2069', (85, 86))	('e', 'Gene', '2069', (20, 21))	('e', 'Gene', '2069', (260, 261))	('e', 'Gene', '2069', (195, 196))	('e', 'Gene', '2069', (52, 53))	('e', 'Gene', '2069', (100, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('e', 'Gene', '2069', (146, 147))	('e', 'Gene', '2069', (187, 188))	('e', 'Gene', '2069', (170, 171))	('GI254023X', 'Var', (119, 128))	('e', 'Gene', '2069', (218, 219))	('e', 'Gene', '2069', (130, 131))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('BxPC3', 'CellLine', 'CVCL:0186', (31, 36))	('e', 'Gene', '2069', (42, 43))	('e', 'Gene', '2069', (257, 258))	('pancreatic cancer', 'Disease', (37, 54))	('pro', 'Chemical', 'MESH:D011392', (225, 228))	('e', 'Gene', '2069', (200, 201))	('E', 'Gene', '2069', (66, 67))	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (232, 233))	('e', 'Gene', '2069', (175, 176))	('e', 'Gene', '2069', (24, 25))	('ADAM10', 'Gene', (102, 108))	('e', 'Gene', '2069', (56, 57))	('GI254023X', 'Chemical', 'MESH:C555398', (119, 128))	('e', 'Gene', '2069', (229, 230))	('ADAM10', 'Gene', '102', (102, 108))	('e', 'Gene', '2069', (160, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('e', 'Gene', '2069', (6, 7))	('e', 'Gene', '2069', (204, 205))
58786	33839455	Consistent with the Trop-2 cleavage reduction seen upon chemical inhibition of ADAM10 activity, RNAi-mediated knock-down of ADAM10 expression resulted in a dramatic reduction of the Trop-2 cleavage (Fig.	('e', 'Gene', '2069', (37, 38))	('e', 'Gene', '2069', (196, 197))	('knock-down', 'Var', (110, 120))	('e', 'Gene', '2069', (107, 108))	('e', 'Gene', '2069', (131, 132))	('e', 'Gene', '2069', (148, 149))	('e', 'Gene', '2069', (34, 35))	('e', 'Gene', '2069', (18, 19))	('e', 'Gene', '2069', (58, 59))	('ADAM10', 'Gene', (79, 85))	('ADAM10', 'Gene', '102', (79, 85))	('e', 'Gene', '2069', (48, 49))	('RNAi', 'biological_process', 'GO:0016246', ('96', '100'))	('e', 'Gene', '2069', (135, 136))	('e', 'Gene', '2069', (166, 167))	('ADAM10', 'Gene', (124, 130))	('e', 'Gene', '2069', (191, 192))	('e', 'Gene', '2069', (102, 103))	('e', 'Gene', '2069', (47, 48))	('e', 'Gene', '2069', (143, 144))	('e', 'Gene', '2069', (7, 8))	('ADAM10', 'Gene', '102', (124, 130))	('e', 'Gene', '2069', (180, 181))	('e', 'Gene', '2069', (29, 30))
58787	33839455	Taken together, our findings indicate that ADAM10 is an effector protease of Trop-2 cleavage at R87-T88.	('ADAM10', 'Gene', (43, 49))	('e', 'Gene', '2069', (36, 37))	('e', 'Gene', '2069', (12, 13))	('pro', 'Chemical', 'MESH:D011392', (65, 68))	('e', 'Gene', '2069', (91, 92))	('R87-T88', 'Var', (96, 103))	('e', 'Gene', '2069', (3, 4))	('e', 'Gene', '2069', (59, 60))	('e', 'Gene', '2069', (72, 73))	('e', 'Gene', '2069', (86, 87))	('e', 'Gene', '2069', (56, 57))	('e', 'Gene', '2069', (69, 70))	('ADAM10', 'Gene', '102', (43, 49))	('e', 'Gene', '2069', (9, 10))
58797	33839455	The Trop-2 cleavage site was mutagenized by switching the R87-T88 residues to alanine.	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (67, 68))	('e', 'Gene', '2069', (23, 24))	('R87-T88', 'Var', (58, 65))	('e', 'Gene', '2069', (34, 35))	('e', 'Gene', '2069', (13, 14))	('e', 'Gene', '2069', (18, 19))	('e', 'Gene', '2069', (38, 39))	('e', 'Gene', '2069', (72, 73))	('e', 'Gene', '2069', (56, 57))	('Trop-2', 'Gene', (4, 10))	('alanine', 'Chemical', 'MESH:D000409', (78, 85))	('e', 'Gene', '2069', (84, 85))
58798	33839455	Flow cytometry analysis on live cells showed that A87-A88 Trop-2 was efficiently transported to the cell membrane, where it retained wt Trop-2-like expression pattern (Fig.	('e', 'Gene', '2069', (30, 31))	('cell membrane', 'cellular_component', 'GO:0005886', ('100', '113'))	('e', 'Gene', '2069', (146, 147))	('e', 'Gene', '2069', (163, 164))	('e', 'Gene', '2069', (69, 70))	('Trop-2', 'Gene', (58, 64))	('e', 'Gene', '2069', (148, 149))	('e', 'Gene', '2069', (98, 99))	('e', 'Gene', '2069', (130, 131))	('e', 'Gene', '2069', (75, 76))	('e', 'Gene', '2069', (106, 107))	('e', 'Gene', '2069', (10, 11))	('e', 'Gene', '2069', (42, 43))	('e', 'Gene', '2069', (90, 91))	('e', 'Gene', '2069', (33, 34))	('e', 'Gene', '2069', (112, 113))	('e', 'Gene', '2069', (152, 153))	('A87-A88', 'Var', (50, 57))	('e', 'Gene', '2069', (119, 120))	('e', 'Gene', '2069', (117, 118))	('e', 'Gene', '2069', (125, 126))	('e', 'Gene', '2069', (101, 102))
58799	33839455	Under high cell density and prolonged culture conditions, the A87-A88 Trop-2 showed considerably reduced cleavage compared with wt Trop-2 (Fig.	('e', 'Gene', '2069', (98, 99))	('e', 'Gene', '2069', (12, 13))	('e', 'Gene', '2069', (112, 113))	('e', 'Gene', '2069', (102, 103))	('e', 'Gene', '2069', (44, 45))	('e', 'Gene', '2069', (60, 61))	('e', 'Gene', '2069', (120, 121))	('e', 'Gene', '2069', (81, 82))	('pro', 'Chemical', 'MESH:D011392', (28, 31))	('e', 'Gene', '2069', (3, 4))	('e', 'Gene', '2069', (17, 18))	('A87-A88', 'Var', (62, 69))	('e', 'Gene', '2069', (90, 91))	('e', 'Gene', '2069', (107, 108))	('e', 'Gene', '2069', (35, 36))	('Trop-2', 'Gene', (70, 76))
58801	33839455	In colon cancer KM12SM and murine MTE4-14 transfectants, the cleavage-impaired A87-A88 Trop-2 mutant did not stimulate cell growth over baseline, at variance with the cell growth enhancement induced by wt Trop-2 (Fig.	('e', 'Gene', '2069', (179, 180))	('e', 'Gene', '2069', (13, 14))	('e', 'Gene', '2069', (133, 134))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('e', 'Gene', '2069', (59, 60))	('e', 'Gene', '2069', (196, 197))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('e', 'Gene', '2069', (76, 77))	('e', 'Gene', '2069', (139, 140))	('A87-A88', 'Var', (79, 86))	('e', 'Gene', '2069', (187, 188))	('cell growth', 'biological_process', 'GO:0016049', ('167', '178'))	('e', 'Gene', '2069', (156, 157))	('E', 'Gene', '2069', (36, 37))	('e', 'Gene', '2069', (68, 69))	('e', 'Gene', '2069', (185, 186))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('e', 'Gene', '2069', (120, 121))	('mutant', 'Var', (94, 100))	('e', 'Gene', '2069', (48, 49))	('e', 'Gene', '2069', (168, 169))	('e', 'Gene', '2069', (63, 64))	('murine', 'Species', '10090', (27, 33))	('colon cancer', 'Disease', (3, 15))	('Trop-2', 'Gene', (87, 93))	('e', 'Gene', '2069', (32, 33))	('e', 'Gene', '2069', (165, 166))	('e', 'Gene', '2069', (143, 144))	('not', 'NegReg', (105, 108))	('cell growth', 'biological_process', 'GO:0016049', ('119', '130'))	('e', 'Gene', '2069', (117, 118))	('KM12SM', 'Chemical', '-', (16, 22))
58807	33839455	The ADAM10 inhibitor GI254023X can also inhibit MMP9.	('MMP9', 'molecular_function', 'GO:0004229', ('48', '52'))	('e', 'Gene', '2069', (2, 3))	('GI254023X', 'Var', (21, 30))	('inhibit', 'NegReg', (40, 47))	('MMP9', 'Gene', '4318', (48, 52))	('MMP9', 'Gene', (48, 52))	('ADAM10', 'Gene', '102', (4, 10))	('ADAM10', 'Gene', (4, 10))	('GI254023X', 'Chemical', 'MESH:C555398', (21, 30))
58814	33839455	Minimal, if any, cleavage at R87-T88 was detected in squamous cell carcinomas (Fig.	('squamous cell carcinomas', 'Disease', (53, 77))	('e', 'Gene', '2069', (19, 20))	('R87-T88', 'Var', (29, 36))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (53, 77))	('e', 'Gene', '2069', (44, 45))	('e', 'Gene', '2069', (47, 48))	('e', 'Gene', '2069', (24, 25))	('e', 'Gene', '2069', (42, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('e', 'Gene', '2069', (63, 64))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (53, 77))
58823	33839455	Protein modifications that operated as central nodes of cleaved/activated Trop-2 were shown to encompass Src, RSK1/2, glycogen synthase, MEK1, CDK9, p21, and BAD as main downstream effectors (Table S4D).	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('e', 'Gene', '2069', (61, 62))	('e', 'Gene', '2069', (4, 5))	('Src', 'Gene', '6714', (105, 108))	('e', 'Gene', '2069', (196, 197))	('e', 'Gene', '2069', (124, 125))	('RSK1/2', 'Gene', '6195;6197', (110, 116))	('MEK1', 'Gene', '5604', (137, 141))	('e', 'Gene', '2069', (82, 83))	('p21', 'Gene', (149, 152))	('modifications', 'Var', (8, 21))	('p21', 'Gene', '644914', (149, 152))	('e', 'Gene', '2069', (58, 59))	('e', 'Gene', '2069', (184, 185))	('e', 'Gene', '2069', (177, 178))	('e', 'Gene', '2069', (50, 51))	('e', 'Gene', '2069', (33, 34))	('CDK9', 'Gene', (143, 147))	('RSK1/2', 'Gene', (110, 116))	('Src', 'Gene', (105, 108))	('e', 'Gene', '2069', (71, 72))	('e', 'Gene', '2069', (181, 182))	('MEK1', 'Gene', (137, 141))	('e', 'Gene', '2069', (134, 135))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (95, 96))	('MEK1', 'molecular_function', 'GO:0004708', ('137', '141'))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('CDK9', 'Gene', '1025', (143, 147))	('e', 'Gene', '2069', (84, 85))	('e', 'Gene', '2069', (29, 30))
58826	33839455	Tumorigenic L fibrosarcoma and transformed HEK293 cells were transfected with the A87-A88 Trop-2 mutant and injected subcutaneously into immunosuppressed mice.	('e', 'Gene', '2069', (59, 60))	('Trop-2', 'Gene', (90, 96))	('e', 'Gene', '2069', (67, 68))	('e', 'Gene', '2069', (148, 149))	('mutant', 'Var', (97, 103))	('e', 'Gene', '2069', (51, 52))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (14, 26))	('e', 'Gene', '2069', (114, 115))	('L fibrosarcoma', 'Disease', 'MESH:D005354', (12, 26))	('mice', 'Species', '10090', (154, 158))	('e', 'Gene', '2069', (57, 58))	('e', 'Gene', '2069', (111, 112))	('L fibrosarcoma', 'Disease', (12, 26))	('e', 'Gene', '2069', (80, 81))	('HEK293', 'CellLine', 'CVCL:0045', (43, 49))	('e', 'Gene', '2069', (40, 41))	('e', 'Gene', '2069', (157, 158))	('e', 'Gene', '2069', (151, 152))	('e', 'Gene', '2069', (7, 8))	('e', 'Gene', '2069', (70, 71))	('e', 'Gene', '2069', (125, 126))
58828	33839455	Comparison of the tumor volumes between these groups indicated that while transfection of wt Trop-2 resulted in increased growth of both L fibrosarcoma and transformed HEK293 cells as tumors in vivo, the R87A-T88A mutagenesis led to complete loss of this growth-inducing activity (Fig.	('L fibrosarcoma', 'Disease', (137, 151))	('e', 'Gene', '2069', (37, 38))	('e', 'Gene', '2069', (116, 117))	('e', 'Gene', '2069', (219, 220))	('HEK293', 'CellLine', 'CVCL:0045', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('e', 'Gene', '2069', (227, 228))	('e', 'Gene', '2069', (36, 37))	('e', 'Gene', '2069', (60, 61))	('tumor', 'Disease', (18, 23))	('e', 'Gene', '2069', (44, 45))	('mutagenesis', 'biological_process', 'GO:0006280', ('214', '225'))	('growth', 'MPA', (122, 128))	('e', 'Gene', '2069', (106, 107))	('T88A', 'Mutation', 'c.88T>A', (209, 213))	('e', 'Gene', '2069', (42, 43))	('tumor', 'Disease', (184, 189))	('loss', 'NegReg', (242, 246))	('e', 'Gene', '2069', (240, 241))	('e', 'Gene', '2069', (202, 203))	('e', 'Gene', '2069', (176, 177))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('e', 'Gene', '2069', (33, 34))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('R87A-T88A', 'Var', (204, 213))	('e', 'Gene', '2069', (72, 73))	('e', 'Gene', '2069', (80, 81))	('e', 'Gene', '2069', (221, 222))	('e', 'Gene', '2069', (238, 239))	('e', 'Gene', '2069', (16, 17))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('R87A', 'Mutation', 'p.R87A', (204, 208))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('e', 'Gene', '2069', (165, 166))	('e', 'Gene', '2069', (119, 120))	('tumors', 'Disease', (184, 190))	('e', 'Gene', '2069', (101, 102))	('L fibrosarcoma', 'Disease', 'MESH:D005354', (137, 151))	('growth-inducing activity', 'MPA', (255, 279))	('e', 'Gene', '2069', (29, 30))
58835	33839455	The individual metastasis volume distribution curves showed that the A87-A88 Trop-2 mutant invariably reduced, or outright abolished, metastasis growth (Fig.	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (16, 17))	('e', 'Gene', '2069', (67, 68))	('e', 'Gene', '2069', (50, 51))	('e', 'Gene', '2069', (57, 58))	('e', 'Gene', '2069', (130, 131))	('e', 'Gene', '2069', (135, 136))	('Trop-2', 'Gene', (77, 83))	('e', 'Gene', '2069', (103, 104))	('e', 'Gene', '2069', (31, 32))	('A87-A88', 'Var', (69, 76))	('e', 'Gene', '2069', (107, 108))
58836	33839455	Boxplot distribution analysis showed that the dataset of A87-A88 mutant Trop-2 had the lowest median, together with the lowest maximum and minimum values of metastasis volume.	('e', 'Gene', '2069', (173, 174))	('e', 'Gene', '2069', (85, 86))	('e', 'Gene', '2069', (105, 106))	('e', 'Gene', '2069', (44, 45))	('e', 'Gene', '2069', (95, 96))	('e', 'Gene', '2069', (34, 35))	('e', 'Gene', '2069', (123, 124))	('e', 'Gene', '2069', (158, 159))	('e', 'Gene', '2069', (108, 109))	('A87-A88', 'Var', (57, 64))	('e', 'Gene', '2069', (151, 152))	('e', 'Gene', '2069', (51, 52))	('e', 'Gene', '2069', (90, 91))	('Trop-2', 'Gene', (72, 78))	('e', 'Gene', '2069', (118, 119))
58837	33839455	The dimensions and volume distributions of mutant liver metastases versus vector-alone control cells and wt Trop-2 transfectants were assessed.	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (53, 54))	('e', 'Gene', '2069', (57, 58))	('e', 'Gene', '2069', (85, 86))	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('e', 'Gene', '2069', (130, 131))	('e', 'Gene', '2069', (137, 138))	('e', 'Gene', '2069', (64, 65))	('e', 'Gene', '2069', (75, 76))	('e', 'Gene', '2069', (140, 141))	('e', 'Gene', '2069', (68, 69))	('e', 'Gene', '2069', (24, 25))	('mutant', 'Var', (43, 49))	('e', 'Gene', '2069', (7, 8))	('e', 'Gene', '2069', (96, 97))	('e', 'Gene', '2069', (121, 122))	('metastases', 'Disease', (56, 66))	('e', 'Gene', '2069', (132, 133))
58838	33839455	These showed that the mutant transfectant metastases volumes were significantly reduced versus wt Trop-2 (nonparametric Mann-Whitney P = 0.0436), due to this loss of the required metastasis activation pathway.	('metastases', 'Disease', 'MESH:D009362', (42, 52))	('e', 'Gene', '2069', (85, 86))	('e', 'Gene', '2069', (20, 21))	('e', 'Gene', '2069', (171, 172))	('e', 'Gene', '2069', (4, 5))	('metastases', 'Disease', (42, 52))	('e', 'Gene', '2069', (148, 149))	('e', 'Gene', '2069', (43, 44))	('e', 'Gene', '2069', (130, 131))	('e', 'Gene', '2069', (10, 11))	('e', 'Gene', '2069', (58, 59))	('e', 'Gene', '2069', (176, 177))	('e', 'Gene', '2069', (35, 36))	('e', 'Gene', '2069', (114, 115))	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (50, 51))	('e', 'Gene', '2069', (81, 82))	('e', 'Gene', '2069', (89, 90))	('e', 'Gene', '2069', (168, 169))	('mutant', 'Var', (22, 28))	('e', 'Gene', '2069', (64, 65))	('e', 'Gene', '2069', (62, 63))	('e', 'Gene', '2069', (180, 181))	('loss', 'NegReg', (158, 162))
58856	33839455	We previously reported that proteolytic cleavage occurs between R80 and R81 in the first loop of the Trop-1 thyroglobulin domain, and that this activates the cell-growth stimulatory properties of Trop-1.	('e', 'Gene', '2069', (61, 62))	('e', 'Gene', '2069', (20, 21))	('R81', 'Var', (72, 75))	('cell-growth', 'biological_process', 'GO:0016049', ('158', '169'))	('e', 'Gene', '2069', (186, 187))	('e', 'Gene', '2069', (156, 157))	('e', 'Gene', '2069', (60, 61))	('e', 'Gene', '2069', (5, 6))	('pro', 'Chemical', 'MESH:D011392', (28, 31))	('e', 'Gene', '2069', (99, 100))	('e', 'Gene', '2069', (42, 43))	('Trop-1', 'Gene', (196, 202))	('e', 'Gene', '2069', (1, 2))	('e', 'Gene', '2069', (57, 58))	('Trop-1', 'Gene', (101, 107))	('R80', 'Var', (64, 67))	('e', 'Gene', '2069', (81, 82))	('e', 'Gene', '2069', (159, 160))	('e', 'Gene', '2069', (190, 191))	('e', 'Gene', '2069', (15, 16))	('Trop-1', 'Gene', '4072', (196, 202))	('pro', 'Chemical', 'MESH:D011392', (182, 185))	('e', 'Gene', '2069', (32, 33))	('e', 'Gene', '2069', (47, 48))	('e', 'Gene', '2069', (151, 152))	('Trop-1', 'Gene', '4072', (101, 107))
58858	33839455	Here we have shown that this is indeed the case, as Edman degradation sequencing and peptide mass fingerprinting of Trop-2 purified to homogeneity revealed that the cleavage of the molecule occurs in the thyroglobulin domain, between R87 and T88.	('e', 'Gene', '2069', (46, 47))	('e', 'Gene', '2069', (140, 141))	('e', 'Gene', '2069', (188, 189))	('e', 'Gene', '2069', (179, 180))	('e', 'Gene', '2069', (59, 60))	('e', 'Gene', '2069', (227, 228))	('e', 'Gene', '2069', (172, 173))	('degradation', 'biological_process', 'GO:0009056', ('58', '69'))	('e', 'Gene', '2069', (163, 164))	('E', 'Gene', '2069', (52, 53))	('e', 'Gene', '2069', (74, 75))	('e', 'Gene', '2069', (36, 37))	('e', 'Gene', '2069', (148, 149))	('e', 'Gene', '2069', (91, 92))	('e', 'Gene', '2069', (3, 4))	('e', 'Gene', '2069', (202, 203))	('e', 'Gene', '2069', (11, 12))	('e', 'Gene', '2069', (35, 36))	('e', 'Gene', '2069', (231, 232))	('e', 'Gene', '2069', (184, 185))	('e', 'Gene', '2069', (1, 2))	('e', 'Gene', '2069', (153, 154))	('e', 'Gene', '2069', (167, 168))	('e', 'Gene', '2069', (129, 130))	('e', 'Gene', '2069', (230, 231))	('e', 'Gene', '2069', (41, 42))	('e', 'Gene', '2069', (142, 143))	('e', 'Gene', '2069', (71, 72))	('e', 'Gene', '2069', (102, 103))	('e', 'Gene', '2069', (150, 151))	('Trop-2', 'Gene', (116, 122))	('e', 'Gene', '2069', (6, 7))	('e', 'Gene', '2069', (86, 87))	('R87', 'Var', (234, 237))
58860	33839455	Cleavage at R87-T88 implies a large conformational rearrangement and potential swiveling of a 10 kDa subunit over the Trop-2 backbone, suggesting a large impact on the interactions of Trop-2 with binding partners.	('binding', 'Interaction', (196, 203))	('binding', 'molecular_function', 'GO:0005488', ('196', '203'))	('e', 'Gene', '2069', (116, 117))	('e', 'Gene', '2069', (61, 62))	('e', 'Gene', '2069', (171, 172))	('e', 'Gene', '2069', (83, 84))	('impact', 'Reg', (154, 160))	('e', 'Gene', '2069', (59, 60))	('e', 'Gene', '2069', (52, 53))	('e', 'Gene', '2069', (139, 140))	('e', 'Gene', '2069', (132, 133))	('e', 'Gene', '2069', (34, 35))	('e', 'Gene', '2069', (209, 210))	('e', 'Gene', '2069', (2, 3))	('e', 'Gene', '2069', (111, 112))	('e', 'Gene', '2069', (72, 73))	('e', 'Gene', '2069', (25, 26))	('e', 'Gene', '2069', (166, 167))	('e', 'Gene', '2069', (152, 153))	('e', 'Gene', '2069', (7, 8))	('R87-T88', 'Var', (12, 19))
58863	33839455	Peptide library screening, combined with crystal structure analysis of known ADAM10 substrates indicated preference for a consensus target site that includes Arg at P1 and Thr at P1', which are both present in the Trop-2 candidate cleavage site.	('e', 'Gene', '2069', (92, 93))	('e', 'Gene', '2069', (109, 110))	('e', 'Gene', '2069', (20, 21))	('e', 'Gene', '2069', (203, 204))	('e', 'Gene', '2069', (212, 213))	('Thr', 'Chemical', 'MESH:D013912', (172, 175))	('e', 'Gene', '2069', (107, 108))	('e', 'Gene', '2069', (155, 156))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (243, 244))	('e', 'Gene', '2069', (233, 234))	('Arg', 'Chemical', 'MESH:D001120', (158, 161))	('e', 'Gene', '2069', (114, 115))	('e', 'Gene', '2069', (201, 202))	('e', 'Gene', '2069', (1, 2))	('e', 'Gene', '2069', (33, 34))	('e', 'Gene', '2069', (57, 58))	('e', 'Gene', '2069', (136, 137))	('ADAM10', 'Gene', (77, 83))	('e', 'Gene', '2069', (192, 193))	('Arg at P1', 'Var', (158, 167))	('e', 'Gene', '2069', (111, 112))	('e', 'Gene', '2069', (142, 143))	('ADAM10', 'Gene', '102', (77, 83))	('e', 'Gene', '2069', (229, 230))	('e', 'Gene', '2069', (238, 239))	('e', 'Gene', '2069', (102, 103))	("Thr at P1'", 'Var', (172, 182))	('e', 'Gene', '2069', (126, 127))	('e', 'Gene', '2069', (6, 7))
58866	33839455	Inhibition of ADAM10 expression or activity in Trop-2-expressing cells was then shown to markedly reduce Trop-2 processing.	('pro', 'Chemical', 'MESH:D011392', (112, 115))	('e', 'Gene', '2069', (93, 94))	('activity', 'MPA', (35, 43))	('e', 'Gene', '2069', (54, 55))	('e', 'Gene', '2069', (116, 117))	('e', 'Gene', '2069', (77, 78))	('e', 'Gene', '2069', (99, 100))	('e', 'Gene', '2069', (21, 22))	('e', 'Gene', '2069', (66, 67))	('Inhibition', 'Var', (0, 10))	('e', 'Gene', '2069', (103, 104))	('e', 'Gene', '2069', (25, 26))	('ADAM10', 'Gene', (14, 20))	('ADAM10', 'Gene', '102', (14, 20))	('e', 'Gene', '2069', (58, 59))
58868	33839455	Recently, matriptase was reported to recognize the R87-T88 Trop-2 cleavage site, which raises the possibility of a finely regulated, multipronged post-translational processing at this position.	('pro', 'Chemical', 'MESH:D011392', (165, 168))	('R87-T88', 'Var', (51, 58))	('e', 'Gene', '2069', (45, 46))	('Trop-2', 'Gene', (59, 65))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (91, 92))	('e', 'Gene', '2069', (123, 124))	('e', 'Gene', '2069', (68, 69))	('pro', 'Chemical', 'MESH:D011392', (138, 141))	('e', 'Gene', '2069', (3, 4))	('e', 'Gene', '2069', (1, 2))	('e', 'Gene', '2069', (169, 170))	('e', 'Gene', '2069', (129, 130))	('e', 'Gene', '2069', (26, 27))	('e', 'Gene', '2069', (96, 97))	('e', 'Gene', '2069', (49, 50))	('e', 'Gene', '2069', (73, 74))	('e', 'Gene', '2069', (78, 79))	('e', 'Gene', '2069', (143, 144))	('e', 'Gene', '2069', (38, 39))	('e', 'Gene', '2069', (31, 32))	('e', 'Gene', '2069', (118, 119))
58871	33839455	Furthermore, this R87-T88-cleaved Trop-2 remains linked to the cytoplasmic tail, which demonstrates that the Trop-2 cleavage at R87-T88 precedes TACE cleavage and RIP in the Trop-2 activation cascade.	('e', 'Gene', '2069', (53, 54))	('e', 'Gene', '2069', (61, 62))	('TACE', 'Gene', '6868', (145, 149))	('e', 'Gene', '2069', (140, 141))	('e', 'Gene', '2069', (28, 29))	('e', 'Gene', '2069', (138, 139))	('e', 'Gene', '2069', (172, 173))	('e', 'Gene', '2069', (107, 108))	('e', 'Gene', '2069', (5, 6))	('e', 'Gene', '2069', (123, 124))	('e', 'Gene', '2069', (10, 11))	('e', 'Gene', '2069', (42, 43))	('e', 'Gene', '2069', (97, 98))	('R87-T88', 'Var', (128, 135))	('e', 'Gene', '2069', (88, 89))	('e', 'Gene', '2069', (142, 143))	('TACE', 'Gene', (145, 149))	('e', 'Gene', '2069', (198, 199))	('e', 'Gene', '2069', (152, 153))	('e', 'Gene', '2069', (157, 158))	('Trop-2', 'Gene', (109, 115))	('e', 'Gene', '2069', (31, 32))	('e', 'Gene', '2069', (118, 119))
58873	33839455	Striking correspondence was observed also in vivo, where the A87-A88 Trop-2 mutant failed to stimulate tumor growth in both murine xenografts of L and HEK-293 cells.	('Trop-2', 'Gene', (69, 75))	('e', 'Gene', '2069', (22, 23))	('e', 'Gene', '2069', (53, 54))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('e', 'Gene', '2069', (13, 14))	('e', 'Gene', '2069', (59, 60))	('HEK-293', 'CellLine', 'CVCL:0045', (151, 158))	('e', 'Gene', '2069', (132, 133))	('e', 'Gene', '2069', (19, 20))	('e', 'Gene', '2069', (34, 35))	('murine', 'Species', '10090', (124, 130))	('tumor', 'Disease', (103, 108))	('e', 'Gene', '2069', (129, 130))	('A87-A88', 'Var', (61, 68))	('e', 'Gene', '2069', (87, 88))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('e', 'Gene', '2069', (160, 161))	('e', 'Gene', '2069', (31, 32))	('e', 'Gene', '2069', (55, 56))	('e', 'Gene', '2069', (101, 102))
58885	33839455	Inhibition of Trop-2 proteolytic processing may correspondingly open new perspectives for such specific therapies to control tumor growth and metastatic dissemination through targeting the Trop-2 activation steps in cancer cells.	('pro', 'Chemical', 'MESH:D011392', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('e', 'Gene', '2069', (37, 38))	('e', 'Gene', '2069', (179, 180))	('e', 'Gene', '2069', (83, 84))	('e', 'Gene', '2069', (52, 53))	('cancer', 'Disease', (216, 222))	('e', 'Gene', '2069', (220, 221))	('e', 'Gene', '2069', (187, 188))	('e', 'Gene', '2069', (74, 75))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('e', 'Gene', '2069', (106, 107))	('e', 'Gene', '2069', (209, 210))	('e', 'Gene', '2069', (66, 67))	('e', 'Gene', '2069', (97, 98))	('Inhibition', 'Var', (0, 10))	('e', 'Gene', '2069', (111, 112))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('e', 'Gene', '2069', (25, 26))	('e', 'Gene', '2069', (224, 225))	('pro', 'Chemical', 'MESH:D011392', (33, 36))	('e', 'Gene', '2069', (78, 79))	('e', 'Gene', '2069', (157, 158))	('tumor', 'Disease', (125, 130))	('e', 'Gene', '2069', (143, 144))	('e', 'Gene', '2069', (70, 71))	('Trop-2', 'Gene', (189, 195))
58935	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))
58945	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', '6627', (141, 146))	('S115', 'Var', (115, 119))	('PhosphoNET', 'Chemical', '-', (22, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('SNRPA', 'Gene', (141, 146))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
58969	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))
58970	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))
58974	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))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
58976	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('phosphorylation level', 'MPA', (13, 34))	('SNRPA', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('S115', 'Var', (42, 46))	('tumor', 'Disease', (156, 161))	('higher', 'PosReg', (173, 179))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
58990	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))
58995	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))
58999	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))
59000	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))
59012	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))
59013	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))	('pathogenesis', 'biological_process', 'GO:0009405', ('201', '213'))	('reduces', 'NegReg', (125, 132))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('involvement', 'Reg', (155, 166))	('genetic mutations', 'Var', (176, 193))
59025	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('SNRPA', 'Gene', (33, 38))
59030	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))
59031	33552128	), acetylation sites (e.g., K122, K80, K96, etc.)	('K122', 'Var', (28, 32))	('K80', 'Gene', '144501', (34, 37))	('K80', 'Gene', (34, 37))	('K96', 'Var', (39, 42))
59039	33542645	The rs1456315 T allele increased the risk of lung cancer [OR=1.95, 95% CI (1.58-2.43), P=0.003] compared to the rs1456315 C allele, and rs1456315 significantly increased the risk of lung cancer in the dominant model [OR=1.86, 95% CI (1.16-3.00), P=0.002].	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('rs1456315', 'Var', (136, 145))	('lung cancer', 'Disease', (182, 193))	('rs1456315 T', 'Var', (4, 15))	('increased', 'PosReg', (160, 169))	('rs1456315', 'Mutation', 'rs1456315', (136, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('lung cancer', 'Disease', (45, 56))	('rs1456315', 'Mutation', 'rs1456315', (112, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rs1456315', 'Mutation', 'rs1456315', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))
59040	33542645	The rs6983267 G allele, compared with the T allele, increased the risk of lung cancer [OR=1.29, 95% CI (1.07-1.57), P=0.007], and rs6983267 was identified as a risk factor for lung cancer [OR=1.28, 95% CI (1.06-1.55), P=0.003] in the additive model.	('lung cancer', 'Disease', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('rs6983267', 'Mutation', 'rs6983267', (130, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rs6983267', 'Mutation', 'rs6983267', (4, 13))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('rs6983267', 'Var', (130, 139))	('rs6983267 G', 'Var', (4, 15))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
59041	33542645	Both rs1456315 and rs6983267 demonstrated significance after adjusting for the smoking status, drinking status and age.	('rs1456315', 'Mutation', 'rs1456315', (5, 14))	('rs1456315', 'Var', (5, 14))	('rs6983267', 'Mutation', 'rs6983267', (19, 28))	('rs6983267', 'Var', (19, 28))
59042	33542645	The structure prediction found rs6983267 and rs1456315 influence the secondary structure of its lncRNA.	('secondary structure of its lncRNA', 'MPA', (69, 102))	('rs6983267', 'Var', (31, 40))	('rs6983267', 'Mutation', 'rs6983267', (31, 40))	('rs1456315', 'Var', (45, 54))	('rs1456315', 'Mutation', 'rs1456315', (45, 54))	('influence', 'Reg', (55, 64))
59043	33542645	The results from lncRNASNP2 indicated that rs6983267 and rs1456315 change gain/loss target of miRNAs.	('rs1456315', 'Var', (57, 66))	('rs1456315', 'Mutation', 'rs1456315', (57, 66))	('rs6983267', 'Var', (43, 52))	('gain/loss', 'MPA', (74, 83))	('rs6983267', 'Mutation', 'rs6983267', (43, 52))
59044	33542645	PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region are significantly associated with lung cancer in the Han population of southern China and alter the potential biological function in bioinformatic analysis, and the results further extended generalism of the susceptibility of cancer-associated lncRNA-SNPs to lung cancer and underlying mechanism involved in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (311, 322))	('lung cancer', 'Disease', (86, 97))	('rs1456315', 'Var', (7, 16))	('cancer', 'Disease', (278, 284))	('lung cancer', 'Disease', 'MESH:D008175', (360, 371))	('cancer', 'Disease', (365, 371))	('lung cancer', 'Phenotype', 'HP:0100526', (311, 322))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('associated', 'Reg', (70, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (360, 371))	('rs1456315', 'Mutation', 'rs1456315', (7, 16))	('cancer', 'Disease', (316, 322))	('PRNCR1', 'Gene', '101867536', (0, 6))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('rs6983267', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('CCAT2', 'Gene', '101805488', (21, 26))	('lung cancer', 'Disease', (311, 322))	('CCAT2', 'Gene', (21, 26))	('cancer', 'Disease', (91, 97))	('lung cancer', 'Disease', (360, 371))	('rs6983267', 'Mutation', 'rs6983267', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('PRNCR1', 'Gene', (0, 6))
59047	33542645	Additionally, accumulative evidence suggested that cancer-associated single nucleotide polymorphism (SNP) on chromosome 8q24 bears susceptibility in common.	('single nucleotide polymorphism', 'Var', (69, 99))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
59051	33542645	However, the correlation between these cancer-associated lncRNA-SNPs (rs710886, rs1456315 and rs6983267) and lung cancer has not yet been assessed.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('cancer', 'Disease', (39, 45))	('rs6983267', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('rs710886', 'Mutation', 'rs710886', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('rs6983267', 'Mutation', 'rs6983267', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs710886', 'Var', (70, 78))	('rs1456315', 'Var', (80, 89))	('rs1456315', 'Mutation', 'rs1456315', (80, 89))	('cancer', 'Disease', (114, 120))
59063	33542645	Genotyping was performed with TaqMan SNP Genotyping Assays (Applied Biosystems, California, USA) on the following SNPs (gene, SNP, ABI identifier assay mix): PCAT1, rs710886, C__753164210; PRNCR1, rs1456315, C__7531200_20; and CCAT2, rs6983267, C__29086771_20.	('rs710886', 'Mutation', 'rs710886', (165, 173))	('rs1456315', 'Var', (197, 206))	('PRNCR1', 'Gene', (189, 195))	('rs1456315', 'Mutation', 'rs1456315', (197, 206))	('C__7531200_20', 'Var', (208, 221))	('CCAT2', 'Gene', (227, 232))	('rs6983267', 'Mutation', 'rs6983267', (234, 243))	('rs710886', 'Var', (165, 173))	('PCAT1', 'Gene', '100750225', (158, 163))	('PRNCR1', 'Gene', '101867536', (189, 195))	('C__29086771_20', 'Var', (245, 259))	('C__753164210', 'Var', (175, 187))	('PCAT1', 'Gene', (158, 163))	('CCAT2', 'Gene', '101805488', (227, 232))
59067	33542645	rs710886 (98.9%), rs1456315 (99.6%) and rs6983267 (99.3%) showed successful genotyping rates.	('rs710886', 'Mutation', 'rs710886', (0, 8))	('rs6983267', 'Mutation', 'rs6983267', (40, 49))	('rs710886', 'Var', (0, 8))	('rs6983267', 'Var', (40, 49))	('rs1456315', 'Var', (18, 27))	('rs1456315', 'Mutation', 'rs1456315', (18, 27))
59068	33542645	The HWE test showed no significant difference in SNPs in the control group (rs710886: Chi2=0.009, P=0.927; rs1456315: Chi2=3.49, P=0.062; rs6983267: Chi2=0.198, P=0.657), indicating that control samples were obtained from the same population.	('rs6983267', 'Var', (138, 147))	('rs710886', 'Mutation', 'rs710886', (76, 84))	('rs6983267', 'Mutation', 'rs6983267', (138, 147))	('rs710886:', 'Var', (76, 85))	('rs1456315', 'Var', (107, 116))	('rs1456315', 'Mutation', 'rs1456315', (107, 116))
59070	33542645	The rs1456315 T allele significantly increased the risk of lung cancer compared to the C allele, and the rs1456315 TT genotype was associated with lung cancer in both the additive and dominant models; however, there was no significant correlation between the rs1456315 genotype and pathological type or clinical stage as illustrated in Table 3.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('rs1456315', 'Mutation', 'rs1456315', (259, 268))	('rs1456315', 'Var', (105, 114))	('rs1456315 T', 'Var', (4, 15))	('rs1456315', 'Mutation', 'rs1456315', (105, 114))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('increased', 'PosReg', (37, 46))	('rs1456315', 'Mutation', 'rs1456315', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
59071	33542645	The rs6983267 G allele significantly increased the risk of lung cancer compared with the T allele.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('rs6983267', 'Mutation', 'rs6983267', (4, 13))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('increased', 'PosReg', (37, 46))	('rs6983267 G', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
59072	33542645	The genotypic analysis found that rs6983267 was significant in both the additive and recessive models and associated positive lymph node; however, there was no relationship between rs6983267 and the pathological type or clinical stage as listed in Table 4, and no significant relationship was found between the risk of lung cancer and the rs710886 genotype.	('rs710886', 'Mutation', 'rs710886', (339, 347))	('lung cancer', 'Disease', (319, 330))	('lung cancer', 'Phenotype', 'HP:0100526', (319, 330))	('rs6983267', 'Mutation', 'rs6983267', (181, 190))	('rs6983267', 'Mutation', 'rs6983267', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('rs710886', 'Var', (339, 347))	('lung cancer', 'Disease', 'MESH:D008175', (319, 330))	('rs6983267', 'Var', (181, 190))	('rs6983267', 'Var', (34, 43))
59073	33542645	The effects of rs1456315, rs6983267, age, smoking status, drinking status, type 2 diabetes and sex on lung cancer were evaluated by multinomial logistic regression analysis.	('rs1456315', 'Mutation', 'rs1456315', (15, 24))	('diabetes', 'Disease', 'MESH:D003920', (82, 90))	('rs6983267', 'Mutation', 'rs6983267', (26, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (75, 90))	('rs6983267', 'Var', (26, 35))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('diabetes', 'Disease', (82, 90))	('rs1456315', 'Var', (15, 24))
59074	33542645	The results demonstrated that rs1456315, rs6983267, smoking status, drinking status, and age were significantly associated with lung cancer, as shown in Table 5, indicating that the rs1456315 and rs6983267 genotypes were still associated with lung cancer after adjusting for the smoking status, drinking status, and age.	('lung cancer', 'Disease', (243, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('rs1456315', 'Var', (30, 39))	('associated', 'Reg', (227, 237))	('rs6983267', 'Mutation', 'rs6983267', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('rs1456315', 'Var', (182, 191))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('rs1456315', 'Mutation', 'rs1456315', (30, 39))	('rs1456315', 'Mutation', 'rs1456315', (182, 191))	('rs6983267', 'Mutation', 'rs6983267', (41, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('associated', 'Reg', (112, 122))	('rs6983267', 'Var', (196, 205))	('rs6983267', 'Var', (41, 50))
59075	33542645	The analysis revealed in Table 6, the rs1456315-TT significantly increased the risk of lung cancer in smokers, nondrinkers and patients older than 50 years, and the rs6983267-GG increased the risk of lung cancer in smokers and drinkers as shown in Table 7.	('increased', 'PosReg', (65, 74))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('rs1456315-TT', 'Var', (38, 50))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('rs6983267-GG', 'Var', (165, 177))	('rs6983267', 'Mutation', 'rs6983267', (165, 174))	('rs1456315', 'Mutation', 'rs1456315', (38, 47))	('patients', 'Species', '9606', (127, 135))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('lung cancer', 'Disease', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('increased', 'PosReg', (178, 187))
59076	33542645	The FPRP values for significant findings at different prior probability levels are illustrated in Table 8, as defined standard that assigned a prior probability of 0.1 to detect an odds ratio (OR) of 0.67/1.5 (protective/risk effects), the evident association for rs1456315 remained noteworthy in allelic comparison (T vs C), additive model (TT/TC/CC), dominant model (TT+TC vs CC) as well as genotypic comparison in subgroup of nondrinker between lung cancer and controls.	('lung cancer', 'Disease', 'MESH:D008175', (448, 459))	('cancer', 'Phenotype', 'HP:0002664', (453, 459))	('lung cancer', 'Disease', (448, 459))	('lung cancer', 'Phenotype', 'HP:0100526', (448, 459))	('rs1456315', 'Var', (264, 273))	('rs1456315', 'Mutation', 'rs1456315', (264, 273))	('TC', 'Chemical', 'MESH:D013667', (372, 374))	('TC', 'Chemical', 'MESH:D013667', (345, 347))
59077	33542645	And for rs6983267, allelic comparison (T vs G), additive model (TT/TG/GG) as well as genotypic comparison in subgroup of smokers between lung cancer and controls demonstrated significantly associations.	('associations', 'Interaction', (189, 201))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rs6983267', 'Var', (8, 17))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('rs6983267', 'Mutation', 'rs6983267', (8, 17))
59079	33542645	The rs1456315 in LncRNA PRNCR1 (NONHSAT216393.1) may bring gain target of hsa-miR-376a-2-5p and loss target of hsa-miR-3149[Table S1 and Figure S1].	('hsa-miR-3149', 'Gene', (111, 123))	('rs1456315', 'Var', (4, 13))	('hsa-miR-3149', 'Gene', '100422921', (111, 123))	('PRNCR1', 'Gene', '101867536', (24, 30))	('PRNCR1', 'Gene', (24, 30))	('rs1456315', 'Mutation', 'rs1456315', (4, 13))	('loss', 'NegReg', (96, 100))	('gain', 'PosReg', (59, 63))
59080	33542645	The rs6983267 in LncRNA CCAT2 (NONHSAT216396.1) might indicate gain target of hsa-miR-6820-3p, hsa-miR-627-3p, hsa-miR-5190, hsa-miR-4276, hsa-miR-3164, while loss target of hsa-miR-519e-3p, hsa-miR-371a-3p, hsa-miR-33b-3p, hsa-miR-515-3p[Table S2 and Figure S2].	('hsa-miR-5190', 'Gene', (111, 123))	('CCAT2', 'Gene', '101805488', (24, 29))	('CCAT2', 'Gene', (24, 29))	('hsa-miR-4276', 'Gene', (125, 137))	('gain', 'PosReg', (63, 67))	('rs6983267', 'Mutation', 'rs6983267', (4, 13))	('hsa-miR-5190', 'Gene', '100847080', (111, 123))	('hsa-miR-4276', 'Gene', '100423042', (125, 137))	('hsa-miR-3164', 'Gene', '100422846', (139, 151))	('hsa-miR-3164', 'Gene', (139, 151))	('rs6983267', 'Var', (4, 13))
59081	33542645	In RNAfold analysis, The centroid secondary and minimum free energy (minimum free energy, MFE) structure of rs1456315 and rs6983267 are shown in Figures 1 and 2, respectively, The genotype of rs1456315 also bring changes to centroid secondary and MFE of the thermodynamic ensemble, and the MFE of the thermodynamic ensemble was alter from -23.17kcal/mol (rs1456315-A) to -27.29kcal/mol (rs1456315-G), indicating rs1456315 may change the structural stability of lncRNA PRNCR1.	('centroid secondary', 'MPA', (224, 242))	('PRNCR1', 'Gene', (468, 474))	('change', 'Reg', (426, 432))	('rs6983267', 'Mutation', 'rs6983267', (122, 131))	('rs1456315', 'Mutation', 'rs1456315', (387, 396))	('changes', 'Reg', (213, 220))	('rs1456315', 'Var', (412, 421))	('rs1456315', 'Var', (192, 201))	('rs1456315', 'Mutation', 'rs1456315', (192, 201))	('structural', 'MPA', (437, 447))	('MFE', 'MPA', (247, 250))	('rs1456315', 'Mutation', 'rs1456315', (412, 421))	('rs1456315', 'Mutation', 'rs1456315', (355, 364))	('PRNCR1', 'Gene', '101867536', (468, 474))	('rs1456315', 'Mutation', 'rs1456315', (108, 117))
59082	33542645	And the rs6983267 in LncRNA CCAT2 would change the secondary structure of lncRNA, moreover, the MFE of the thermodynamic ensemble was change from -45.3kcal/mol (rs6983267-G) to -46.47kcal/mol (rs6983267-T), which suggests rs6983267-T may increase the structural stability of lncRNA CCAT2, comparing to rs6983267-G.	('rs6983267', 'Mutation', 'rs6983267', (222, 231))	('CCAT2', 'Gene', '101805488', (282, 287))	('change', 'Reg', (40, 46))	('CCAT2', 'Gene', (28, 33))	('structural stability', 'MPA', (251, 271))	('increase', 'PosReg', (238, 246))	('rs6983267', 'Mutation', 'rs6983267', (161, 170))	('secondary structure', 'MPA', (51, 70))	('rs6983267', 'Var', (8, 17))	('rs6983267-T', 'Var', (222, 233))	('CCAT2', 'Gene', (282, 287))	('rs6983267', 'Mutation', 'rs6983267', (302, 311))	('CCAT2', 'Gene', '101805488', (28, 33))	('rs6983267', 'Mutation', 'rs6983267', (8, 17))	('rs6983267', 'Mutation', 'rs6983267', (193, 202))
59083	33542645	In expression analysis for rs1456315 (T>C) and rs6983267 (T>G), we found that rs6983267 contribute to expression quantitative trait loci (eQTL) based on the public database GTEx Portal.	('rs6983267', 'Mutation', 'rs6983267', (47, 56))	('rs6983267', 'Mutation', 'rs6983267', (78, 87))	('expression', 'MPA', (102, 112))	('rs6983267', 'Var', (78, 87))	('rs6983267', 'Var', (47, 56))	('rs1456315', 'Mutation', 'rs1456315', (27, 36))
59084	33542645	rs6983267-GG upregulated the expression CASC8 (cancer susceptibility 8, minus strand) in whole blood (Median value GG:0.409; GT:-0.071;TT:-0.3567, P= 6.3e-10) [Figure S3], while rs1456315 have no found related information, we further explored rs1456315 in its haplotype, including the tag-SNPs of rs146315, rs7007694, 7841060, rs16901946, rs1016343, rs13252298, rs13254738 and rs6983561, there are no related information available.	('rs6983267', 'Mutation', 'rs6983267', (0, 9))	('rs13252298', 'Mutation', 'rs13252298', (350, 360))	('upregulated', 'PosReg', (13, 24))	('rs16901946', 'Var', (327, 337))	('rs16901946', 'Mutation', 'rs16901946', (327, 337))	('CASC8', 'Gene', (40, 45))	('rs13252298', 'Var', (350, 360))	('rs7007694', 'Var', (307, 316))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CASC8', 'Gene', '727677', (40, 45))	('rs13254738', 'Mutation', 'rs13254738', (362, 372))	('cancer susceptibility 8', 'Gene', (47, 70))	('rs7007694', 'Mutation', 'rs7007694', (307, 316))	('7841060', 'Var', (318, 325))	('rs6983267-GG', 'Var', (0, 12))	('rs1456315', 'Mutation', 'rs1456315', (243, 252))	('rs13254738', 'Var', (362, 372))	('rs6983561', 'Mutation', 'rs6983561', (377, 386))	('rs1016343', 'Mutation', 'rs1016343', (339, 348))	('cancer susceptibility 8', 'Gene', '727677', (47, 70))	('rs6983561', 'Var', (377, 386))	('rs146315', 'Var', (297, 305))	('rs1456315', 'Mutation', 'rs1456315', (178, 187))	('rs1016343', 'Var', (339, 348))	('rs146315', 'Mutation', 'rs146315', (297, 305))
59085	33542645	This study investigated the association of cancer-associated lncRNA-SNPs (rs710886, rs1456315 and rs6983267) with lung cancer.	('rs710886', 'Var', (74, 82))	('rs6983267', 'Mutation', 'rs6983267', (98, 107))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('rs1456315', 'Mutation', 'rs1456315', (84, 93))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('association', 'Interaction', (28, 39))	('rs6983267', 'Var', (98, 107))	('cancer', 'Disease', (119, 125))	('lung cancer', 'Disease', (114, 125))	('rs710886', 'Mutation', 'rs710886', (74, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('rs1456315', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
59086	33542645	The major finding was that the lncRNA-SNP PRNCR1 rs1456315 and lncRNA CCAT2 rs6983267 were correlated with lung cancer in the Han population of southern China, the stratification study shows rs1456315-TT significantly increased the risk of lung cancer in smokers, nondrinkers and patients older than 50 years, and rs6983267-GG increased the risk of lung cancer in smokers and drinkers, which addressed the significance of cancer-associated lncRNA-SNPs in lung cancer.	('lung cancer', 'Disease', (349, 360))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Disease', 'MESH:D008175', (455, 466))	('cancer', 'Disease', (422, 428))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('rs6983267-GG', 'Var', (314, 326))	('cancer', 'Disease', 'MESH:D009369', (354, 360))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('rs1456315', 'Mutation', 'rs1456315', (49, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (455, 466))	('lung cancer', 'Disease', 'MESH:D008175', (240, 251))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('rs1456315', 'Mutation', 'rs1456315', (191, 200))	('increased', 'PosReg', (218, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (240, 251))	('lung cancer', 'Disease', 'MESH:D008175', (349, 360))	('cancer', 'Disease', (460, 466))	('PRNCR1', 'Gene', (42, 48))	('CCAT2', 'Gene', '101805488', (70, 75))	('patients', 'Species', '9606', (280, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (349, 360))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('increased', 'PosReg', (327, 336))	('cancer', 'Disease', (245, 251))	('CCAT2', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('lung cancer', 'Disease', (107, 118))	('rs6983267', 'Mutation', 'rs6983267', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('rs6983267', 'Mutation', 'rs6983267', (314, 323))	('lung cancer', 'Disease', (455, 466))	('cancer', 'Disease', (354, 360))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('lung cancer', 'Disease', (240, 251))	('rs1456315-TT', 'Var', (191, 203))	('cancer', 'Disease', 'MESH:D009369', (460, 466))	('PRNCR1', 'Gene', '101867536', (42, 48))	('rs1456315', 'Var', (49, 58))
59087	33542645	In further bioinformatic exploration, we found rs6983267 and rs1456315 may influence the secondary structure of LncRNA and affect the bind to those miRNAs, rs6983267 alter the expression in eQTL on the GTEx analysis.	('rs1456315', 'Var', (61, 70))	('rs6983267', 'Mutation', 'rs6983267', (47, 56))	('rs6983267', 'Var', (156, 165))	('influence', 'Reg', (75, 84))	('eQTL', 'Protein', (190, 194))	('rs1456315', 'Mutation', 'rs1456315', (61, 70))	('expression', 'MPA', (176, 186))	('rs6983267', 'Var', (47, 56))	('bind', 'Interaction', (134, 138))	('rs6983267', 'Mutation', 'rs6983267', (156, 165))	('affect', 'Reg', (123, 129))	('alter', 'Reg', (166, 171))	('secondary structure', 'MPA', (89, 108))	('LncRNA', 'Protein', (112, 118))
59088	33542645	The rs1456315 genotype led to increased susceptibility of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('rs1456315', 'Var', (4, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('rs1456315', 'Mutation', 'rs1456315', (4, 13))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
59089	33542645	rs1456315, which is located in the 8q24 gene desert region, exerts susceptibility to various cancers, including prostate cancer, in both Japanese and Iranian populations, and is related to breast cancer and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs1456315', 'Mutation', 'rs1456315', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('colorectal cancer', 'Disease', (207, 224))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('susceptibility', 'Reg', (67, 81))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('related', 'Reg', (178, 185))	('breast cancer', 'Disease', (189, 202))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('prostate cancer', 'Disease', (112, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancers', 'Disease', (93, 100))	('rs1456315', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
59094	33542645	rs1456315 exerts strong linkage disequilibrium with rs7463708 and rs72725879 (r2>0.8) based on HaploReg 4.1, indicating that the rs1456315 genotype is identical to the rs7463708 and rs72725879 genotypes, thus extending the functional significance of rs1456315.	('linkage', 'Interaction', (24, 31))	('rs1456315', 'Mutation', 'rs1456315', (129, 138))	('rs1456315', 'Var', (0, 9))	('rs1456315', 'Mutation', 'rs1456315', (250, 259))	('rs1456315', 'Mutation', 'rs1456315', (0, 9))	('rs72725879', 'Mutation', 'rs72725879', (182, 192))	('rs72725879', 'Mutation', 'rs72725879', (66, 76))	('rs7463708', 'Mutation', 'rs7463708', (168, 177))	('rs1456315', 'Var', (129, 138))	('rs7463708', 'Mutation', 'rs7463708', (52, 61))
59095	33542645	The T allele of rs1456315 can increase the gene expression of PRNCR1, which is involved in prostate carcinogenesis, possibly by changing androgen receptor affinity.	('PRNCR1', 'Gene', (62, 68))	('rs1456315', 'Var', (16, 25))	('androgen receptor', 'Gene', '367', (137, 154))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('gene expression', 'MPA', (43, 58))	('prostate carcinogenesis', 'Disease', (91, 114))	('rs1456315', 'Mutation', 'rs1456315', (16, 25))	('androgen receptor', 'Gene', (137, 154))	('prostate carcinogenesis', 'Disease', 'MESH:D011471', (91, 114))	('increase', 'PosReg', (30, 38))	('PRNCR1', 'Gene', '101867536', (62, 68))	('changing', 'Reg', (128, 136))	('affinity', 'Interaction', (155, 163))
59096	33542645	SNPs in 8q24 have been reported to alter the secondary structure of PRNCR1 mRNA and the stability of mRNA conformation, therefore rs1456315 actively involved the process of PRNCR1 regulation might also occur in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('PRNCR1', 'Gene', '101867536', (173, 179))	('rs1456315', 'Var', (130, 139))	('regulation', 'biological_process', 'GO:0065007', ('180', '190'))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('rs1456315', 'Mutation', 'rs1456315', (130, 139))	('secondary structure', 'MPA', (45, 64))	('occur', 'Reg', (202, 207))	('PRNCR1', 'Gene', (173, 179))	('SNPs', 'Var', (0, 4))	('mRNA', 'MPA', (75, 79))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('PRNCR1', 'Gene', '101867536', (68, 74))	('stability', 'MPA', (88, 97))	('alter', 'Reg', (35, 40))	('PRNCR1', 'Gene', (68, 74))	('lung cancer', 'Disease', (211, 222))
59097	33542645	rs6983267 is located at the conserved region of 8q24.21, and the lncRNA CCAT2 rs6983267-GG genotype was reported to have a reproducible association with colon cancer, cervical cancer and lung cancer.	('rs6983267', 'Mutation', 'rs6983267', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('colon cancer', 'Phenotype', 'HP:0003003', (153, 165))	('cancer', 'Disease', (159, 165))	('CCAT2', 'Gene', '101805488', (72, 77))	('rs6983267', 'Mutation', 'rs6983267', (78, 87))	('CCAT2', 'Gene', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('lung cancer', 'Disease', (187, 198))	('colon cancer', 'Disease', 'MESH:D015179', (153, 165))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('rs6983267', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('rs6983267-GG', 'Var', (78, 90))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('colon cancer', 'Disease', (153, 165))	('cancer', 'Disease', (176, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))
59098	33542645	The rs6983267 of lncRNA CCAT2 is transcribed with G (CCAT2-G) or T (CCAT2-T) in a 1.7-kb RNA transcript.	('CCAT2', 'Gene', (68, 73))	('CCAT2', 'Gene', '101805488', (24, 29))	('CCAT2', 'Gene', (24, 29))	('rs6983267', 'Mutation', 'rs6983267', (4, 13))	('CCAT2', 'Gene', '101805488', (53, 58))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('CCAT2', 'Gene', '101805488', (68, 73))	('CCAT2', 'Gene', (53, 58))	('rs6983267', 'Var', (4, 13))
59100	33542645	rs6983267-GG increases the expression of CCAT2, and high CCAT2 expression is related to lung adenocarcinoma susceptibility and a poor response to cisplatin chemotherapy.	('increases', 'PosReg', (13, 22))	('related', 'Reg', (77, 84))	('rs6983267-GG', 'Var', (0, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('rs6983267', 'Mutation', 'rs6983267', (0, 9))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('expression', 'MPA', (63, 73))	('expression', 'MPA', (27, 37))	('CCAT2', 'Gene', (41, 46))	('CCAT2', 'Gene', '101805488', (57, 62))	('lung adenocarcinoma', 'Disease', (88, 107))	('high', 'Var', (52, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('response to cisplatin', 'biological_process', 'GO:0072718', ('134', '155'))	('CCAT2', 'Gene', (57, 62))	('CCAT2', 'Gene', '101805488', (41, 46))
59101	33542645	Additionally, CCAT2 rs6983267-TT genotype is associated with a decreased incidence of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('rs6983267-TT', 'Var', (20, 32))	('lung adenocarcinoma', 'Disease', (86, 105))	('CCAT2', 'Gene', (14, 19))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('decreased', 'NegReg', (63, 72))	('rs6983267', 'Mutation', 'rs6983267', (20, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('CCAT2', 'Gene', '101805488', (14, 19))
59102	33542645	Based on the theory that T/G is a protective/risk allele, rs6983267-GG also assume a risk allele for lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('lung adenocarcinoma', 'Disease', (101, 120))	('rs6983267-GG', 'Var', (58, 70))	('rs6983267', 'Mutation', 'rs6983267', (58, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (101, 120))
59103	33542645	And in expression quantitative trait locus analysis of whole blood, rs6983267-GG increased expression of CASC8 (also name CCAT) in whole blood, thus, taken together, rs6983267 increase likelihood to influence expressive modulation.	('expression', 'MPA', (91, 101))	('rs6983267-GG', 'Var', (68, 80))	('rs6983267', 'Var', (166, 175))	('CCAT', 'Gene', (122, 126))	('expressive modulation', 'MPA', (209, 230))	('rs6983267', 'Mutation', 'rs6983267', (68, 77))	('CCAT', 'Gene', '2651', (122, 126))	('influence', 'Reg', (199, 208))	('CASC8', 'Gene', (105, 110))	('CASC8', 'Gene', '727677', (105, 110))	('rs6983267', 'Mutation', 'rs6983267', (166, 175))	('increased', 'PosReg', (81, 90))
59104	33542645	After FPRP analysis, the significance showed the power that further confirmed the association of rs6983267 and rs1456315 with lung cancer.	('association', 'Interaction', (82, 93))	('rs6983267', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('rs1456315', 'Var', (111, 120))	('rs6983267', 'Mutation', 'rs6983267', (97, 106))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('rs1456315', 'Mutation', 'rs1456315', (111, 120))
59105	33542645	The bioinformatic analysis indicated that both rs6983267 and rs1456315 may influence lncRNA binding to miRNAs.	('lncRNA binding', 'molecular_function', 'GO:0106222', ('85', '99'))	('rs1456315', 'Var', (61, 70))	('rs6983267', 'Mutation', 'rs6983267', (47, 56))	('lncRNA', 'Protein', (85, 91))	('influence', 'Reg', (75, 84))	('rs1456315', 'Mutation', 'rs1456315', (61, 70))	('rs6983267', 'Var', (47, 56))
59106	33542645	The rs6983267 might indicate gain target of hsa-miR-6820-3p, hsa-miR-627-3p, hsa-miR-5190, hsa-miR-4276, hsa-miR-3164, while loss target of hsa-miR-519e-3p, hsa-miR-371a-3p, hsa-miR-33b-3p, hsa-miR-515-3p.	('hsa-miR-5190', 'Gene', '100847080', (77, 89))	('rs6983267', 'Mutation', 'rs6983267', (4, 13))	('hsa-miR-4276', 'Gene', '100423042', (91, 103))	('hsa-miR-4276', 'Gene', (91, 103))	('gain', 'PosReg', (29, 33))	('hsa-miR-5190', 'Gene', (77, 89))	('hsa-miR-3164', 'Gene', '100422846', (105, 117))	('hsa-miR-3164', 'Gene', (105, 117))	('rs6983267', 'Var', (4, 13))
59108	33542645	The rs1456315 may bring gain target of hsa-miR-376a-2-5p and loss target of hsa-miR-3149, and hsa-mir-3149 have reported to play important role in DNA repair and immunity by inhibiting expression of ovarian tumor protease deubiquitinase 5 (OTUD5), as a member of the ovarian tumor protease family, therefore rs1456315 and rs6983267 may influence binding between LncRNA and miRNA to modulate epigenetic process.	('rs1456315', 'Var', (308, 317))	('expression', 'MPA', (185, 195))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('222', '236'))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('rs6983267', 'Var', (322, 331))	('ovarian tumor protease deubiquitinase 5', 'Gene', (199, 238))	('hsa-miR-3149', 'Gene', '100422921', (76, 88))	('binding', 'Interaction', (346, 353))	('OTUD5', 'Gene', '55593', (240, 245))	('ovarian tumor protease deubiquitinase 5', 'Gene', '55593', (199, 238))	('rs1456315', 'Mutation', 'rs1456315', (308, 317))	('ovarian tumor', 'Phenotype', 'HP:0100615', (267, 280))	('rs1456315', 'Var', (4, 13))	('hsa-miR-3149', 'Gene', (76, 88))	('binding', 'molecular_function', 'GO:0005488', ('346', '353'))	('ovarian tumor', 'Disease', 'MESH:D010051', (199, 212))	('LncRNA', 'Protein', (362, 368))	('epigenetic process', 'MPA', (391, 409))	('rs6983267', 'Mutation', 'rs6983267', (322, 331))	('modulate', 'Reg', (382, 390))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('rs1456315', 'Mutation', 'rs1456315', (4, 13))	('OTUD5', 'Gene', (240, 245))	('ovarian tumor', 'Disease', (267, 280))	('inhibiting', 'NegReg', (174, 184))	('influence', 'Reg', (336, 345))	('hsa-mir-3149', 'Gene', (94, 106))	('hsa-mir-3149', 'Gene', '100422921', (94, 106))	('ovarian tumor', 'Disease', 'MESH:D010051', (267, 280))	('ovarian tumor', 'Phenotype', 'HP:0100615', (199, 212))	('miRNA', 'Protein', (373, 378))	('DNA repair', 'biological_process', 'GO:0006281', ('147', '157'))
59109	33542645	Additionally, rs1456315 and rs6983267 characterize genotypic stability of LncRNA PRNCR1 and lncRNA CCAT2 secondary structure.	('CCAT2', 'Gene', (99, 104))	('rs1456315', 'Var', (14, 23))	('characterize', 'Reg', (38, 50))	('PRNCR1', 'Gene', (81, 87))	('rs6983267', 'Mutation', 'rs6983267', (28, 37))	('PRNCR1', 'Gene', '101867536', (81, 87))	('rs1456315', 'Mutation', 'rs1456315', (14, 23))	('CCAT2', 'Gene', '101805488', (99, 104))	('rs6983267', 'Var', (28, 37))
59113	33542645	The lncRNA PRNCR1 locus rs1456315 and lncRNACCAT2 locus rs6983267 polymorphisms associated with lung cancer in the Han population of southern China, the SNP-lncRNAs may contribute to the structure and function alteration of lncRNA PRNCR1 and lncRNACCAT2, thus, the SNP-lncRNAs can be used as functional genetic markers for lung cancer and its underlying mechanism.	('CCAT2', 'Gene', (248, 253))	('rs1456315', 'Mutation', 'rs1456315', (24, 33))	('rs6983267', 'Mutation', 'rs6983267', (56, 65))	('polymorphisms', 'Var', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('rs6983267 polymorphisms', 'Var', (56, 79))	('PRNCR1', 'Gene', '101867536', (231, 237))	('associated with', 'Reg', (80, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('lung cancer', 'Disease', (323, 334))	('CCAT2', 'Gene', (44, 49))	('PRNCR1', 'Gene', (11, 17))	('lung cancer', 'Disease', 'MESH:D008175', (323, 334))	('rs1456315', 'Var', (24, 33))	('lung cancer', 'Disease', (96, 107))	('PRNCR1', 'Gene', (231, 237))	('CCAT2', 'Gene', '101805488', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (323, 334))	('CCAT2', 'Gene', '101805488', (248, 253))	('PRNCR1', 'Gene', '101867536', (11, 17))
59115	33237626	Their dysregulation is increasingly recognized to contribute to the development and progression of human cancers, including lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('contribute', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('dysregulation', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('human', 'Species', '9606', (99, 104))
59120	33237626	Xenotransplantation experiments showed that Linc00485 silencing significantly weakened the proliferation potential of A549 cells in vivo.	('Linc00485', 'Gene', (44, 53))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('silencing', 'Var', (54, 63))	('proliferation potential of A549 cells in vivo', 'CPA', (91, 136))	('weakened', 'NegReg', (78, 86))	('Linc00485', 'Chemical', '-', (44, 53))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('A549', 'CellLine', 'CVCL:0023', (118, 122))
59131	33237626	14 ,  15 ,  16 ,  17  Linc00152 was shown to promote the proliferation of colorectal cancer by regulating the expression of miR-139-5p, which is associated with metastasis and chemotherapy resistance.	('si', 'Chemical', 'MESH:D012825', (191, 193))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('expression', 'Species', '29278', (110, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('promote', 'PosReg', (45, 52))	('Linc00152', 'Var', (22, 31))	('expression', 'MPA', (110, 120))	('proliferation', 'CPA', (57, 70))	('si', 'Chemical', 'MESH:D012825', (168, 170))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('miR-139-5p', 'Var', (124, 134))	('colorectal cancer', 'Disease', (74, 91))
59149	33237626	For animal experiments, lentivirus-mediated short hairpin RNA was employed to knock down Linc00485 expression in the A549 cell line.	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('Linc00485', 'Gene', (89, 98))	('knock', 'Var', (78, 83))	('Linc00485', 'Chemical', '-', (89, 98))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('expression', 'Species', '29278', (99, 109))
59152	33237626	Wild-type (WT) Linc00485 (WT-00485), mutant Linc00485 (MUT-00485), WT c-Myc 3'-UTR (WT-c-Myc), and mutant c-Myc 3'-UTR (MUT-c-Myc) plasmid vectors were constructed by Sangon Biotech (Shanghai) Co., Ltd.	('c-Myc', 'Gene', (106, 111))	('Linc00485', 'Gene', (44, 53))	('c-Myc', 'Gene', '4609', (87, 92))	('Linc00485', 'Chemical', '-', (15, 24))	('c-Myc', 'Gene', (87, 92))	('c-Myc', 'Gene', '4609', (124, 129))	('Linc00485', 'Chemical', '-', (44, 53))	('c-Myc', 'Gene', (70, 75))	('c-Myc', 'Gene', (124, 129))	('mutant', 'Var', (37, 43))	('c-Myc', 'Gene', '4609', (106, 111))	('mutant', 'Var', (99, 105))	('c-Myc', 'Gene', '4609', (70, 75))
59196	33237626	Linc00485 levels were associated with TNM stage in patients with lung cancer; the expression of Linc00485 was strikingly elevated in the tumour tissues of patients with stage III/IV lung cancer in comparison with those of patients with stage I/II lung cancer (Figure 1B).	('lung cancer', 'Disease', (182, 193))	('patients', 'Species', '9606', (222, 230))	('lung cancer', 'Disease', 'MESH:D008175', (247, 258))	('patients', 'Species', '9606', (155, 163))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('II lung cancer', 'Disease', 'MESH:D008175', (244, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('expression', 'MPA', (82, 92))	('Linc00485', 'Chemical', '-', (0, 9))	('Linc00485', 'Var', (96, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('Linc00485', 'Chemical', '-', (96, 105))	('patients', 'Species', '9606', (51, 59))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('elevated', 'PosReg', (121, 129))	('II lung cancer', 'Disease', (244, 258))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('tumour', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('expression', 'Species', '29278', (82, 92))	('lung cancer', 'Disease', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
59198	33237626	Survival analysis suggested that patients with high expression of Linc00485 had significantly shorter survival times than those with low expression (Figure 1E).	('si', 'Chemical', 'MESH:D012825', (14, 16))	('patients', 'Species', '9606', (33, 41))	('expression', 'Species', '29278', (52, 62))	('Linc00485', 'Var', (66, 75))	('shorter', 'NegReg', (94, 101))	('high expression', 'Var', (47, 62))	('Linc00485', 'Chemical', '-', (66, 75))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('survival times', 'CPA', (102, 116))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('expression', 'Species', '29278', (137, 147))
59201	33237626	Our findings suggested that Linc00485 silencing significantly attenuated the viability of lung cancer cells (A549, H460, and H1975) (Figure 2A,B,I-L), suppressed cell colony formation (Figure 2C), and decreased the Ki-67-positive rate in A549 cells (Figure 2D).	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('Ki-67', 'Chemical', '-', (215, 220))	('H1975', 'CellLine', 'CVCL:1511', (125, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('Ki-67-positive rate', 'CPA', (215, 234))	('cell colony formation', 'CPA', (162, 183))	('si', 'Chemical', 'MESH:D012825', (223, 225))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('silencing', 'Var', (38, 47))	('suppressed', 'NegReg', (151, 161))	('H460', 'CellLine', 'CVCL:0459', (115, 119))	('A549', 'CellLine', 'CVCL:0023', (238, 242))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('viability', 'CPA', (77, 86))	('attenuated', 'NegReg', (62, 72))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('lung cancer', 'Disease', (90, 101))	('Linc00485', 'Gene', (28, 37))	('Linc00485', 'Chemical', '-', (28, 37))	('decreased', 'NegReg', (201, 210))
59202	33237626	By contrast, Linc00485 overexpression facilitated the proliferation of A549 cells (Figure 2E-H).	('Linc00485', 'Var', (13, 22))	('expression', 'Species', '29278', (27, 37))	('Linc00485', 'Chemical', '-', (13, 22))	('facilitated', 'PosReg', (38, 49))	('proliferation', 'CPA', (54, 67))	('A549', 'CellLine', 'CVCL:0023', (71, 75))
59205	33237626	Through in vitro scratch assays and transwell migration and invasion assays, we further confirmed that Linc00485 silencing significantly reduced the migrative and invasive capabilities of lung cancer cells (A549, H460, and H1975) (Figure 3A-F), whereas the overexpression of Linc00485 significantly enhanced malignant phenotypes of A549 cells (Figure 3G,H).	('H460', 'CellLine', 'CVCL:0459', (213, 217))	('expression', 'Species', '29278', (261, 271))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('A549', 'CellLine', 'CVCL:0023', (207, 211))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('reduced', 'NegReg', (137, 144))	('lung cancer', 'Disease', (188, 199))	('Linc00485', 'Gene', (103, 112))	('Linc00485', 'Chemical', '-', (103, 112))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('A549', 'CellLine', 'CVCL:0023', (332, 336))	('si', 'Chemical', 'MESH:D012825', (285, 287))	('si', 'Chemical', 'MESH:D012825', (267, 269))	('lung cancer', 'Disease', 'MESH:D008175', (188, 199))	('H1975', 'CellLine', 'CVCL:1511', (223, 228))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('Linc00485', 'Chemical', '-', (275, 284))	('silencing', 'Var', (113, 122))
59208	33237626	The silencing of Linc00485 significantly down-regulated the expression of vimentin and N-cadherin but up-regulated that of E-cadherin and cytokeratin 19 (CK-19).	('expression', 'MPA', (60, 70))	('CK-19', 'Gene', '16669', (154, 159))	('down-regulated', 'NegReg', (41, 55))	('N-cadherin', 'Gene', '12558', (87, 97))	('vimentin', 'Gene', (74, 82))	('vimentin', 'cellular_component', 'GO:0045098', ('74', '82'))	('up-regulated', 'PosReg', (102, 114))	('Linc00485', 'Gene', (17, 26))	('Linc00485', 'Chemical', '-', (17, 26))	('vimentin', 'Gene', '22352', (74, 82))	('E-cadherin', 'Gene', (123, 133))	('expression', 'Species', '29278', (60, 70))	('CK-19', 'Gene', (154, 159))	('silencing', 'Var', (4, 13))	('vimentin', 'cellular_component', 'GO:0045099', ('74', '82'))	('E-cadherin', 'Gene', '12550', (123, 133))	('cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('N-cadherin', 'Gene', (87, 97))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('si', 'Chemical', 'MESH:D012825', (27, 29))
59209	33237626	Moreover, the expression levels of matrix metalloproteinase family members MMP-9 and MMP-2 were strikingly reduced in A549 cells with Linc00485 silencing (Figure 3I).	('MMP-2', 'Gene', (85, 90))	('expression levels', 'MPA', (14, 31))	('Linc00485', 'Chemical', '-', (134, 143))	('MMP-9', 'molecular_function', 'GO:0004229', ('75', '80'))	('MMP-2', 'Gene', '17390', (85, 90))	('expression', 'Species', '29278', (14, 24))	('silencing', 'Var', (144, 153))	('reduced', 'NegReg', (107, 114))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('MMP-2', 'molecular_function', 'GO:0004228', ('85', '90'))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('MMP-9', 'Gene', '17395', (75, 80))	('MMP-9', 'Gene', (75, 80))	('Linc00485', 'Gene', (134, 143))
59214	33237626	Moreover, Pearson correlation analysis indicated that Linc00485 was negatively correlated with miR-298 expression in adjacent normal tissues and tumour tissues of patients with lung cancer, respectively (Figure 4G).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', (145, 151))	('patients', 'Species', '9606', (163, 171))	('expression', 'Species', '29278', (103, 113))	('miR-298', 'Gene', (95, 102))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('expression', 'MPA', (103, 113))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('Linc00485', 'Var', (54, 63))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('miR-298', 'Gene', '100126296', (95, 102))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('lung cancer', 'Disease', (177, 188))	('Linc00485', 'Chemical', '-', (54, 63))	('negatively', 'NegReg', (68, 78))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
59215	33237626	Silencing or overexpression of Linc00485 in A549 cells significantly increased or decreased expression levels of miR-298, respectively (Figure 4I,J).	('expression', 'Species', '29278', (92, 102))	('miR-298', 'Gene', (113, 120))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('expression', 'Species', '29278', (17, 27))	('Linc00485', 'Gene', (31, 40))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('Linc00485', 'Chemical', '-', (31, 40))	('overexpression', 'PosReg', (13, 27))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('expression levels', 'MPA', (92, 109))	('miR-298', 'Gene', '100126296', (113, 120))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (82, 91))	('si', 'Chemical', 'MESH:D012825', (55, 57))
59217	33237626	Notably, silencing Linc00485 up-regulated the expression of miR-298 in xenograft tumour tissues compared with the control group (n = 6 mice in each group) (Figure 4M).	('miR-298', 'Gene', (60, 67))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('silencing', 'Var', (9, 18))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('tumour', 'Disease', (81, 87))	('up-regulated', 'PosReg', (29, 41))	('miR-298', 'Gene', '100126296', (60, 67))	('Linc00485', 'Gene', (19, 28))	('mice', 'Species', '10090', (135, 139))	('expression', 'Species', '29278', (46, 56))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('expression', 'MPA', (46, 56))	('Linc00485', 'Chemical', '-', (19, 28))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
59220	33237626	Moreover, the migration and invasion abilities of A549 cells were significantly elevated by knockdown of miR-298 (Figure 5D-F).	('miR-298', 'Gene', (105, 112))	('elevated', 'PosReg', (80, 88))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('knockdown', 'Var', (92, 101))	('invasion abilities of A549 cells', 'CPA', (28, 60))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('miR-298', 'Gene', '100126296', (105, 112))	('si', 'Chemical', 'MESH:D012825', (66, 68))
59222	33237626	Furthermore, miR-298 mimic transfection in combination with Linc00485 silencing had a synergistic inhibitory effect on the malignant behaviours of A549 cells in comparison with the cells treated with sh-LincRNA 00 485 alone.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('silencing', 'NegReg', (70, 79))	('A549', 'CellLine', 'CVCL:0023', (147, 151))	('Linc00485', 'Chemical', '-', (60, 69))	('miR-298', 'Gene', (13, 20))	('malignant behaviours of A549 cells', 'CPA', (123, 157))	('transfection', 'Var', (27, 39))	('miR-298', 'Gene', '100126296', (13, 20))	('sh-LincRNA 00 485', 'Chemical', '-', (200, 217))	('inhibitory', 'NegReg', (98, 108))	('Linc00485', 'Gene', (60, 69))
59224	33237626	These results indicate that Linc00485 exerts its oncogenic activity in lung cancer by directly binding to miR-298.	('oncogenic activity', 'MPA', (49, 67))	('Linc00485', 'Var', (28, 37))	('Linc00485', 'Chemical', '-', (28, 37))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('miR-298', 'Gene', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('binding', 'Interaction', (95, 102))	('miR-298', 'Gene', '100126296', (106, 113))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
59230	33237626	Transient silencing or overexpression of Linc00485 led to a significant down-regulation or up-regulation, respectively, of c-Myc in A549 cells compared with control cells (Figure 6J,K).	('overexpression', 'PosReg', (23, 37))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('c-Myc', 'Gene', (123, 128))	('expression', 'Species', '29278', (27, 37))	('Linc00485', 'Var', (41, 50))	('A549', 'CellLine', 'CVCL:0023', (132, 136))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('up-regulation', 'PosReg', (91, 104))	('Linc00485', 'Chemical', '-', (41, 50))	('c-Myc', 'Gene', '4609', (123, 128))	('silencing', 'NegReg', (10, 19))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('regulation', 'biological_process', 'GO:0065007', ('77', '87'))	('down-regulation', 'NegReg', (72, 87))
59234	33237626	As expected, c-Myc expression was markedly decreased in tumour tissues with Linc00485 knockdown compared with the control group (n = 6 mice per group) (Figure 6N).	('c-Myc', 'Gene', (13, 18))	('knockdown', 'Var', (86, 95))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('Linc00485', 'Gene', (76, 85))	('mice', 'Species', '10090', (135, 139))	('c-Myc', 'Gene', '4609', (13, 18))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('Linc00485', 'Chemical', '-', (76, 85))	('tumour', 'Disease', (56, 62))	('decreased', 'NegReg', (43, 52))	('expression', 'Species', '29278', (19, 29))
59236	33237626	Linc00485 silencing in combination with c-Myc knockdown markedly attenuated the viability, migration, and invasion of lung cancer A549 cells, whereas overexpression of c-Myc antagonized the effects of Linc00485 silencing (Figure 7A-F).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', (118, 129))	('viability', 'CPA', (80, 89))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('Linc00485', 'Gene', (0, 9))	('c-Myc', 'Gene', (168, 173))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('Linc00485', 'Chemical', '-', (0, 9))	('attenuated', 'NegReg', (65, 75))	('invasion', 'CPA', (106, 114))	('c-Myc', 'Gene', '4609', (168, 173))	('c-Myc', 'Gene', (40, 45))	('expression', 'Species', '29278', (154, 164))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('c-Myc', 'Gene', '4609', (40, 45))	('migration', 'CPA', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('silencing', 'Var', (10, 19))	('si', 'Chemical', 'MESH:D012825', (211, 213))	('Linc00485', 'Chemical', '-', (201, 210))	('A549', 'CellLine', 'CVCL:0023', (130, 134))
59238	33237626	Furthermore, silencing Linc00485 and treatment with c-Myc inhibitor 10074-G5 had stronger inhibitory effects on cell proliferation, migration, and invasion in comparison with silencing alone (Figure 7M-P).	('cell proliferation', 'CPA', (112, 130))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('c-Myc', 'Gene', '4609', (52, 57))	('10074-G5', 'Chemical', 'MESH:C534883', (68, 76))	('stronger', 'PosReg', (81, 89))	('c-Myc', 'Gene', (52, 57))	('invasion', 'CPA', (147, 155))	('migration', 'CPA', (132, 141))	('inhibitory effects', 'NegReg', (90, 108))	('silencing Linc00485', 'Var', (13, 32))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('Linc00485', 'Var', (23, 32))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('Linc00485', 'Chemical', '-', (23, 32))
59240	33237626	Cumulatively, these data suggest that Linc00485 functions as an miR-298 sponge to promote c-Myc gene expression, resulting in proliferation, migration, and invasion of lung cancer cells (Figure 7U).	('proliferation', 'CPA', (126, 139))	('migration', 'CPA', (141, 150))	('miR-298', 'Gene', (64, 71))	('Linc00485', 'Var', (38, 47))	('c-Myc', 'Gene', '4609', (90, 95))	('promote', 'PosReg', (82, 89))	('lung cancer', 'Disease', (168, 179))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('c-Myc', 'Gene', (90, 95))	('Linc00485', 'Chemical', '-', (38, 47))	('gene expression', 'biological_process', 'GO:0010467', ('96', '111'))	('expression', 'Species', '29278', (101, 111))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('miR-298', 'Gene', '100126296', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('invasion', 'CPA', (156, 164))
59244	33237626	25 ,  26 ,  27  In this study, we showed that the expression of Linc00485 was significantly up-regulated in lung cancer tissues, suggesting that Linc00485 may be an oncogene.	('Linc00485', 'Gene', (64, 73))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('Linc00485', 'Chemical', '-', (64, 73))	('lung cancer', 'Disease', (108, 119))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('up-regulated', 'PosReg', (92, 104))	('Linc00485', 'Var', (145, 154))	('Linc00485', 'Chemical', '-', (145, 154))	('expression', 'Species', '29278', (50, 60))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('expression', 'MPA', (50, 60))
59245	33237626	Previous studies have found that Linc00485 plays an important part in the development of uterine leiomyoma.	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (89, 106))	('leiomyoma', 'Disease', (97, 106))	('leiomyoma', 'Disease', 'MESH:D007889', (97, 106))	('Linc00485', 'Var', (33, 42))	('Linc00485', 'Chemical', '-', (33, 42))
59246	33237626	28  Moreover, in lung adenocarcinoma, Linc00485 up-regulated the expression of cell cycle checkpoint kinase 1, thereby enhancing the resistance of lung cancer cells to chemotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('79', '100'))	('up-regulated', 'PosReg', (48, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('enhancing', 'PosReg', (119, 128))	('expression', 'MPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung adenocarcinoma', 'Disease', (17, 36))	('Linc00485', 'Var', (38, 47))	('lung cancer', 'Disease', (147, 158))	('Linc00485', 'Chemical', '-', (38, 47))	('cell cycle checkpoint kinase 1', 'Gene', (79, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (17, 36))	('resistance', 'CPA', (133, 143))	('expression', 'Species', '29278', (65, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (17, 36))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
59248	33237626	18 ,  30  Linc00485 could directly bind to miR-298, leading to the up-regulation of c-Myc gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('Linc00485', 'Var', (10, 19))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('miR-298', 'Gene', (43, 50))	('c-Myc', 'Gene', '4609', (84, 89))	('Linc00485', 'Chemical', '-', (10, 19))	('up-regulation', 'PosReg', (67, 80))	('c-Myc', 'Gene', (84, 89))	('miR-298', 'Gene', '100126296', (43, 50))	('expression', 'Species', '29278', (95, 105))
59249	33237626	In addition, patients with high expression of Linc00485 had significantly shorter survival times, suggesting that Linc00485 could be used as prognostic biomarker in patients diagnosed with lung cancer.	('shorter', 'NegReg', (74, 81))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('patients', 'Species', '9606', (13, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Linc00485', 'Var', (46, 55))	('lung cancer', 'Disease', (189, 200))	('high expression', 'Var', (27, 42))	('Linc00485', 'Var', (114, 123))	('expression', 'Species', '29278', (32, 42))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('patients', 'Species', '9606', (165, 173))	('Linc00485', 'Chemical', '-', (46, 55))	('Linc00485', 'Chemical', '-', (114, 123))	('survival times', 'CPA', (82, 96))
59257	33237626	Taken together, this evidence suggests that Linc00485 modulates the expression of c-Myc, thus participating in lung cancer progression.	('Linc00485', 'Var', (44, 53))	('expression', 'Species', '29278', (68, 78))	('expression', 'MPA', (68, 78))	('Linc00485', 'Chemical', '-', (44, 53))	('participating in', 'Reg', (94, 110))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('c-Myc', 'Gene', '4609', (82, 87))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('modulates', 'Reg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('c-Myc', 'Gene', (82, 87))
59262	33237626	42  Therefore, we speculated that the overexpression of Linc00485 elevated the expression of c-Myc by sponging miR-298, thereby activating multiple downstream genes including H19 and ANRIL, and thus driving lung cancer development.	('activating', 'PosReg', (128, 138))	('H19', 'Gene', (175, 178))	('expression', 'MPA', (79, 89))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('Linc00485', 'Var', (56, 65))	('Linc00485', 'Chemical', '-', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('elevated', 'PosReg', (66, 74))	('expression', 'Species', '29278', (42, 52))	('c-Myc', 'Gene', (93, 98))	('miR-298', 'Gene', '100126296', (111, 118))	('sponging', 'NegReg', (102, 110))	('miR-298', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('expression', 'Species', '29278', (79, 89))	('c-Myc', 'Gene', '4609', (93, 98))	('driving', 'PosReg', (199, 206))	('overexpression', 'PosReg', (38, 52))	('lung cancer', 'Disease', (207, 218))
59264	33237626	Collectively, our findings reveal that Linc00485 regulates the expression of oncogene c-Myc by adsorbing miR-298.	('adsorbing', 'MPA', (95, 104))	('miR-298', 'Gene', (105, 112))	('c-Myc', 'Gene', '4609', (86, 91))	('Linc00485', 'Chemical', '-', (39, 48))	('expression', 'Species', '29278', (63, 73))	('c-Myc', 'Gene', (86, 91))	('expression', 'MPA', (63, 73))	('miR-298', 'Gene', '100126296', (105, 112))	('regulates', 'Reg', (49, 58))	('Linc00485', 'Var', (39, 48))
59274	33364431	Gain- or loss-of-function assays indicated that the upregulation of GPR37 contributed to improving the proliferation, migration, and invasion of LUAD cells in vitro, while knockdown of GPR37 can inhibit the malignant biological behaviors.	('upregulation', 'PosReg', (52, 64))	('proliferation', 'CPA', (103, 116))	('malignant biological behaviors', 'CPA', (207, 237))	('migration', 'CPA', (118, 127))	('invasion of LUAD cells', 'CPA', (133, 155))	('GPR37', 'Gene', '2861', (68, 73))	('improving', 'PosReg', (89, 98))	('GPR37', 'Gene', (185, 190))	('GPR37', 'Gene', (68, 73))	('GPR37', 'Gene', '2861', (185, 190))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('inhibit', 'NegReg', (195, 202))	('LUAD', 'Phenotype', 'HP:0030078', (145, 149))	('knockdown', 'Var', (172, 181))
59329	33364431	In addition, Kaplan-Meier survival analysis indicated that high GPR37 expression indicated the shorter survival time in LUAD patients (Figure 1e).	('GPR37', 'Gene', '2861', (64, 69))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('high', 'Var', (59, 63))	('expression', 'MPA', (70, 80))	('survival time', 'CPA', (103, 116))	('GPR37', 'Gene', (64, 69))	('LUAD', 'Phenotype', 'HP:0030078', (120, 124))	('shorter', 'NegReg', (95, 102))	('patients', 'Species', '9606', (125, 133))
59333	33364431	In order to explore the function of GPR37 in LUAD, we first transfected A549 cells with si-GPR37#1, si-GPR37#2, and si-con and transfected LTEP-a-2 cells with pcDNA3.1-GPR37 and vector.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('GPR37', 'Gene', '2861', (168, 173))	('GPR37', 'Gene', '2861', (103, 108))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('GPR37', 'Gene', (91, 96))	('GPR37', 'Gene', (36, 41))	('si-con', 'Var', (116, 122))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('GPR37', 'Gene', '2861', (36, 41))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('a-2', 'CellLine', 'CVCL:0470', (144, 147))	('GPR37', 'Gene', '2861', (91, 96))	('GPR37', 'Gene', (168, 173))	('GPR37', 'Gene', (103, 108))	('si', 'Chemical', 'MESH:D012825', (100, 102))
59353	33364431	These findings demonstrated that TGF-beta/Smad pathway mediated the modulation of GPR37 on the malignant phenotype of LUAD cells in vitro.	('modulation', 'Var', (68, 78))	('malignant phenotype of LUAD cells', 'CPA', (95, 128))	('GPR37', 'Gene', (82, 87))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('GPR37', 'Gene', '2861', (82, 87))	('TGF-beta', 'Gene', (33, 41))	('TGF-beta', 'Gene', '7039', (33, 41))
59362	33364431	found that GPR37 was upregulated in LUAD patients with TP53/EGFR co-mutation, while TP53/EGFR co-mutation made LUAD patients resistant to chemotherapy, resulting in poor prognosis.	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('upregulated', 'PosReg', (21, 32))	('co-mutation', 'Var', (65, 76))	('TP53', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (55, 59))	('patients', 'Species', '9606', (116, 124))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('EGFR', 'Gene', '1956', (60, 64))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('EGFR', 'Gene', (89, 93))	('GPR37', 'Gene', '2861', (11, 16))	('TP53', 'Gene', '7157', (84, 88))	('patients', 'Species', '9606', (41, 49))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('EGFR', 'Gene', (60, 64))	('TP53', 'Gene', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('si', 'Chemical', 'MESH:D012825', (176, 178))	('EGFR', 'Gene', '1956', (89, 93))	('GPR37', 'Gene', (11, 16))
59366	33364431	With more evidences showing that TGF-beta plays an important role in the development of tumor, inhibiting TGF-beta signaling has become a new thinking in cancer treatment.	('TGF-beta', 'Gene', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TGF-beta', 'Gene', '7039', (106, 114))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('TGF-beta', 'Gene', (33, 41))	('inhibiting', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (88, 93))	('TGF-beta', 'Gene', '7039', (33, 41))
59481	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))
59540	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.,).	('DNA repair', 'biological_process', 'GO:0006281', ('196', '206'))	('proteolysis', 'biological_process', 'GO:0006508', ('208', '219'))	('kinase-related signaling pathways', 'Pathway', (225, 258))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cell cycle', 'biological_process', 'GO:0007049', ('168', '178'))	('cell cycle', 'CPA', (168, 178))	('to', 'Gene', '6999', (98, 100))	('proteolysis', 'CPA', (208, 219))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('deregulation', 'Var', (180, 192))	('to', 'Gene', '6999', (123, 125))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('DNA repair', 'Protein', (196, 206))
59604	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))
59665	33235138	To investigate the role of CD74 in BPD, GSEA was conducted to analyze the enrichment of datasets between high-expression CD74 (defined as the mRNA level higher than the median one) and low-expression CD74 (defined as the mRNA level lower than the median one) groups.	('CD74', 'Gene', (121, 125))	('CD74', 'Gene', (200, 204))	('GSEA', 'Chemical', '-', (40, 44))	('high-expression', 'Var', (105, 120))
59671	33235138	CD74 was the highest expressed in BPD patients with a P-value < .001, followed by HLA-DPB1 (P = .017), HLA-DOB (P = .023), HLA-DMA (P = .025), HLA-DRA (P = .038), and HLA-DQA1 (P = .038).	('HLA-DPB1', 'Gene', (82, 90))	('HLA-DRA', 'Gene', '3122', (143, 150))	('HLA', 'Gene', '3117', (123, 126))	('HLA-DRA', 'Gene', (143, 150))	('HLA', 'Gene', (143, 146))	('HLA', 'Gene', (167, 170))	('patients', 'Species', '9606', (38, 46))	('DMA', 'Chemical', 'MESH:C405765', (127, 130))	('HLA', 'Gene', (103, 106))	('HLA', 'Gene', '3117', (82, 85))	('HLA-DQA1', 'Gene', (167, 175))	('HLA-DOB', 'Gene', (103, 110))	('CD74', 'Var', (0, 4))	('HLA', 'Gene', '3117', (167, 170))	('HLA', 'Gene', '3117', (143, 146))	('HLA', 'Gene', (123, 126))	('HLA', 'Gene', '3117', (103, 106))	('HLA-DOB', 'Gene', '3112', (103, 110))	('HLA-DPB1', 'Gene', '3115', (82, 90))	('HLA-DQA1', 'Gene', '3117', (167, 175))	('HLA', 'Gene', (82, 85))
59675	33235138	To better understand the function of CD74 and signaling pathways activated in BPD, we applied GSEA comparing the datasets of low-expression and high-expression of CD74.	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('GSEA', 'Chemical', '-', (94, 98))	('high-expression', 'Var', (144, 159))	('CD74', 'Gene', (163, 167))	('low-expression', 'NegReg', (125, 139))
59676	33235138	The results showed the gene sets associated with lupus erythematosus, viral myocarditis, immune network for IgA production, graft versus host disease, cell adhesion molecules, B cell receptor signaling pathway, auto immune thyroid disease, asthma, and antigen processing and presentation pathway were differentially enriched with the phenotype of high-expression CD74 (Fig.	('lupus erythematosus', 'Disease', 'MESH:D008180', (49, 68))	('lupus erythematosus', 'Phenotype', 'HP:0002725', (49, 68))	('thyroid disease', 'Phenotype', 'HP:0000820', (223, 238))	('IgA', 'Gene', (108, 111))	('viral myocarditis', 'Disease', (70, 87))	('B cell receptor signaling pathway', 'biological_process', 'GO:0050853', ('176', '209'))	('auto immune thyroid disease', 'Disease', 'MESH:C538437', (211, 238))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('252', '287'))	('viral myocarditis', 'Disease', 'None', (70, 87))	('graft versus host disease', 'Disease', 'MESH:D006086', (124, 149))	('asthma', 'Disease', 'MESH:D001249', (240, 246))	('asthma', 'Phenotype', 'HP:0002099', (240, 246))	('graft versus host disease', 'Disease', (124, 149))	('auto immune thyroid disease', 'Disease', (211, 238))	('B cell', 'Pathway', (176, 182))	('asthma', 'Disease', (240, 246))	('cell adhesion', 'biological_process', 'GO:0007155', ('151', '164'))	('myocarditis', 'Phenotype', 'HP:0012819', (76, 87))	('lupus erythematosus', 'Disease', (49, 68))	('IgA', 'Gene', '973', (108, 111))	('high-expression', 'Var', (347, 362))
59713	33142748	Overexpression of SFs CELF2 and SRSF5 was associated with better OS.	('SRSF5', 'Gene', '6430', (32, 37))	('CELF2', 'Gene', (22, 27))	('CELF2', 'Gene', '10659', (22, 27))	('better OS', 'Disease', (58, 67))	('Overexpression', 'Var', (0, 14))	('SRSF5', 'Gene', (32, 37))
59717	33142748	Genetic susceptibility is also a lung cancer risk factor.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('Genetic susceptibility', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('lung cancer', 'Disease', (33, 44))
59719	33142748	Numerous lung cancer genomic studies have shown hot gene mutations, such as in the EGFR, TP53, KRAS and BRAF genes, and these driver genes have shown ethnic differences.	('KRAS', 'Gene', '3845', (95, 99))	('Numerous lung cancer', 'Disease', 'MESH:D008175', (0, 20))	('TP53', 'Gene', '7157', (89, 93))	('EGFR', 'Gene', '1956', (83, 87))	('TP53', 'Gene', (89, 93))	('Numerous lung cancer', 'Disease', (0, 20))	('EGFR', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (57, 66))	('BRAF', 'Gene', '673', (104, 108))	('hot', 'Gene', '137872', (48, 51))	('KRAS', 'Gene', (95, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('BRAF', 'Gene', (104, 108))	('hot', 'Gene', (48, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
59722	33142748	More than 95% of human genes undergo AS in physiological processes, and aberrant RNA splicing may play an important role in driving cancer development and progression by influencing the metabolism, apoptosis, cell cycle control, invasion, metastasis and angiogenesis of cancer cells and their microenvironment.	('apoptosis', 'CPA', (198, 207))	('angiogenesis', 'biological_process', 'GO:0001525', ('254', '266'))	('metastasis', 'CPA', (239, 249))	('driving', 'PosReg', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('human', 'Species', '9606', (17, 22))	('cancer', 'Disease', (270, 276))	('influencing', 'Reg', (170, 181))	('metabolism', 'biological_process', 'GO:0008152', ('186', '196'))	('angiogenesis', 'CPA', (254, 266))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))	('aberrant RNA splicing', 'Var', (72, 93))	('RNA splicing', 'biological_process', 'GO:0008380', ('81', '93'))	('cell cycle control', 'biological_process', 'GO:1901987', ('209', '227'))	('cancer', 'Disease', (132, 138))	('invasion', 'CPA', (229, 237))	('cell cycle control', 'CPA', (209, 227))	('metabolism', 'CPA', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('198', '207'))	('apoptosis', 'biological_process', 'GO:0006915', ('198', '207'))
59725	33142748	Splicing factors (SFs) are regulators of AS events, and changes in the expression and/or mutation of SFs can alter the splicing of oncogenes and tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('splicing', 'MPA', (119, 127))	('SFs', 'Gene', (101, 104))	('oncogenes', 'Protein', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('alter', 'Reg', (109, 114))	('mutation', 'Var', (89, 97))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('tumor', 'Disease', (145, 150))	('splicing', 'biological_process', 'GO:0045292', ('119', '127'))	('changes', 'Var', (56, 63))
59726	33142748	Thus, aberrant AS and SFs are considered to be defining hallmarks of cancer.	('aberrant', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('SFs', 'Disease', (22, 25))
59756	33142748	From our AS study of ABHD14A, we showed that ENST00000637025 disrupted the function of ABHD14A, which is similar to the downregulation of ABHD14A and resulted in poor prognosis.	('ENST00000637025', 'Var', (45, 60))	('function', 'MPA', (75, 83))	('ABHD14A', 'Gene', '25864', (21, 28))	('disrupted', 'NegReg', (61, 70))	('ABHD14A', 'Gene', (21, 28))	('ABHD14A', 'Gene', '25864', (138, 145))	('ABHD14A', 'Gene', '25864', (87, 94))	('ABHD14A', 'Gene', (87, 94))	('ABHD14A', 'Gene', (138, 145))
59757	33142748	The sequence reads of splicing isoforms of ABHD14A (ENST00000637025 and ENST00000635937) are shown in Figure S2.	('ABHD14A', 'Gene', '25864', (43, 50))	('ENST00000635937', 'Var', (72, 87))	('ABHD14A', 'Gene', (43, 50))	('ENST00000637025', 'Var', (52, 67))	('splicing', 'biological_process', 'GO:0045292', ('22', '30'))
59779	33142748	We suggest that this was the result of simultaneous interactions between the splicing enhancers and silencers on the same gene and at the same or different sites.	('silencers', 'Disease', (100, 109))	('silencers', 'Disease', 'None', (100, 109))	('interactions', 'Interaction', (52, 64))	('splicing', 'Var', (77, 85))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))
59780	33142748	In our cases, there was SRSF5 or HNRNPC mutation in only one person.	('mutation', 'Var', (40, 48))	('HNRNPC', 'Gene', (33, 39))	('HNRNPC', 'Gene', '3183', (33, 39))	('SRSF5', 'Gene', (24, 29))	('SRSF5', 'Gene', '6430', (24, 29))
59842	33221688	showed that radiomics has been widely used to identify the specific driver mutational status of non-small cell lung cancer, predictors of treatment response and prognosis, and the immune phenotype of tumors.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('mutational', 'Var', (75, 85))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
59884	32887739	As shown in figure 1E, tumour uptake increased in patients with injected In-111-neutrophils with a median of 0.0038 mL/min/mL (IQR; 0.0231-0.0531) compared with a median of 0.0009 mL/min/mL for In-111-transferrin (IQR; 0.0004-0.0013).	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('uptake', 'biological_process', 'GO:0098739', ('30', '36'))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('patients', 'Species', '9606', (50, 58))	('transferrin', 'Gene', '7018', (201, 212))	('transferrin', 'Gene', (201, 212))	('tumour', 'Disease', (23, 29))	('In-111-neutrophils', 'Var', (73, 91))	('increased', 'PosReg', (37, 46))	('uptake', 'biological_process', 'GO:0098657', ('30', '36'))
59885	32887739	SPECT-CT with attenuation correction (figure 1F) showed an overall increase in In-111-neutrophil clearance into tumour with a median of 0.0103 mL/min/mL (IQR; 0.0021-0.0387) compared with a median of 0.0037 mL/min/mL for In-111-transferrin clearance (IQR; 0.0008-0.0066).	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('transferrin', 'Gene', '7018', (228, 239))	('0.0103 mL/min/mL', 'Var', (136, 152))	('increase', 'PosReg', (67, 75))	('transferrin', 'Gene', (228, 239))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('neutrophil clearance', 'biological_process', 'GO:0097350', ('86', '106'))
59886	32887739	Of note, SPECT-CT without attenuation correction increased In-111-neutrophil clearance compared with In-111-transferrin clearance in all four patients, but only in two patients following attenuation correction.	('SPECT-CT', 'Var', (9, 17))	('transferrin', 'Gene', '7018', (108, 119))	('neutrophil clearance', 'biological_process', 'GO:0097350', ('66', '86'))	('increased', 'PosReg', (49, 58))	('transferrin', 'Gene', (108, 119))	('In-111-neutrophil clearance', 'MPA', (59, 86))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (142, 150))
59902	32887739	Given the broadly pro-tumourigenic role of neutrophils, modulation of neutrophil migration into tumours is an attractive therapeutic approach in NSCLC.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('modulation', 'Var', (56, 66))	('tumour', 'Disease', (22, 28))	('neutrophil migration', 'biological_process', 'GO:1990266', ('70', '90'))	('NSCLC', 'Disease', (145, 150))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumours', 'Disease', (96, 103))	('tumour', 'Disease', (96, 102))
59903	32887739	The CXCR2 pathway has a major role in the control of neutrophil recruitment into tumours, and antagonists of the CXCR2 receptor have reduced tumour growth in murine studies.	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('antagonists', 'Var', (94, 105))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumours', 'Disease', (81, 88))	('tumour growth', 'Disease', (141, 154))	('murine', 'Species', '10090', (158, 164))	('tumour growth', 'Disease', 'MESH:D006130', (141, 154))	('CXCR2', 'Pathway', (4, 9))	('reduced', 'NegReg', (133, 140))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
59917	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.	('EGFR', 'Gene', '1956', (111, 115))	('death', 'Disease', (223, 228))	('epidermal growth factor receptor gene', 'Gene', (72, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('decreased', 'NegReg', (24, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('epidermal growth factor receptor gene', 'Gene', '1956', (72, 109))	('death', 'Disease', 'MESH:D003643', (42, 47))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (117, 136))	('stage IV disease', 'Disease', 'MESH:D058625', (252, 268))	('death', 'Disease', 'MESH:D003643', (223, 228))	('EGFR', 'Gene', (111, 115))	('ALK', 'Gene', '238', (150, 153))	('stage IV disease', 'Disease', (252, 268))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (117, 136))	('ALK', 'Gene', (150, 153))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('72', '95'))	('mutations/rearrangements', 'Var', (155, 179))	('death', 'Disease', (42, 47))	('anaplastic lymphoma', 'Disease', (117, 136))
59919	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', 'molecular_function', 'GO:0005006', ('167', '171'))	('EGFR', 'Gene', '1956', (167, 171))	('ALK', 'Gene', '238', (172, 175))
59931	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))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('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))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('72', '95'))	('SCLC', 'Phenotype', 'HP:0030357', (253, 257))
59966	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))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('OS', 'Chemical', '-', (116, 118))	('ALK', 'Gene', '238', (29, 32))	('mutational/rearrangement', 'Var', (33, 57))	('brain metastases', 'Disease', 'MESH:D009362', (96, 112))
59974	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))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('patients', 'Species', '9606', (18, 26))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('NSQ', 'Chemical', '-', (32, 35))
59975	32912174	Among the 617 patients with NSQ tested for EGFR mutations, 124 (20.1%) had an EGFR mutation (Additional file 1: Table S3).	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('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', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
59983	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.	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('231', '235'))	('ALK', 'Gene', '238', (51, 54))	('EGFR', 'Gene', (145, 149))	('ALK', 'Gene', (51, 54))	('OS', 'Chemical', '-', (95, 97))	('EGFR', 'Gene', (231, 235))	('ALK', 'Gene', '238', (240, 243))	('SQ', 'Phenotype', 'HP:0002860', (40, 42))	('ALK', 'Gene', '238', (153, 156))	('ALK', 'Gene', (240, 243))	('patients', 'Species', '9606', (25, 33))	('EGFR', 'Gene', (46, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('NSQ', 'Chemical', '-', (39, 42))	('ALK', 'Gene', (153, 156))	('mutations/rearrangements', 'Var', (157, 181))	('EGFR', 'Gene', '1956', (145, 149))	('EGFR', 'Gene', '1956', (231, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))
59985	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', (214, 217))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('reduced', 'NegReg', (50, 57))	('patients', 'Species', '9606', (69, 77))	('death', 'Disease', 'MESH:D003643', (12, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))	('SQ', 'Phenotype', 'HP:0002860', (144, 146))	('EGFR', 'Gene', (152, 156))	('NSQ', 'Chemical', '-', (143, 146))	('EGFR', 'Gene', (205, 209))	('ALK', 'Gene', '238', (160, 163))	('NSQ', 'Disease', (143, 146))	('ALK', 'Gene', (160, 163))	('death', 'Disease', (12, 17))	('mutations/rearrangements', 'Var', (164, 188))	('EGFR', 'Gene', '1956', (152, 156))	('patients', 'Species', '9606', (127, 135))	('ALK', 'Gene', '238', (214, 217))
59994	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', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'Gene', '1956', (72, 76))	('SACT', 'Chemical', '-', (4, 8))	('NSQ', 'Chemical', '-', (48, 51))	('EGFR', 'Gene', (72, 76))	('ALK', 'Gene', '238', (80, 83))	('mutational/rearrangement', 'Var', (84, 108))	('patients', 'Species', '9606', (34, 42))	('ALK', 'Gene', (80, 83))	('NSQ', 'Disease', (48, 51))
59995	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))	('erlotinib', 'Chemical', 'MESH:D000069347', (138, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (265, 274))	('EGFR', 'Gene', '1956', (27, 31))	('patients', 'Species', '9606', (13, 21))	('carboplatin', 'Chemical', 'MESH:D016190', (278, 289))	('gefitinib', 'Chemical', 'MESH:D000077156', (173, 182))	('ALK', 'Gene', (35, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('mutations/rearrangements', 'Var', (39, 63))	('patients', 'Species', '9606', (111, 119))
60005	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))	('patients', 'Species', '9606', (16, 24))	('mutations/rearrangements', 'Var', (115, 139))	('ALK', 'Gene', '238', (171, 174))	('EGFR', 'Gene', '1956', (149, 153))	('ALK', 'Gene', (171, 174))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('patients', 'Species', '9606', (227, 235))	('SACT', 'Chemical', '-', (3, 7))	('EGFR', 'Gene', (103, 107))	('SQ', 'Phenotype', 'HP:0002860', (31, 33))	('NSQ', 'Chemical', '-', (30, 33))	('ALK', 'Gene', '238', (111, 114))	('NSQ', 'Disease', (30, 33))	('patients', 'Species', '9606', (89, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('EGFR', 'Gene', (149, 153))	('ALK', 'Gene', (111, 114))
60007	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))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('ALK', 'Gene', (41, 44))	('NSQ', 'Chemical', '-', (15, 18))	('EGFR', 'Gene', (33, 37))	('ALK', 'Gene', '238', (41, 44))	('SACT', 'Chemical', '-', (153, 157))	('patients', 'Species', '9606', (166, 174))
60016	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', (26, 30))	('mutations', 'Var', (31, 40))	('IPO-Porto', 'Chemical', '-', (3, 12))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
60018	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))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('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))
60019	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))
60021	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))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('mutations/rearrangements', 'Var', (70, 94))	('IPO-Porto', 'Chemical', '-', (19, 28))	('SQ', 'Phenotype', 'HP:0002860', (35, 37))	('patients', 'Species', '9606', (7, 15))
60022	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', 'molecular_function', 'GO:0005006', ('165', '169'))	('EGFR', 'Gene', '1956', (165, 169))
60027	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.	('ALK', 'Gene', '238', (24, 27))	('IPO-Porto', 'Chemical', '-', (123, 132))	('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', 'molecular_function', 'GO:0005006', ('16', '20'))	('EGFR', 'Gene', (16, 20))
60028	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))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('mutations/rearrangements', 'Var', (125, 149))	('ALK', 'Gene', (121, 124))
60037	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))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('ALK', 'Gene', (118, 121))
60040	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.	('patients', 'Species', '9606', (7, 15))	('NSQ', 'Disease', (128, 131))	('ALK', 'Gene', '238', (144, 147))	('TKI', 'Disease', (176, 179))	('ALK', 'Gene', (144, 147))	('mutations/rearrangements', 'Var', (148, 172))	('NSQ', 'Chemical', '-', (128, 131))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('SQ', 'Phenotype', 'HP:0002860', (129, 131))	('patients', 'Species', '9606', (114, 122))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('EGFR', 'Gene', (136, 140))	('SACT', 'Chemical', '-', (43, 47))
60046	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))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('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', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('ALK', 'Gene', (191, 194))	('ALK', 'Gene', '238', (122, 125))
60047	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))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('ALK', 'Gene', (181, 184))	('EGFR', 'Gene', (173, 177))	('ALK', 'Gene', '238', (181, 184))
60048	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))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('ALK', 'Gene', (82, 85))	('mutations/rearrangements', 'Var', (86, 110))	('ALK', 'Gene', (178, 181))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
60050	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))
60073	32093717	These mucinous adenocarcinomas and the mucinous clusters in CPAM commonly harbor a specific KRAS mutation.	('mucinous adenocarcinomas', 'Disease', (6, 30))	('harbor', 'Reg', (74, 80))	('KRAS', 'Gene', (92, 96))	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (6, 30))	('mutation', 'Var', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('KRAS', 'Gene', '3845', (92, 96))	('CPAM', 'Disease', (60, 64))	('CPAM', 'Disease', 'MESH:D056151', (60, 64))
60074	32093717	we present a case of a 6-weeks-old girl with CPAM type 1 where evaluation after lobectomy revealed a highly unusual complex non-mucinous papillary architecture in all cystic parts, in which both mucinous clusters and non-mucinous papillary areas harbored the known KRAS mutation.	('harbored', 'Reg', (246, 254))	('mucinous papillary', 'Phenotype', 'HP:0007482', (128, 146))	('mucinous papillary', 'Phenotype', 'HP:0007482', (221, 239))	('CPAM', 'Disease', (45, 49))	('girl', 'Species', '9606', (35, 39))	('mutation', 'Var', (270, 278))	('KRAS', 'Gene', (265, 269))	('KRAS', 'Gene', '3845', (265, 269))	('CPAM', 'Disease', 'MESH:D056151', (45, 49))	('mucinous papillary areas', 'Phenotype', 'HP:0007482', (221, 245))
60075	32093717	we found that a KRAS mutation thought to be premalignant in mucinous clusters only, was also present in the other cyst lining epithelial cells of this unusual non-mucinous papillary variant of CPAM type 1, warranting clinical follow-up because of uncertain malignant potential.	('mutation', 'Var', (21, 29))	('CPAM', 'Disease', (193, 197))	('KRAS', 'Gene', (16, 20))	('CPAM', 'Disease', 'MESH:D056151', (193, 197))	('KRAS', 'Gene', '3845', (16, 20))	('mucinous papillary', 'Phenotype', 'HP:0007482', (163, 181))
60081	32093717	We present a case of CPAM type 1 with a highly unusual complex non-mucinous papillary architecture, in which both mucinous clusters and non-mucinous papillary areas harbored the known KRAS mutation.	('mucinous papillary areas', 'Phenotype', 'HP:0007482', (140, 164))	('CPAM', 'Disease', (21, 25))	('KRAS', 'Gene', (184, 188))	('mucinous papillary', 'Phenotype', 'HP:0007482', (67, 85))	('CPAM', 'Disease', 'MESH:D056151', (21, 25))	('KRAS', 'Gene', '3845', (184, 188))	('harbored', 'Reg', (165, 173))	('mucinous papillary', 'Phenotype', 'HP:0007482', (140, 158))	('mutation', 'Var', (189, 197))
60094	32093717	Library preparation was performed using a custom Ampliseq panel, which included the hotspots of KRAS (codon 12, 13, 61, 117 and 146).	('KRAS', 'Gene', '3845', (96, 100))	('KRAS', 'Gene', (96, 100))	('codon 12', 'Var', (102, 110))
60095	32093717	Sequencing showed a KRAS: c.35G > A p.(G12D) mutation in the mucinous areas (20% neoplastic cells, variant allele frequency 32%) as well as in the papillary areas (80% neoplastic cells, variant allele frequency 20%).	('KRAS', 'Gene', '3845', (20, 24))	('p.(G12D', 'Var', (36, 43))	('c.35G > A', 'Mutation', 'rs121913529', (26, 35))	('KRAS', 'Gene', (20, 24))	('p.(G12D)', 'Mutation', 'rs121913529', (36, 44))
60110	32093717	In mucinous adenocarcinoma a specific KRAS mutation is found: KRAS c.35G > A, p.(G12D).	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (38, 42))	('p.(G12D)', 'Mutation', 'rs121913529', (78, 86))	('KRAS', 'Gene', '3845', (62, 66))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (3, 26))	('p.(G12D', 'Var', (78, 85))	('mucinous adenocarcinoma', 'Disease', (3, 26))	('c.35G > A', 'Mutation', 'rs121913529', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('KRAS', 'Gene', (38, 42))
60111	32093717	This KRAS mutation has also been found in the mucinous clusters in CPAM, possibly being premalignant precursors, and was also present our case.	('CPAM', 'Disease', 'MESH:D056151', (67, 71))	('KRAS', 'Gene', (5, 9))	('mutation', 'Var', (10, 18))	('KRAS', 'Gene', '3845', (5, 9))	('CPAM', 'Disease', (67, 71))
60115	32093717	Importantly, we found that a KRAS mutation thought to be premalignant in mucinous clusters only, was also present in the other cyst lining epithelial cells of this unusual non-mucinous papillary variant of CPAM type 1, warranting clinical follow-up because of uncertain malignant potential.	('CPAM', 'Disease', (206, 210))	('KRAS', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('CPAM', 'Disease', 'MESH:D056151', (206, 210))	('KRAS', 'Gene', '3845', (29, 33))	('mucinous papillary', 'Phenotype', 'HP:0007482', (176, 194))
60135	32194659	Overexpressed BGN has been reported to be associated with the aggressive growth and metastasis of tumors, and with a worse prognosis for patients with gastric cancer and pancreatic adenocarcinoma.	('Overexpressed', 'Var', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('aggressive growth', 'CPA', (62, 79))	('associated', 'Reg', (42, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('metastasis of tumors', 'Disease', (84, 104))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BGN', 'Gene', '633', (14, 17))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (170, 195))	('pancreatic adenocarcinoma', 'Disease', (170, 195))	('gastric cancer', 'Disease', (151, 165))	('metastasis of tumors', 'Disease', 'MESH:D009362', (84, 104))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (170, 195))	('BGN', 'Gene', (14, 17))
60147	32194659	KM plotter also contain the gene chip data [from GEO (breast cancer: GSE12276, GSE16391, GSE12093, GSE11121, GSE9195, GSE7390, GSE6532, GSE5327, GSE4922, GSE3494, GSE2990, GSE2034, GSE1456; ovarian cancer: GSE14764, GSE15622, GSE19829, GSE3149, GSE9891, GSE18520, GSE26712; lung cancer: GSE4573, GSE14814, GSE8894, GSE19188, GSE3141, GSE31210, GSE29013, GSE37745; gastric cancer: GSE44740, GSE51725, GSE13911, GSE43346, and GSE3526)] for breast cancer (BC), lung cancer (LC), gastric cancer (GC) and ovarian cancer (OC).	('GC', 'Disease', 'MESH:D013274', (492, 494))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('gastric cancer', 'Disease', (476, 490))	('gastric cancer', 'Disease', (364, 378))	('lung cancer', 'Disease', (458, 469))	('BC', 'Disease', 'MESH:D001943', (453, 455))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('GSE13911', 'Var', (400, 408))	('breast cancer', 'Disease', (54, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (476, 490))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('OC', 'Disease', 'MESH:D010051', (516, 518))	('LC', 'Disease', 'MESH:D008175', (471, 473))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('GSE44740', 'Var', (380, 388))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('gastric cancer', 'Disease', 'MESH:D013274', (364, 378))	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('lung cancer', 'Disease', (274, 285))	('ovarian cancer', 'Disease', 'MESH:D010051', (500, 514))	('GSE43346', 'Var', (410, 418))	('lung cancer', 'Disease', 'MESH:D008175', (458, 469))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('gastric cancer', 'Phenotype', 'HP:0012126', (476, 490))	('lung cancer', 'Phenotype', 'HP:0100526', (458, 469))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (438, 451))	('GSE51725', 'Var', (390, 398))	('ovarian cancer', 'Disease', (190, 204))	('gastric cancer', 'Phenotype', 'HP:0012126', (364, 378))	('ovarian cancer', 'Disease', (500, 514))	('breast cancer', 'Disease', 'MESH:D001943', (438, 451))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('lung cancer', 'Disease', 'MESH:D008175', (274, 285))	('breast cancer', 'Disease', (438, 451))	('ovarian cancer', 'Phenotype', 'HP:0100615', (500, 514))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
60185	32194659	Therefore, high BGN mRNA expression may potentially be associated with the prognosis in patients with BLC, LSCC, and OSC, as the present analyses provided RNA-seq analysis results (P<0.05) without microarray analysis confirmation (Table II).	('BLC', 'Gene', '10563', (102, 105))	('OSC', 'Disease', (117, 120))	('BGN', 'Gene', (16, 19))	('patients', 'Species', '9606', (88, 96))	('associated', 'Reg', (55, 65))	('BLC', 'Gene', (102, 105))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('high', 'Var', (11, 15))	('LSCC', 'Disease', (107, 111))	('OSC', 'molecular_function', 'GO:0000250', ('117', '120'))	('BGN', 'Gene', '633', (16, 19))
60187	32194659	2, high expression of BGN was significantly associated with shorter OS time in patients with GC [HR=1.9 (1.56-2.32), P=1.3x10-10 in microarry analysis; HR=1.59 (1.13-2.24), P=6.8x10-3 in RNA-seq analysis] and OC [HR=1.28 (1.11-1.47), P=4.4x10-4 in microarry analysis; HR=1.45 (1.09-1.93), P=9.3x10-3 in RNA-seq analysis].	('RNA', 'cellular_component', 'GO:0005562', ('303', '306'))	('OC', 'Disease', 'MESH:D010051', (209, 211))	('RNA', 'cellular_component', 'GO:0005562', ('187', '190'))	('high expression', 'Var', (3, 18))	('GC', 'Disease', 'MESH:D013274', (93, 95))	('BGN', 'Gene', (22, 25))	('OS time', 'CPA', (68, 75))	('patients', 'Species', '9606', (79, 87))	('shorter', 'NegReg', (60, 67))	('BGN', 'Gene', '633', (22, 25))
60188	32194659	In summary, high BGN mRNA expression in gastric cancer and ovarian cancer was significantly associated with poor overall survival.	('high', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('BGN', 'Gene', '633', (17, 20))	('gastric cancer', 'Disease', (40, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ovarian cancer', 'Disease', 'MESH:D010051', (59, 73))	('BGN', 'Gene', (17, 20))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('associated', 'Reg', (92, 102))	('ovarian cancer', 'Disease', (59, 73))
60189	32194659	High BGN mRNA expression was indicated to be associated with poor clinical outcome in the prognosis of patients with bladder cancer, lung squamous cell carcinoma, and ovarian serous cystadenocarcinoma.	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (167, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('BGN', 'Gene', '633', (5, 8))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 161))	('High', 'Var', (0, 4))	('lung squamous cell carcinoma', 'Disease', (133, 161))	('ovarian serous cystadenocarcinoma', 'Disease', (167, 200))	('clinical', 'Species', '191496', (66, 74))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (167, 200))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('BGN', 'Gene', (5, 8))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('patients', 'Species', '9606', (103, 111))	('bladder cancer', 'Disease', (117, 131))
60198	32194659	In addition, high expression of BGN in patients with solid cancer is significantly associated with poor outcome.	('patients', 'Species', '9606', (39, 47))	('BGN', 'Gene', (32, 35))	('high', 'Var', (13, 17))	('BGN', 'Gene', '633', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('associated', 'Reg', (83, 93))	('solid cancer', 'Disease', (53, 65))	('solid cancer', 'Disease', 'MESH:D009369', (53, 65))
60201	32194659	In addition, the current prognosis analyses revealed that high tissue BGN expression predicts worse survival in GC and OC.	('BGN', 'Gene', (70, 73))	('OC', 'Disease', 'MESH:D010051', (119, 121))	('GC', 'Disease', 'MESH:D013274', (112, 114))	('worse', 'NegReg', (94, 99))	('BGN', 'Gene', '633', (70, 73))	('high tissue', 'Var', (58, 69))
60202	32194659	High BGN mRNA expression was associated with poor overall survival in patients with BLC, LSCC, and OSC.	('patients', 'Species', '9606', (70, 78))	('BGN', 'Gene', '633', (5, 8))	('High', 'Var', (0, 4))	('overall survival', 'MPA', (50, 66))	('LSCC', 'Disease', (89, 93))	('BLC', 'Gene', (84, 87))	('BGN', 'Gene', (5, 8))	('poor', 'NegReg', (45, 49))	('OSC', 'molecular_function', 'GO:0000250', ('99', '102'))	('OSC', 'Disease', (99, 102))	('BLC', 'Gene', '10563', (84, 87))
60233	32014012	MiRNAs, which are approximately 20 to 24 nucleotides in length, are a well-known group of small ncRNAs that epigenetically or posttranscriptionally regulate the expression of target mRNAs by imperfectly base pairing with the mRNA 3'-untranslated region (3'-UTR) of target mRNAs.	('ncRNA', 'Gene', '220202', (96, 101))	('base pairing', 'molecular_function', 'GO:0003676', ('203', '215'))	('expression', 'MPA', (161, 171))	('imperfectly base pairing', 'Var', (191, 215))	('ncRNA', 'Gene', (96, 101))	('regulate', 'Reg', (148, 156))
60270	32014012	Moreover, miR-204 is inhibited by HIF-1alpha to upregulate VASP at the posttranscriptional level, providing a typical instance in which HIF-1alpha and suppressed miRNAs synergistically regulate the same gene in different ways.	('VASP', 'Gene', (59, 63))	('miR-204', 'Gene', '406987', (10, 17))	('VASP', 'Gene', '7408', (59, 63))	('miR-204', 'Gene', (10, 17))	('miR', 'Gene', '220972', (10, 13))	('regulate', 'Reg', (185, 193))	('miR', 'Gene', (10, 13))	('upregulate', 'PosReg', (48, 58))	('HIF-1alpha', 'Var', (136, 146))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
60291	32014012	CircDENND2A was predicted to be an HRC in glioma via bioinformatic analysis.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('CircDENND2A', 'Var', (0, 11))	('HRC', 'Gene', '3270', (35, 38))	('glioma', 'Disease', (42, 48))	('HRC', 'Gene', (35, 38))
60292	32014012	Hypoxia-induced overexpression of circDENND2A promotes the migration and invasion of glioma cells by sponging miR-625-5p.	('miR', 'Gene', (110, 113))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('circDENND2A', 'Var', (34, 45))	('Hypoxia', 'Disease', (0, 7))	('glioma', 'Disease', (85, 91))	('miR', 'Gene', '220972', (110, 113))	('promotes', 'PosReg', (46, 54))	('migration', 'CPA', (59, 68))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
60293	32014012	In addition, more HRCs, including circRNA_403658, circDENND4C, and circRNA_0000977, have been identified to participate in cancer progression by sponging corresponding miRNAs.	('participate', 'Reg', (108, 119))	('403658, circDENND4C', 'Chemical', 'MESH:C060809', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HRC', 'Gene', (18, 21))	('circRNA_403658', 'Var', (34, 48))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('HRC', 'Gene', '3270', (18, 21))	('circRNA_0000977', 'Var', (67, 82))
60310	32014012	This mechanism mainly involves three kinds of RNAs, including mRNAs, pseudogene transcripts and lncRNAs, but circRNAs have followed lncRNAs in becoming a novel hotspot of research on the ceRNA family.	('ncRNA', 'Gene', '220202', (97, 102))	('ncRNA', 'Gene', (133, 138))	('pseudogene transcripts', 'Var', (69, 91))	('ncRNA', 'Gene', '220202', (133, 138))	('ncRNA', 'Gene', (97, 102))
60312	32014012	In addition, in hepatocellular carcinoma, circRNA_0046600 could upregulate HIF-1alpha by sponging miR-640 to promote cancer progression.	('miR-640', 'Gene', '693225', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('promote', 'PosReg', (109, 116))	('miR-640', 'Gene', (98, 105))	('HIF-1alpha', 'Protein', (75, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('upregulate', 'PosReg', (64, 74))	('hepatocellular carcinoma', 'Disease', (16, 40))	('circRNA_0046600', 'Var', (42, 57))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
60324	32014012	MiR-128, which is regulated by snail family zinc finger 1 (SNAIL) transcriptionally, in turn modulates the expression of ribosomal protein S6 kinase, polypeptide 1 (RPS6KB1), also known as p70S6K, and afterwards disrupts downstream HIF-1alpha at the translational level and consequently suppresses pyruvate kinase 2 (PKM2) expression to inhibit the growth and metabolism of prostate cancer cells, which expands the interplay between HIF-1alpha and miRNA at the translational level.	('metabolism of prostate cancer', 'Disease', (360, 389))	('metabolism of prostate cancer', 'Disease', 'MESH:D011471', (360, 389))	('PKM2', 'Gene', (317, 321))	('snail family zinc finger 1', 'Gene', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('modulates', 'Var', (93, 102))	('PKM2', 'Gene', '5315', (317, 321))	('metabolism', 'biological_process', 'GO:0008152', ('360', '370'))	('SNAIL', 'Gene', '6615', (59, 64))	('SNAIL', 'Gene', (59, 64))	('p70S6K', 'Gene', '6198', (189, 195))	('RPS6KB1', 'Gene', '6198', (165, 172))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('121', '138'))	('prostate cancer', 'Phenotype', 'HP:0012125', (374, 389))	('MiR-128', 'Gene', (0, 7))	('disrupts', 'NegReg', (212, 220))	('miR', 'Gene', '220972', (448, 451))	('suppresses', 'NegReg', (287, 297))	('pyruvate', 'Chemical', 'MESH:D011773', (298, 306))	('miR', 'Gene', (448, 451))	('snail family zinc finger 1', 'Gene', '6615', (31, 57))	('p70S6K', 'Gene', (189, 195))	('RPS6KB1', 'Gene', (165, 172))	('inhibit', 'NegReg', (337, 344))	('expression', 'MPA', (107, 117))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('expression', 'MPA', (323, 333))
60326	32014012	Enhanced phosphorylation at Ser235/236 of the 40S ribosomal protein S6 therefore boosts HIF-1alpha translation in the nickel-induced malignant transformation of human bronchial epithelial cells.	('human', 'Species', '9606', (161, 166))	('translation', 'biological_process', 'GO:0006412', ('99', '110'))	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('boosts', 'PosReg', (81, 87))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('Ser235/236', 'Var', (28, 38))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('50', '67'))	('Ser', 'Chemical', 'MESH:C530429', (28, 31))	('HIF-1alpha translation', 'MPA', (88, 110))	('nickel', 'Chemical', 'MESH:D009532', (118, 124))	('40S ribosomal protein S6', 'Gene', '6194', (46, 70))	('40S ribosomal protein S6', 'Gene', (46, 70))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))	('phosphorylation', 'MPA', (9, 24))	('Enhanced', 'PosReg', (0, 8))
60371	32014012	In human umbilical vein endothelial cells, there is a negative regulatory loop containing miR-439 and HIF-1alpha in which HIF-1alpha induces miR-439 to bind to and destabilize HIF-1alpha mRNA, hence reducing the activity of HIF-1alpha in turn.	('HIF-1alpha', 'Protein', (176, 186))	('bind', 'Interaction', (152, 156))	('human', 'Species', '9606', (3, 8))	('miR', 'Gene', '220972', (90, 93))	('reducing', 'NegReg', (199, 207))	('miR', 'Gene', (90, 93))	('destabilize', 'NegReg', (164, 175))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('HIF-1alpha', 'Var', (122, 132))	('activity', 'MPA', (212, 220))
60382	32014012	Not surprisingly, scholars have revealed that aberrant expression of lncRNA H19 and miR-215 in glioblastoma confers a poor prognosis for patients.	('miR-215', 'Gene', (84, 91))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('miR-215', 'Gene', '406997', (84, 91))	('H19', 'Gene', '283120', (76, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('patients', 'Species', '9606', (137, 145))	('H19', 'Gene', (76, 79))	('ncRNA', 'Gene', (70, 75))	('aberrant expression', 'Var', (46, 65))	('ncRNA', 'Gene', '220202', (70, 75))
60384	32014012	In addition, a strong correlation between high lncRNA EFNA3 expression and shorter metastasis-free survival was found in breast cancer patients, undoubtedly enriching the prognostic value of lncRNAs in this prevalent cancer.	('expression', 'MPA', (60, 70))	('patients', 'Species', '9606', (135, 143))	('EFNA3', 'Gene', '1944', (54, 59))	('shorter', 'NegReg', (75, 82))	('cancer', 'Disease', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('EFNA3', 'Gene', (54, 59))	('ncRNA', 'Gene', (192, 197))	('ncRNA', 'Gene', (48, 53))	('ncRNA', 'Gene', '220202', (192, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('ncRNA', 'Gene', '220202', (48, 53))	('metastasis-free survival', 'CPA', (83, 107))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Disease', (217, 223))	('breast cancer', 'Disease', (121, 134))	('high', 'Var', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
60391	32014012	found that the levels of specific biomarkers associated with drug resistance in clear cell renal cell carcinoma, such as HIFs, oncogenic miR-155 and miR-210, and VEGF, could be selectively downregulated by methylselenocysteine or seleno-L-methionine in a dose- and time-dependent manner, which conferred existing anticancer therapies with enhanced therapeutic efficacy and selectivity.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('VEGF', 'Gene', '7422', (162, 166))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (80, 111))	('methylselenocysteine', 'Chemical', 'MESH:C002979', (206, 226))	('VEGF', 'Gene', (162, 166))	('seleno-L-methionine', 'Var', (230, 249))	('clear cell renal cell carcinoma', 'Disease', (80, 111))	('levels', 'MPA', (15, 21))	('methylselenocysteine', 'Var', (206, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Disease', (317, 323))	('downregulated', 'NegReg', (189, 202))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (80, 111))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('drug resistance', 'biological_process', 'GO:0009315', ('61', '76'))	('miR-210', 'Gene', (149, 156))	('drug resistance', 'biological_process', 'GO:0042493', ('61', '76'))	('miR-155', 'Gene', (137, 144))	('miR-210', 'Gene', '406992', (149, 156))	('seleno-L-methionine', 'Chemical', 'MESH:C517785', (230, 249))	('drug resistance', 'Phenotype', 'HP:0020174', (61, 76))	('miR-155', 'Gene', '406947', (137, 144))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
60430	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.	('autophagy', 'biological_process', 'GO:0006914', ('77', '86'))	('metabolism', 'biological_process', 'GO:0008152', ('155', '165'))	('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))	('autophagy', 'biological_process', 'GO:0016236', ('77', '86'))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
60431	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))	('autophagy', 'biological_process', 'GO:0016236', ('100', '109'))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('lung tumors', 'Phenotype', 'HP:0100526', (14, 25))	('Brafv600E', 'Var', (40, 49))	('autophagy', 'biological_process', 'GO:0006914', ('100', '109'))
60433	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))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('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))	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))
60454	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))
60460	31811814	As illustrated, patients in the high risk group were more likely to express risk genes.	('risk genes', 'Var', (76, 86))	('patients', 'Species', '9606', (16, 24))	('express', 'Reg', (68, 75))
60481	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))
60515	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', 'biological_process', 'GO:0006914', ('168', '177'))	('autophagy', 'CPA', (168, 177))	('NSCLC', 'Disease', (48, 53))	('augmented', 'PosReg', (178, 187))	('signaling pathway', 'biological_process', 'GO:0007165', ('93', '110'))	('salinomycin-mediated', 'MPA', (188, 208))	('salinomycin', 'Chemical', 'MESH:C010327', (188, 199))	('autophagy', 'biological_process', 'GO:0006914', ('145', '154'))	('inhibiting', 'NegReg', (68, 78))	('blockage', 'Var', (156, 164))	('AKT1', 'Gene', '207', (83, 87))	('mTOR', 'Gene', (88, 92))	('AKT1', 'Gene', (83, 87))	('mTOR', 'Gene', '2475', (88, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('209', '218'))	('autophagy', 'biological_process', 'GO:0016236', ('168', '177'))	('apoptosis', 'biological_process', 'GO:0006915', ('209', '218'))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('autophagy', 'CPA', (145, 154))	('Salinomycin', 'Chemical', 'MESH:C010327', (0, 11))	('autophagy', 'biological_process', 'GO:0016236', ('145', '154'))
60535	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))
60539	31791387	Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection.	('DNA', 'Protein', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('aberrant', 'Var', (77, 85))
60556	31791387	Aberrant DNA promoter methylation, which is closely associated with inappropriate gene transcription and is thought to precede the emergence of the malignant phenotype, can be easily detected with minimal-invasiveness in circulating cell-free DNA (ccfDNA) from body fluids, such as serum/plasma, representing a valuable tool for early cancer detection.	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('DNA promoter', 'Gene', (9, 21))	('Aberrant', 'Var', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Disease', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))
60557	31791387	Several studies have assessed the feasibility of ccfDNA methylation for specific cancer type detection, including "Epi proColon" (SEPT9me) and "Epi proLung" (PTGER4me and SHOX2me), two commercially available tests for CRC and LC detection, respectively.	('SEPT9', 'Gene', '10801', (130, 135))	('PTGER4', 'Gene', '5734', (158, 164))	('SHOX2', 'Gene', (171, 176))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('SEPT9', 'Gene', (130, 135))	('PTGER4', 'Gene', (158, 164))	('SHOX2', 'Gene', '6474', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('methylation', 'Var', (56, 67))
60564	31791387	In PCa patients, significantly higher levels were observed for FOXA1me, GSTP1me, HOXD3me, RARbeta2me, SOX17me (p < 0.0001), RASSF1Ame and SEPT9me (p = 0.014 and p = 0.0001, respectively), although no differences were apparent for APCme (p = 0.443) (Fig.	('FOXA1', 'Gene', (63, 68))	('SOX17', 'Gene', '64321', (102, 107))	('RASSF1A', 'Gene', (124, 131))	('APC', 'Disease', 'MESH:D011125', (230, 233))	('APC', 'Disease', (230, 233))	('HOXD3', 'Gene', '3232', (81, 86))	('higher', 'PosReg', (31, 37))	('levels', 'MPA', (38, 44))	('patients', 'Species', '9606', (7, 15))	('HOXD3', 'Gene', (81, 86))	('RARbeta2me', 'Var', (90, 100))	('PCa', 'Disease', (3, 6))	('SEPT9', 'Gene', (138, 143))	('SOX17', 'Gene', (102, 107))	('GSTP1', 'Gene', '2950', (72, 77))	('GSTP1', 'Gene', (72, 77))	('RARbeta2me', 'Chemical', '-', (90, 100))	('SEPT9', 'Gene', '10801', (138, 143))	('FOXA1', 'Gene', '3169', (63, 68))	('RASSF1A', 'Gene', '11186', (124, 131))
60573	31791387	Hence, the best LC panel (FOXA1me, RARbeta2me, RASSF1Ame and SOX17me) achieved 66% sensitivity and 70% specificity, whereas for PCa, the panel (FOXA1me, RARbeta2me, RASSF1Ame and GSTP1me) depicted 72% sensitivity and specificity (Table 2).	('RASSF1A', 'Gene', (47, 54))	('RASSF1A', 'Gene', (165, 172))	('RARbeta2me', 'Var', (153, 163))	('FOXA1', 'Gene', (144, 149))	('GSTP1', 'Gene', (179, 184))	('FOXA1', 'Gene', '3169', (26, 31))	('RASSF1A', 'Gene', '11186', (47, 54))	('SOX17', 'Gene', '64321', (61, 66))	('FOXA1', 'Gene', '3169', (144, 149))	('RASSF1A', 'Gene', '11186', (165, 172))	('GSTP1', 'Gene', '2950', (179, 184))	('SOX17', 'Gene', (61, 66))	('RARbeta2me', 'Chemical', '-', (35, 45))	('RARbeta2me', 'Chemical', '-', (153, 163))	('FOXA1', 'Gene', (26, 31))
60587	31791387	Similar results were found for RARbeta2me and SEPT9me in CRC patients (p = 0.012 and p = 0.019, respectively) (Fig.	('patients', 'Species', '9606', (61, 69))	('SEPT9', 'Gene', '10801', (46, 51))	('CRC', 'Disease', (57, 60))	('RARbeta2me', 'Chemical', '-', (31, 41))	('RARbeta2me', 'Var', (31, 41))	('SEPT9', 'Gene', (46, 51))
60595	31791387	Interestingly, methylation of APC (p < 0.001), FOXA1 (p = 0.033), HOXD3 (p = 0.047), RASSF1A (p < 0.001), SEPT9 (p = 0.009) and SOX17 (p = 0.037) also significantly associated with increased cumulative incidence of DSM (Fig.	('RASSF1A', 'Gene', (85, 92))	('methylation', 'Var', (15, 26))	('SOX17', 'Gene', '64321', (128, 133))	('DSM', 'Disease', (215, 218))	('SEPT9', 'Gene', '10801', (106, 111))	('APC', 'Disease', (30, 33))	('APC', 'Disease', 'MESH:D011125', (30, 33))	('FOXA1', 'Gene', '3169', (47, 52))	('RASSF1A', 'Gene', '11186', (85, 92))	('associated', 'Reg', (165, 175))	('HOXD3', 'Gene', '3232', (66, 71))	('SEPT9', 'Gene', (106, 111))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('HOXD3', 'Gene', (66, 71))	('SOX17', 'Gene', (128, 133))	('FOXA1', 'Gene', (47, 52))	('APC', 'cellular_component', 'GO:0005680', ('30', '33'))
60596	31791387	As both APC and RASSF1A methylation positivity were strongly associated with increased cumulative incidence of DSM, the value as a prognostic panel to better stratify outcome in LC patients was assessed for the combined genes.	('DSM', 'Disease', (111, 114))	('methylation positivity', 'Var', (24, 46))	('APC', 'cellular_component', 'GO:0005680', ('8', '11'))	('patients', 'Species', '9606', (181, 189))	('RASSF1A', 'Gene', (16, 23))	('APC', 'Disease', 'MESH:D011125', (8, 11))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('RASSF1A', 'Gene', '11186', (16, 23))	('APC', 'Disease', (8, 11))
60605	31791387	Nonetheless, no relevant significant associations were disclosed between circulating methylation positivity and PFS or DFS (data not shown).	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('DFS', 'Disease', (119, 122))	('circulating methylation positivity', 'Var', (73, 107))	('DFS', 'Disease', 'None', (119, 122))	('PFS', 'Disease', (112, 115))
60616	31791387	Aberrant DNA methylation of cancer-related genes occurs at very early stages of tumorigenesis, is cancer-specific, and amenable to be assessed in ccfDNA, representing a valuable candidate tool for minimally invasive early cancer detection.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ccfDNA', 'Disease', (146, 152))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (222, 228))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (28, 34))	('men', 'Species', '9606', (120, 123))
60620	31791387	Concerning PCa, except for APCme that was only reported in tissue and urine of cancer patients, our results are in line with previously published studies showing GSTP1me, RARbeta2me and RASSF1Ame hypermethylation in ccfDNA of PCa patients.	('GSTP1', 'Gene', '2950', (162, 167))	('RASSF1A', 'Gene', '11186', (186, 193))	('RARbeta2me', 'Chemical', '-', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (86, 94))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('PCa', 'Disease', (11, 14))	('patients', 'Species', '9606', (230, 238))	('APC', 'Disease', (27, 30))	('GSTP1', 'Gene', (162, 167))	('RASSF1A', 'Gene', (186, 193))	('ccfDNA', 'Disease', (216, 222))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('hypermethylation', 'Var', (196, 212))
60624	31791387	We also confirmed SEPT9 and SOX17 hypermethylation in ccfDNA of CRC patients, although displaying modest sensitivity (12%), in contrast with previous reports.	('hypermethylation', 'Var', (34, 50))	('SOX17', 'Gene', (28, 33))	('ccfDNA', 'Disease', (54, 60))	('SEPT9', 'Gene', '10801', (18, 23))	('patients', 'Species', '9606', (68, 76))	('SEPT9', 'Gene', (18, 23))	('SOX17', 'Gene', '64321', (28, 33))
60626	31791387	Interestingly, HOXD3 was significantly hypomethylated in CRC samples.	('HOXD3', 'Gene', '3232', (15, 20))	('HOXD3', 'Gene', (15, 20))	('hypomethylated', 'Var', (39, 53))
60637	31791387	Interestingly, higher FOXA1me and RARbeta2me associated with advanced LC tumour stage.	('LC tumour', 'Disease', 'MESH:D009369', (70, 79))	('higher', 'PosReg', (15, 21))	('FOXA1', 'Gene', '3169', (22, 27))	('RARbeta2me', 'Chemical', '-', (34, 44))	('LC tumour', 'Disease', (70, 79))	('RARbeta2me', 'Var', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('FOXA1', 'Gene', (22, 27))
60641	31791387	Increased HOXD3me levels were similarly observed in all five PCa patients with distant metastasis at diagnosis, along with higher APCme, GSTP1me, RARbeta2me, RASSF1Ame and SEPT9me in four out of the same five patients.	('RARbeta2me', 'Var', (146, 156))	('RASSF1A', 'Gene', (158, 165))	('RARbeta2me', 'Chemical', '-', (146, 156))	('PCa', 'Disease', (61, 64))	('APC', 'Disease', 'MESH:D011125', (130, 133))	('HOXD3', 'Gene', (10, 15))	('RASSF1A', 'Gene', '11186', (158, 165))	('higher', 'PosReg', (123, 129))	('GSTP1', 'Gene', (137, 142))	('SEPT9', 'Gene', '10801', (172, 177))	('APC', 'Disease', (130, 133))	('Increased', 'PosReg', (0, 9))	('patients', 'Species', '9606', (209, 217))	('distant metastasis', 'CPA', (79, 97))	('SEPT9', 'Gene', (172, 177))	('GSTP1', 'Gene', '2950', (137, 142))	('patients', 'Species', '9606', (65, 73))	('HOXD3', 'Gene', '3232', (10, 15))
60643	31791387	Thus, despite the early onset of epigenetic alterations in tumorigenesis, higher circulating methylation levels are detectable in cancer progression probably owing to increased tumour burden and metastatic spread.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', (177, 183))	('circulating methylation levels', 'MPA', (81, 111))	('higher', 'PosReg', (74, 80))	('epigenetic alterations', 'Var', (33, 55))	('cancer', 'Disease', (130, 136))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('increased', 'PosReg', (167, 176))	('metastatic spread', 'CPA', (195, 212))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
60650	31791387	Moreover, detectable circulating APCme, GSTP1me, RARbeta2me, RASSF1Ame, SEPT9me and SOX17me methylation, in PCa patients, and RARbeta2me, SEPT9me and SOX17me, in CRC patients, associated with increased cumulative incidence of DSM, suggesting that methylation of selected genes in plasma might convey prognostic information already at the time of diagnosis.	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('RASSF1A', 'Gene', '11186', (61, 68))	('RARbeta2me', 'Chemical', '-', (126, 136))	('SOX17', 'Gene', '64321', (150, 155))	('SOX17', 'Gene', '64321', (84, 89))	('RASSF1A', 'Gene', (61, 68))	('methylation', 'biological_process', 'GO:0032259', ('247', '258'))	('SEPT9', 'Gene', '10801', (72, 77))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('SEPT9', 'Gene', (138, 143))	('RARbeta2me', 'Var', (49, 59))	('SOX17', 'Gene', (150, 155))	('methylation', 'Var', (92, 103))	('RARbeta2me', 'Var', (126, 136))	('DSM', 'Disease', (226, 229))	('GSTP1', 'Gene', '2950', (40, 45))	('SOX17', 'Gene', (84, 89))	('SEPT9', 'Gene', (72, 77))	('GSTP1', 'Gene', (40, 45))	('SEPT9', 'Gene', '10801', (138, 143))	('patients', 'Species', '9606', (112, 120))	('RARbeta2me', 'Chemical', '-', (49, 59))	('patients', 'Species', '9606', (166, 174))
60696	31819480	However, the discovery of somatic mutations in epidermal growth factor receptors (EGFRs) and the use of targeted therapy via oral tyrosine kinase inhibitors (TKIs) has improved therapeutic prospects of patients with advanced NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (225, 230))	('EGFR', 'Gene', (82, 86))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('47', '70'))	('improved', 'PosReg', (168, 176))	('tyrosine', 'Chemical', 'None', (130, 138))	('NSCLC', 'Disease', (225, 230))	('patients', 'Species', '9606', (202, 210))	('NSCLC', 'Disease', 'MESH:D002289', (225, 230))	('EGFR', 'Gene', '1956', (82, 86))	('mutations', 'Var', (34, 43))
60697	31819480	The incidence of EGFR mutations has been reported to be approximately 62% in Asian populations and 10-15% in North American and European populations.	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
60700	31819480	Approximately 80% of NSCLC patients harboring EGFR-activating mutations respond well to EGFR-TKIs.	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('NSCLC', 'Disease', (21, 26))	('EGFR', 'Gene', '1956', (46, 50))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('patients', 'Species', '9606', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('EGFR', 'Gene', (88, 92))	('mutations', 'Var', (62, 71))
60704	31819480	The T790M mutation in EGFR and amplification of the MET oncogene have been proved to be the leading reasons behind EGFR-TKI acquired resistance.	('acquired resistance', 'MPA', (124, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'Gene', '1956', (115, 119))	('T790M', 'Mutation', 'rs121434569', (4, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('EGFR', 'Gene', '1956', (22, 26))	('T790M', 'Var', (4, 9))	('EGFR', 'Gene', (22, 26))
60705	31819480	In addition, hepatocyte growth factor (HGF) overexpression, EGFR amplification, epithelial-mesenchymal transition (EMT), and conversion to small-cell lung cancer have also been shown to be crucial mechanisms supporting the development of EGFR-TKI acquired resistance.	('hepatocyte growth factor', 'Gene', (13, 37))	('EGFR', 'Gene', '1956', (238, 242))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (139, 161))	('small-cell lung cancer', 'Disease', (139, 161))	('overexpression', 'PosReg', (44, 58))	('EGFR', 'Gene', '1956', (60, 64))	('amplification', 'Var', (65, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('HGF', 'Gene', '3082', (39, 42))	('EMT', 'biological_process', 'GO:0001837', ('115', '118'))	('EGFR', 'Gene', (238, 242))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (139, 161))	('epithelial-mesenchymal transition', 'CPA', (80, 113))	('HGF', 'Gene', (39, 42))	('EGFR', 'Gene', (60, 64))	('hepatocyte growth factor', 'Gene', '3082', (13, 37))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('80', '113'))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('13', '37'))
60709	31819480	Silencing of FGFR1 expression or inhibiting its activity inhibits NSCLC proliferation.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('NSCLC', 'Disease', (66, 71))	('activity', 'MPA', (48, 56))	('FGFR1', 'Gene', (13, 18))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('FGFR1', 'Gene', '2260', (13, 18))	('Silencing', 'Var', (0, 9))	('inhibits', 'NegReg', (57, 65))	('inhibiting', 'NegReg', (33, 43))
60720	31819480	Western blotting was performed using antibodies against FGFR1 (#9740, Cell Signaling Technology), Akt (#2920, CST), phospho-Akt (#4060, CST), beta-Actin (#3700, CST), mTOR (#2983, CST), and phospho-mTOR (#5536, CST).	('FGFR1', 'Gene', (56, 61))	('CST', 'Gene', '106478911', (136, 139))	('#5536', 'Var', (204, 209))	('CST', 'Gene', '106478911', (110, 113))	('Akt', 'Gene', (124, 127))	('CST', 'Gene', (161, 164))	('phospho', 'Chemical', 'MESH:C033601', (190, 197))	('#2920', 'Var', (103, 108))	('mTOR', 'Gene', (167, 171))	('#2983', 'Var', (173, 178))	('#3700', 'Var', (154, 159))	('Akt', 'Gene', '207', (124, 127))	('Signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('CST', 'Gene', (136, 139))	('CST', 'Gene', '106478911', (180, 183))	('CST', 'Gene', '106478911', (211, 214))	('phospho', 'Chemical', 'MESH:C033601', (116, 123))	('mTOR', 'Gene', (198, 202))	('CST', 'Gene', (110, 113))	('mTOR', 'Gene', '2475', (167, 171))	('Akt', 'Gene', (98, 101))	('FGFR1', 'Gene', '2260', (56, 61))	('Akt', 'Gene', '207', (98, 101))	('beta-Actin', 'Gene', (142, 152))	('mTOR', 'Gene', '2475', (198, 202))	('beta-Actin', 'Gene', '728378', (142, 152))	('CST', 'Gene', '106478911', (161, 164))	('CST', 'Gene', (180, 183))	('CST', 'Gene', (211, 214))	('#4060', 'Var', (129, 134))
60749	31819480	PC9-GR cells were treated with gefitinib (100 nM) and/or PD173074 (20 nM) for 24 h. The results showed that PD173074 significantly enhanced the sensitivity of PC9-GR cells to gefitinib (Figure 3A and B).	('PD173074', 'Chemical', 'MESH:C115711', (57, 65))	('PD173074', 'Chemical', 'MESH:C115711', (108, 116))	('gefitinib', 'Chemical', 'MESH:C419708', (31, 40))	('PC9-GR', 'CellLine', 'CVCL:S706', (0, 6))	('PC9-GR', 'CellLine', 'CVCL:S706', (159, 165))	('PD173074', 'Var', (108, 116))	('gefitinib', 'Chemical', 'MESH:C419708', (175, 184))	('enhanced', 'PosReg', (131, 139))	('sensitivity', 'MPA', (144, 155))
60750	31819480	Subsequently, we used small interfering RNA (siRNA) to knockdown FGFR1 in PC9-GR cells, and then incubated them in complete medium containing 100 nM gefitinib for 24 h. The results showed that the tolerance of PC9-GR cells towards gefitinib decreased significantly after FGFR1 knockdown (Figure 3C and D).	('PC9-GR', 'CellLine', 'CVCL:S706', (74, 80))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('decreased', 'NegReg', (241, 250))	('tolerance', 'MPA', (197, 206))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('FGFR', 'molecular_function', 'GO:0005007', ('271', '275'))	('knockdown', 'Var', (277, 286))	('PC9-GR', 'CellLine', 'CVCL:S706', (210, 216))	('FGFR1', 'Gene', (65, 70))	('gefitinib', 'Chemical', 'MESH:C419708', (149, 158))	('gefitinib', 'Chemical', 'MESH:C419708', (231, 240))	('FGFR1', 'Gene', (271, 276))	('FGFR1', 'Gene', '2260', (65, 70))	('FGFR1', 'Gene', '2260', (271, 276))
60752	31819480	The results showed that the proliferation, migration, and cloning abilities of PC9-GR cells decreased significantly after FGFR1 knockdown or inhibition (Figure 3E-K).	('inhibition', 'NegReg', (141, 151))	('knockdown', 'Var', (128, 137))	('FGFR1', 'Gene', (122, 127))	('FGFR1', 'Gene', '2260', (122, 127))	('PC9-GR', 'CellLine', 'CVCL:S706', (79, 85))	('migration', 'CPA', (43, 52))	('decreased', 'NegReg', (92, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('cloning abilities', 'CPA', (58, 75))
60755	31819480	Western blotting and immunofluorescence results showed that AKT and mTOR phosphorylation levels increased significantly in PC9-GR cells (Figure 4A and B and Supporting Information Figure S1).	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('increased', 'PosReg', (96, 105))	('PC9-GR', 'CellLine', 'CVCL:S706', (123, 129))	('AKT', 'Gene', '207', (60, 63))	('PC9-GR', 'Var', (123, 129))	('mTOR', 'Gene', '2475', (68, 72))	('mTOR', 'Gene', (68, 72))	('AKT', 'Gene', (60, 63))	('phospho', 'Chemical', 'MESH:C033601', (73, 80))
60756	31819480	To determine if FGFR1 mediated gefitinib resistance in NSCLC by activating the AKT/mTOR signaling pathway, we knocked down FGFR1 expression in PC9-GR cells using 2 individual siRNAs that targeted different sequences of the transcript (Figure 4C and D).	('activating', 'Reg', (64, 74))	('mTOR', 'Gene', (83, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('FGFR1', 'Gene', '2260', (16, 21))	('NSCLC', 'Disease', (55, 60))	('gefitinib', 'Chemical', 'MESH:C419708', (31, 40))	('AKT', 'Gene', (79, 82))	('PC9-GR', 'CellLine', 'CVCL:S706', (143, 149))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('FGFR1', 'Gene', (123, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('AKT', 'Gene', '207', (79, 82))	('FGFR1', 'Gene', '2260', (123, 128))	('knocked', 'Var', (110, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('signaling pathway', 'biological_process', 'GO:0007165', ('88', '105'))	('FGFR1', 'Gene', (16, 21))	('mTOR', 'Gene', '2475', (83, 87))
60757	31819480	Western blotting analysis revealed that FGFR1 silencing remarkably repressed AKT and mTOR phosphorylation levels (Figure 4E).	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('AKT', 'Gene', '207', (77, 80))	('phospho', 'Chemical', 'MESH:C033601', (90, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('FGFR1', 'Gene', (40, 45))	('silencing', 'Var', (46, 55))	('FGFR1', 'Gene', '2260', (40, 45))	('repressed', 'NegReg', (67, 76))	('mTOR', 'Gene', '2475', (85, 89))	('AKT', 'Gene', (77, 80))	('mTOR', 'Gene', (85, 89))
60759	31819480	PC9-GR cells were also treated with PD173074 for 24 h and AKT and mTOR phosphorylation levels were again detected using Western blotting.	('mTOR', 'Gene', (66, 70))	('phospho', 'Chemical', 'MESH:C033601', (71, 78))	('mTOR', 'Gene', '2475', (66, 70))	('AKT', 'Gene', (58, 61))	('PC9-GR', 'CellLine', 'CVCL:S706', (0, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('AKT', 'Gene', '207', (58, 61))	('PD173074', 'Var', (36, 44))	('PD173074', 'Chemical', 'MESH:C115711', (36, 44))
60760	31819480	The results showed that PD173074 significantly inhibited AKT and mTOR phosphorylation (Figure 4F).	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('inhibited', 'NegReg', (47, 56))	('PD173074', 'Chemical', 'MESH:C115711', (24, 32))	('AKT', 'Gene', '207', (57, 60))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('PD173074', 'Var', (24, 32))	('phospho', 'Chemical', 'MESH:C033601', (70, 77))	('AKT', 'Gene', (57, 60))
60834	31187604	For univariate analysis of grade >= 3 toxicity, dosimetry factors were also examined, including TPBT Dmax and D4cc; esophagus Dmax and D5cc; heart Dmax and D15cc; spinal cord Dmax; MLD; and lung V5, V15, and V20.	('D15cc', 'Var', (156, 161))	('V15', 'Gene', '28814', (199, 202))	('D4cc', 'Var', (110, 114))	('toxicity', 'Disease', 'MESH:D064420', (38, 46))	('toxicity', 'Disease', (38, 46))	('TPBT', 'Chemical', '-', (96, 100))	('MLD', 'Disease', 'MESH:D007966', (181, 184))	('MLD', 'Disease', (181, 184))	('V15', 'Gene', (199, 202))
60859	31187604	In univariate analysis, the following four factors showed a significant association with longer OS: gender (female > male, P = 0.047), tumor maximum diameter < 7 cm (P = 0.004), GTV < 100 cc (P = 0.004), and PTV < 150 cc (P = 0.000).	('GTV < 100 cc', 'Var', (178, 190))	('PTV', 'cellular_component', 'GO:1990257', ('208', '211'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('longer OS', 'Disease', (89, 98))	('PTV', 'Chemical', '-', (208, 211))	('PTV < 150 cc', 'Var', (208, 220))
60894	31033571	Icotinib plus osimertinib overcome epidermal growth factor receptor 19del/T790 M/C797S/V834L quadruplet resistance mutation in a patient with non-small cell lung cancer To the Editor: A 66-year-old woman presented with a severe cough and was admitted into hospital in April 2014.	('cough', 'Disease', 'MESH:D003371', (228, 233))	('woman', 'Species', '9606', (198, 203))	('C797S', 'Var', (81, 86))	('cough', 'Disease', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (142, 168))	('C797S', 'SUBSTITUTION', 'None', (81, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('35', '58'))	('non-small cell lung cancer', 'Disease', (142, 168))	('cough', 'Phenotype', 'HP:0012735', (228, 233))	('epidermal growth factor receptor', 'Gene', (35, 67))	('Icotinib', 'Chemical', 'MESH:C531470', (0, 8))	('epidermal growth factor receptor', 'Gene', '1956', (35, 67))	('V834L', 'Mutation', 'rs397517127', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('osimertinib', 'Chemical', 'MESH:C000603933', (14, 25))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('patient', 'Species', '9606', (129, 136))
60898	31033571	Direct genetic sequencing was performed with tumor tissue and epidermal growth factor receptor (EGFR) exon 19 deletion was found.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('epidermal growth factor receptor', 'Gene', (62, 94))	('EGFR', 'Gene', (96, 100))	('tumor', 'Disease', (45, 50))	('epidermal growth factor receptor', 'Gene', '1956', (62, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('62', '85'))	('deletion', 'Var', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('EGFR', 'Gene', '1956', (96, 100))
60903	31033571	Re-biopsy was performed from left lung lesion, the EGFR gene panel was examined, by Amplification Refractory Mutation System polymerase chain reaction (ARMS PCR), EGFR 19 del and EGFR T790 M mutations were detected.	('EGFR', 'Gene', (179, 183))	('EGFR', 'Gene', '1956', (179, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('179', '183'))	('EGFR', 'Gene', (51, 55))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (163, 174))	('EGFR', 'Gene', '1956', (163, 167))	('left lung lesion', 'Disease', 'MESH:D008171', (29, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('T790 M', 'Var', (184, 190))	('left lung lesion', 'Disease', (29, 45))	('EGFR', 'Gene', (163, 167))	('T790 M', 'Mutation', 'rs121434569', (184, 190))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('EGFR', 'Gene', '1956', (51, 55))
60906	31033571	Next-generation sequencing (NGS) was done with new biopsied lung tissue, EGFR 19 del, T790 M, C797G, and V834L mutations were found; and the mutant allele fractions (MAFs) were 85.5%, 61.5%, 36.6%, and 91.1%, respectively.	('del', 'Var', (81, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('EGFR', 'Gene', (73, 77))	('V834L', 'Var', (105, 110))	('T790 M', 'Mutation', 'rs121434569', (86, 92))	('V834L', 'Mutation', 'rs397517127', (105, 110))	('C797G', 'Mutation', 'rs17336639', (94, 99))	('T790 M', 'Var', (86, 92))	('MAF', 'Gene', '4094', (166, 169))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (73, 84))	('C797G', 'Var', (94, 99))	('MAF', 'Gene', (166, 169))
60907	31033571	EGFR T790 M and C797G were located in cis.	('C797G', 'Var', (16, 21))	('T790 M', 'Mutation', 'rs121434569', (5, 11))	('EGFR', 'Gene', (0, 4))	('T790 M', 'Var', (5, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('C797G', 'Mutation', 'rs17336639', (16, 21))
60912	31033571	NGS was done with patient's blood; the results indicated EGFR19 del/T790 M/C797G/V834L mutation and MAF were 0.4%, 0.3%, 0.6%, and 0.8%, respectively.	('EGFR19', 'Gene', (57, 63))	('MAF', 'Gene', '4094', (100, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR19 del', 'Mutation', 'c.19delEGFR', (57, 67))	('del/T790 M/C797G/V834L', 'Var', (64, 86))	('MAF', 'Gene', (100, 103))	('V834L', 'Mutation', 'rs397517127', (81, 86))	('patient', 'Species', '9606', (18, 25))	('C797G', 'Mutation', 'rs17336639', (75, 80))
60915	31033571	EGFR-C797S/G mutation is the most common secondary mutation leading to the resistance of the third-generation EGFR-TKIs.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('C797S', 'Var', (5, 10))	('leading', 'Reg', (60, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('C797S', 'SUBSTITUTION', 'None', (5, 10))	('EGFR', 'Gene', '1956', (0, 4))
60916	31033571	The mutation disrupts the covalent binding between the cysteine at position C797 and third-generation EGFR TKIs.In vitro study, cancer cells would be sensitive to a combination of first- and third-generation EGFR TKIs if the EGFR T790 M mutation and C797S mutation happened in trans, but would be resistant to it if they happened in cis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cysteine', 'Chemical', 'MESH:D003545', (55, 63))	('C797S', 'Mutation', 'rs1057519861', (250, 255))	('EGFR', 'molecular_function', 'GO:0005006', ('225', '229'))	('C797S', 'Var', (250, 255))	('T790 M', 'Mutation', 'rs121434569', (230, 236))	('EGFR', 'Gene', '1956', (208, 212))	('EGFR', 'Gene', '1956', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('EGFR', 'Gene', (208, 212))	('EGFR', 'Gene', (225, 229))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('cancer', 'Disease', (128, 134))
60917	31033571	Wang et al first reported the clinical evidence of efficacy generated by combination therapy of first- and third-generation of EGFR TKIs targeting concomitant EGFR T790 M and C797S in trans.	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('T790 M', 'Mutation', 'rs121434569', (164, 170))	('EGFR', 'Gene', '1956', (159, 163))	('C797S', 'Mutation', 'rs1057519861', (175, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('159', '163'))	('T790 M', 'Var', (164, 170))	('C797S', 'Var', (175, 180))	('EGFR', 'Gene', (159, 163))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
60919	31033571	Subsequent gene panels showed EGFR T790 M mutation and V834L mutations.	('V834L', 'Mutation', 'rs397517127', (55, 60))	('EGFR', 'Gene', (30, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('V834L mutations', 'Var', (55, 70))	('T790 M', 'Mutation', 'rs121434569', (35, 41))	('EGFR', 'Gene', '1956', (30, 34))
60920	31033571	EGFR V834L mutation was barely reported in literature.	('EGFR', 'Gene', (0, 4))	('V834L', 'Var', (5, 10))	('V834L', 'Mutation', 'rs397517127', (5, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
60922	31033571	The treatment method for patients with secondary C797S/G mutation after the third generation of EGFR TKIs is still in the exploratory stage.	('EGFR', 'Gene', (96, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('C797S', 'SUBSTITUTION', 'None', (49, 54))	('patients', 'Species', '9606', (25, 33))	('C797S', 'Var', (49, 54))	('EGFR', 'Gene', '1956', (96, 100))
60923	31033571	For patients harboring EGFR exon 19 del/V834L/T790 M/C797G, the combination of the first- and third-generation of EGFR TKIs may achieve certain results.	('V834L', 'SUBSTITUTION', 'None', (40, 45))	('V834L', 'Var', (40, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'Gene', '1956', (23, 27))	('patients', 'Species', '9606', (4, 12))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('C797G', 'Mutation', 'rs17336639', (53, 58))	('EGFR', 'Gene', (23, 27))
60925	31033571	In conclusion, EGFR 19 del/T790 M/C797G/V834L quadruplet mutation is very rare in non-small cell lung cancer after resistance to osimertinib treatment; it may benefit from first- and third-generation EGFR TKIs, but more patients are needed into the study in the future.	('osimertinib', 'Chemical', 'MESH:C000603933', (129, 140))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (86, 108))	('del/T790 M/C797G/V834L', 'Var', (23, 45))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (82, 108))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('C797G', 'Mutation', 'rs17336639', (34, 39))	('non-small cell lung cancer', 'Disease', (82, 108))	('EGFR', 'Gene', '1956', (200, 204))	('EGFR', 'molecular_function', 'GO:0005006', ('200', '204'))	('EGFR', 'Gene', (200, 204))	('EGFR', 'Gene', '1956', (15, 19))	('patients', 'Species', '9606', (220, 228))	('EGFR', 'Gene', (15, 19))	('V834L', 'Mutation', 'rs397517127', (40, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (82, 108))
60989	31182960	The rates of grade 3 or higher acute toxicity were higher with RFA (11%) than with SBRT (5%).	('toxicity', 'Disease', (37, 45))	('RFA', 'Var', (63, 66))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
60993	31182960	While no OS differences were noted, 2-year LC rates were higher with SBRT than with TACE (91% versus 23%).	('higher', 'PosReg', (57, 63))	('LC rates', 'CPA', (43, 51))	('OS', 'Chemical', '-', (9, 11))	('SBRT', 'Var', (69, 73))	('TACE', 'Chemical', '-', (84, 88))
61006	31182960	Many ongoing studies are currently evaluating the combination of TACE with SBRT [NCT01918683, NCT02507765, NCT02513199, and NCT02794337] and comparing SBRT to TACE [NCT02182687 and NCT02470533].	('NCT02794337]', 'Var', (124, 136))	('NCT02507765', 'Var', (94, 105))	('TACE', 'Chemical', '-', (65, 69))	('TACE', 'Chemical', '-', (159, 163))	('NCT02513199', 'Var', (107, 118))
61064	31182960	A phase II trial evaluated whether testing for mismatch-repair (MMR) deficiencies in treatment-refractory cases of IHC might be of help in identifying those who might benefit from PD-1 pathway blockade.	('MMR', 'biological_process', 'GO:0006298', ('64', '67'))	('mismatch-repair', 'biological_process', 'GO:0006298', ('47', '62'))	('men', 'Species', '9606', (90, 93))	('IHC', 'Disease', (115, 118))	('deficiencies', 'Var', (69, 81))	('PD-1 pathway', 'Pathway', (180, 192))
61077	31182960	The addition of anti-PD-1 antibodies to RT is therefore expected to promote the proimmunogenic tumor microenvironment.	('anti-PD-1 antibodies', 'Var', (16, 36))	('antibodies', 'Var', (26, 36))	('promote', 'PosReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('men', 'Species', '9606', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
61079	31182960	In a study by Yoshimoto et al., mice exposed to the combination of RT and anti-CTLA-4 antibody had improved antitumor immunity and prolonged tumor growth delay (from 13.1 to 19.5 days) when compared to those exposed to RT alone.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('anti-CTLA-4', 'Var', (74, 85))	('improved', 'PosReg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('antibody', 'cellular_component', 'GO:0042571', ('86', '94'))	('growth delay', 'Phenotype', 'HP:0001510', (147, 159))	('prolonged tumor growth delay', 'Disease', 'MESH:D006130', (131, 159))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('antibody', 'cellular_component', 'GO:0019815', ('86', '94'))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('antibody', 'cellular_component', 'GO:0019814', ('86', '94'))	('mice', 'Species', '10090', (32, 36))	('prolonged tumor growth delay', 'Disease', (131, 159))	('tumor', 'Disease', (112, 117))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))	('combination', 'Interaction', (52, 63))
61119	31182960	Gene expression analysis of cells from the irradiated tumors revealed an IFN type I gene signature following exposure to 8Gy in 3 fractions but not following a single dose of 20 or 30Gy.	('8Gy', 'Var', (121, 124))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('IFN', 'Gene', '3439', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('IFN', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
61193	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))
61195	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))
61260	29390527	AT40% seems, therefore, the best segmentation method in low FDG uptake nodules.	('low FDG uptake', 'CPA', (56, 70))	('segmentation', 'biological_process', 'GO:0035282', ('33', '45'))	('AT40%', 'Var', (0, 5))	('uptake', 'biological_process', 'GO:0098657', ('64', '70'))	('uptake', 'biological_process', 'GO:0098739', ('64', '70'))	('FDG', 'Chemical', 'MESH:D019788', (60, 63))
61264	29390527	In this study, T42% and T42% x RC overestimated the MTV of nonsolid nodules in almost all of the cases.	('MTV', 'Chemical', '-', (52, 55))	('MTV', 'MPA', (52, 55))	('T42%', 'Var', (15, 19))	('overestimated', 'PosReg', (34, 47))	('T42% x RC', 'Var', (24, 33))
61271	28938696	The molecular mechanisms of chemoresistance in cancers Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death.	('cancer', 'Disease', (138, 144))	('drug resistance', 'biological_process', 'GO:0042493', ('89', '104'))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (47, 53))	('cancer dissemination', 'Disease', 'MESH:D009369', (197, 217))	('chemoresistance', 'Var', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))	('cancer', 'Disease', (197, 203))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('patients', 'Species', '9606', (145, 153))	('recurrence', 'Disease', (185, 195))	('cancer dissemination', 'Disease', (197, 217))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('causes', 'Reg', (178, 184))	('death', 'CPA', (222, 227))	('drug resistance', 'biological_process', 'GO:0009315', ('89', '104'))
61274	28938696	Chemoresistance causes disease relapse and metastasis, challenges the improvement of clinical outcome for the cancer patients, and remains the main obstacle to cancer therapy.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('disease relapse', 'CPA', (23, 38))	('cancer', 'Disease', (160, 166))	('Chemoresistance', 'Var', (0, 15))	('metastasis', 'CPA', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('challenges', 'NegReg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('causes', 'Reg', (16, 22))
61298	28938696	MVP-specific antisense oligonucleotides and anti- LRP monoclonal antibody were found to increase cellular ciplastin level and induce its chemosensitivity of ovarian cancer cells.	('antisense oligonucleotides', 'Var', (13, 39))	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('induce', 'PosReg', (126, 132))	('MVP', 'Gene', (0, 3))	('oligonucleotides', 'Chemical', 'MESH:D009841', (23, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('LRP', 'Gene', '9961', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('increase', 'PosReg', (88, 96))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('MVP', 'Gene', '9961', (0, 3))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))	('ovarian cancer', 'Disease', (157, 171))	('chemosensitivity of', 'CPA', (137, 156))	('cellular ciplastin level', 'MPA', (97, 121))	('LRP', 'Gene', (50, 53))
61302	28938696	However, gefitinib particularly targets mutatant EGFR in lung cancer, and suppresses EGF-triggered and HER3-mediated Akt activation in chemoresistant cells.	('HER3', 'Gene', '2065', (103, 107))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('EGF', 'molecular_function', 'GO:0005154', ('85', '88'))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('Akt', 'Gene', (117, 120))	('EGF', 'Gene', (85, 88))	('EGFR', 'Gene', (49, 53))	('suppresses', 'NegReg', (74, 84))	('Akt', 'Gene', '207', (117, 120))	('EGF', 'Gene', '1950', (49, 52))	('HER3', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('activation', 'MPA', (121, 131))	('lung cancer', 'Disease', (57, 68))	('mutatant', 'Var', (40, 48))	('EGFR', 'Gene', '1956', (49, 53))	('EGF', 'Gene', '1950', (85, 88))	('gefitinib', 'Chemical', 'MESH:D000077156', (9, 18))	('EGF', 'Gene', (49, 52))
61304	28938696	The exposure to anti-EGFR monoclonal antibody C225 reduced EGFR expression and the phosphorylation of its downstream Akt and MAPK for the reversal of cellular radioresistance.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('expression', 'MPA', (64, 74))	('reduced', 'NegReg', (51, 58))	('EGFR', 'Gene', (59, 63))	('Akt', 'Gene', (117, 120))	('antibody', 'cellular_component', 'GO:0019815', ('37', '45'))	('phosphorylation', 'MPA', (83, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('antibody', 'cellular_component', 'GO:0019814', ('37', '45'))	('antibody', 'molecular_function', 'GO:0003823', ('37', '45'))	('C225', 'Var', (46, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('125', '129'))	('Akt', 'Gene', '207', (117, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('EGFR', 'Gene', '1956', (59, 63))	('antibody', 'cellular_component', 'GO:0042571', ('37', '45'))
61307	28938696	CD133 overexpression or E3 ubiquitin ligase CBL knockdown conferred the chemoresistance by stabilizing EGFR-Akt signaling or EGFR activation respectively.	('EGFR', 'Gene', '1956', (103, 107))	('CBL', 'Gene', '867', (44, 47))	('activation', 'PosReg', (130, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('CD133', 'Gene', (0, 5))	('CD133', 'Gene', '8842', (0, 5))	('ubiquitin', 'molecular_function', 'GO:0031386', ('27', '36'))	('Akt signaling', 'biological_process', 'GO:0043491', ('108', '121'))	('stabilizing', 'NegReg', (91, 102))	('Akt', 'Gene', (108, 111))	('EGFR', 'Gene', '1956', (125, 129))	('Akt', 'Gene', '207', (108, 111))	('EGFR', 'Gene', (103, 107))	('conferred', 'PosReg', (58, 67))	('CBL', 'Gene', (44, 47))	('chemoresistance', 'CPA', (72, 87))	('knockdown', 'Var', (48, 57))	('EGFR', 'Gene', (125, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))
61308	28938696	miR-20b reduced 5-FU resistance for apoptotic induction by inhibiting ADAM9/EGFR pathway in colon cancer cells, whereas miRNA-34c-5p inhibited amphiregulin-induced chemoresistance to docetaxel and carboplatin in ovarian cancer cells via the downregulation of AREG-EGFR pathway.	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('AREG', 'Gene', (259, 263))	('amphiregulin', 'Gene', '374', (143, 155))	('EGFR', 'Gene', (76, 80))	('ovarian cancer', 'Disease', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('EGFR', 'Gene', (264, 268))	('miRNA-34c-5p', 'Var', (120, 132))	('docetaxel', 'Chemical', 'MESH:D000077143', (183, 192))	('reduced', 'NegReg', (8, 15))	('inhibiting', 'NegReg', (59, 69))	('colon cancer', 'Disease', (92, 104))	('miR-20b', 'Gene', '574032', (0, 7))	('ADAM9', 'Gene', '8754', (70, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('264', '268'))	('EGFR', 'Gene', '1956', (76, 80))	('AREG', 'Gene', '374', (259, 263))	('ADAM9', 'Gene', (70, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('downregulation', 'NegReg', (241, 255))	('5-FU resistance for apoptotic induction', 'MPA', (16, 55))	('amphiregulin', 'Gene', (143, 155))	('carboplatin', 'Chemical', 'MESH:D016190', (197, 208))	('5-FU', 'Chemical', 'MESH:D005472', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('EGFR', 'Gene', '1956', (264, 268))	('inhibited', 'NegReg', (133, 142))	('ovarian cancer', 'Disease', 'MESH:D010051', (212, 226))	('miR-20b', 'Gene', (0, 7))
61312	28938696	Akt is also phosphorylated at T308 and S473 and subsequently ubiquitinated partly by E3 ligase NEDD4 for proteasomal degradation.	('NEDD4', 'Gene', '4734', (95, 100))	('Akt', 'Gene', '207', (0, 3))	('S473', 'Var', (39, 43))	('T308', 'Var', (30, 34))	('Akt', 'Gene', (0, 3))	('degradation', 'biological_process', 'GO:0009056', ('117', '128'))	('NEDD4', 'Gene', (95, 100))
61316	28938696	Akt1 overexpression and Akt2 gene amplification caused ovarian cancer cells more highly resistant to paclitaxel.	('ovarian cancer', 'Disease', (55, 69))	('Akt1', 'Gene', (0, 4))	('resistant to paclitaxel', 'MPA', (88, 111))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('overexpression', 'PosReg', (5, 19))	('Akt1', 'Gene', '207', (0, 4))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('gene amplification', 'Var', (29, 47))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))	('Akt2', 'Gene', (24, 28))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))	('Akt2', 'Gene', '208', (24, 28))
61320	28938696	found that FKBP51 could promote PHLPP-Akt interaction and following Akt dephosphorylation at ser473, so that USP49 enhanced cellular response to gemcitabine through FKBP51-Akt signaling.	('gemcitabine', 'Chemical', 'MESH:C056507', (145, 156))	('dephosphorylation', 'biological_process', 'GO:0016311', ('72', '89'))	('ser', 'cellular_component', 'GO:0005790', ('93', '96'))	('FKBP51', 'Var', (11, 17))	('Akt', 'Gene', (172, 175))	('Akt', 'Gene', (38, 41))	('PHLPP', 'Gene', '23239', (32, 37))	('Akt', 'Gene', '207', (172, 175))	('PHLPP', 'Gene', (32, 37))	('Akt', 'Gene', '207', (38, 41))	('promote', 'PosReg', (24, 31))	('Akt', 'Gene', (68, 71))	('USP49', 'Gene', (109, 114))	('Akt', 'Gene', '207', (68, 71))	('cellular response to gemcitabine', 'MPA', (124, 156))	('ser473', 'Chemical', '-', (93, 99))	('FKBP', 'molecular_function', 'GO:0030051', ('165', '169'))	('response to gemcitabine', 'biological_process', 'GO:0036272', ('133', '156'))	('FKBP', 'molecular_function', 'GO:0030051', ('11', '15'))	('interaction', 'Interaction', (42, 53))	('USP49', 'Gene', '25862', (109, 114))	('Akt signaling', 'biological_process', 'GO:0043491', ('172', '185'))	('enhanced', 'PosReg', (115, 123))	('USP', 'molecular_function', 'GO:0051748', ('109', '112'))
61321	28938696	LncARSR promoted doxorubicin resistance in HCC cells via PTEN-PI3K/Akt pathway, and miRNA-130b targeted PTEN to mediate chemoresistance to adriamycin in breast cancer cells via PI3K/Akt pathway.	('mediate', 'Reg', (112, 119))	('doxorubicin resistance', 'MPA', (17, 39))	('Akt', 'Gene', '207', (182, 185))	('doxorubicin', 'Chemical', 'MESH:D004317', (17, 28))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))	('Akt', 'Gene', (67, 70))	('targeted', 'Reg', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('PTEN', 'Gene', (104, 108))	('Akt', 'Gene', '207', (67, 70))	('adriamycin', 'Chemical', 'MESH:D004317', (139, 149))	('PTEN', 'Gene', (57, 61))	('miRNA-130b', 'Var', (84, 94))	('PTEN', 'Gene', '5728', (104, 108))	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('HCC', 'Phenotype', 'HP:0001402', (43, 46))	('PTEN', 'Gene', '5728', (57, 61))	('Akt', 'Gene', (182, 185))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('promoted', 'PosReg', (8, 16))	('breast cancer', 'Disease', (153, 166))	('chemoresistance', 'CPA', (120, 135))
61326	28938696	K-ras mutation was reported to result in primary chemoresistance of lung cancer to gefitinib, erlotinib or sunitinib.	('lung cancer', 'Disease', (68, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (94, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('gefitinib', 'Chemical', 'MESH:D000077156', (83, 92))	('sunitinib', 'Chemical', 'MESH:D000077210', (107, 116))	('mutation', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('result in', 'Reg', (31, 40))
61342	28938696	Aspirin or dehydroxymethylepoxyquinomicin could suppress acquired chemoresistance by disrupting NF-kappaB-IL6 or NF-kappaB-ABC transporter axis respectively.	('suppress', 'NegReg', (48, 56))	('NF-kappaB', 'Gene', '4790', (113, 122))	('IL6', 'Gene', '3569', (106, 109))	('acquired chemoresistance', 'CPA', (57, 81))	('Aspirin', 'Chemical', 'MESH:D001241', (0, 7))	('disrupting', 'NegReg', (85, 95))	('IL6', 'Gene', (106, 109))	('dehydroxymethylepoxyquinomicin', 'Chemical', 'MESH:C464444', (11, 41))	('IL6', 'molecular_function', 'GO:0005138', ('106', '109'))	('NF-kappaB', 'Gene', (113, 122))	('NF-kappaB', 'Gene', '4790', (96, 105))	('dehydroxymethylepoxyquinomicin', 'Var', (11, 41))	('ABC transporter', 'molecular_function', 'GO:0140359', ('123', '138'))	('NF-kappaB', 'Gene', (96, 105))
61346	28938696	In cisplatin-sensitive testicular cancer cell line and its acquired cisplatin-resistant sublines, p53 knockdown decreased cisplatin-induced apoptosis and membrane Fas expression, but versa for intrinsically resistant testicular cancer cell lines.	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('membrane', 'cellular_component', 'GO:0016020', ('154', '162'))	('p53', 'Gene', (98, 101))	('decreased', 'NegReg', (112, 121))	('testicular cancer', 'Disease', 'MESH:D013736', (23, 40))	('testicular cancer', 'Disease', (217, 234))	('testicular cancer', 'Phenotype', 'HP:0010788', (217, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cisplatin-induced', 'MPA', (122, 139))	('testicular cancer', 'Disease', (23, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('membrane Fas expression', 'MPA', (154, 177))	('testicular cancer', 'Phenotype', 'HP:0010788', (23, 40))	('knockdown', 'Var', (102, 111))	('testicular cancer', 'Disease', 'MESH:D013736', (217, 234))	('p53', 'Gene', '7157', (98, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
61347	28938696	Reportedly, mutant p53 induced drug resistance via miR-223 down-regulation in breast and colon cancer cells by the transcription control of Zeb-1 on miR-223 promoter because miR-223 targets microtubule-modulated stathmin-1 for chemoresistance.	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('p53', 'Gene', (19, 22))	('miR-223', 'Gene', '407008', (51, 58))	('miR-223', 'Gene', (174, 181))	('Zeb-1', 'Gene', (140, 145))	('drug resistance', 'biological_process', 'GO:0009315', ('31', '46'))	('drug resistance', 'biological_process', 'GO:0042493', ('31', '46'))	('stathmin-1', 'Gene', (212, 222))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('stathmin-1', 'Gene', '3925', (212, 222))	('miR-223', 'Gene', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('induced', 'Reg', (23, 30))	('microtubule', 'cellular_component', 'GO:0005874', ('190', '201'))	('miR-223', 'Gene', '407008', (174, 181))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('drug resistance', 'MPA', (31, 46))	('down-regulation', 'NegReg', (59, 74))	('miR-223', 'Gene', '407008', (149, 156))	('Zeb-1', 'Gene', '6935', (140, 145))	('miR-223', 'Gene', (51, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (31, 46))	('mutant', 'Var', (12, 18))	('p53', 'Gene', '7157', (19, 22))	('colon cancer', 'Disease', (89, 101))
61350	28938696	reported the aggregating p53 mutant Arg282Trp might mediate cisplatin resistance by binding to the promoter of ERP29 and up-regulating its expression.	('p53', 'Gene', (25, 28))	('Arg282Trp', 'Var', (36, 45))	('p53', 'Gene', '7157', (25, 28))	('Arg282Trp', 'SUBSTITUTION', 'None', (36, 45))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('ERP29', 'Gene', '10961', (111, 116))	('expression', 'MPA', (139, 149))	('ERP29', 'Gene', (111, 116))	('binding', 'Interaction', (84, 91))	('up-regulating', 'PosReg', (121, 134))	('cisplatin resistance', 'MPA', (60, 80))	('mediate', 'Reg', (52, 59))
61353	28938696	In contrast, WP1130 attenuated cisplatin resistance via USP9X-p53 ubiquitination-mediated degradation pathway.	('cisplatin resistance', 'MPA', (31, 51))	('WP1130', 'Var', (13, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('degradation', 'biological_process', 'GO:0009056', ('90', '101'))	('USP9X', 'Gene', (56, 61))	('USP9X', 'Gene', '8239', (56, 61))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('USP', 'molecular_function', 'GO:0051748', ('56', '59'))	('attenuated', 'NegReg', (20, 30))
61361	28938696	The majority of cancer cells harbors somatic mutations in mitochondrial genome (mtDNA), finally to result in mitochondrial dysfunction.	('mutations', 'Var', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('mtDNA', 'cellular_component', 'GO:0000262', ('80', '85'))	('cancer', 'Disease', (16, 22))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (109, 134))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (109, 134))	('result in', 'Reg', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('58', '78'))	('mitochondrial dysfunction', 'Disease', (109, 134))
61362	28938696	Many mutations in mitochondrial genes of cancer cells can't shut down the mitochondrial energy metabolism because some cancer cells may completely depend on more glycolysis and some on more oxidation.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('glycolysis', 'biological_process', 'GO:0006096', ('162', '172'))	('metabolism', 'biological_process', 'GO:0008152', ('95', '105'))	('mutations', 'Var', (5, 14))	('mitochondrial energy metabolism', 'MPA', (74, 105))	('cancer', 'Disease', (119, 125))	('oxidation', 'MPA', (190, 199))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('glycolysis', 'MPA', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
61364	28938696	found that PGC-1beta mediated adaptive chemoresistance of lung cancer cells to cisplatin associated with mtDNA mutations.	('mutations', 'Var', (111, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('mtDNA', 'cellular_component', 'GO:0000262', ('105', '110'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('PGC-1beta', 'Gene', '133522', (11, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('mtDNA', 'Gene', (105, 110))	('adaptive chemoresistance', 'CPA', (30, 54))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('PGC-1beta', 'Gene', (11, 20))
61383	28938696	found that MGMT was overexpressed for the development of cancer chemoresistance via Wnt pathway, whose inhibition downregulated MGMT expression and restored the chemosensitivity to DNA-alkylating drugs.	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('expression', 'MPA', (133, 143))	('Wnt pathway', 'Pathway', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('MGMT', 'molecular_function', 'GO:0003908', ('128', '132'))	('MGMT', 'Gene', (128, 132))	('cancer', 'Disease', (57, 63))	('chemosensitivity to DNA-alkylating drugs', 'MPA', (161, 201))	('MGMT', 'molecular_function', 'GO:0003908', ('11', '15'))	('inhibition', 'Var', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('restored', 'PosReg', (148, 156))	('downregulated', 'NegReg', (114, 127))
61384	28938696	As a double-strand break repair protein, MRE11 hypoexpression was positively associated with good response to chemotherapy and surgical resection after down-staging by chemotherapy.	('MRE11', 'Gene', '4361', (41, 46))	('MRE11', 'Gene', (41, 46))	('hypoexpression', 'Var', (47, 61))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('double-strand break repair', 'biological_process', 'GO:0006302', ('5', '31'))
61387	28938696	Wip1 silencing attenuated DNA damage repair and strengthened the cisplatin chemosensitivity of oral squamous cell carcinoma cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('oral squamous cell carcinoma', 'Disease', (95, 123))	('cisplatin chemosensitivity', 'MPA', (65, 91))	('DNA damage repair', 'MPA', (26, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('silencing', 'Var', (5, 14))	('attenuated', 'NegReg', (15, 25))	('Wip1', 'Gene', '8493', (0, 4))	('Wip1', 'Gene', (0, 4))	('strengthened', 'PosReg', (48, 60))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 123))
61402	28938696	found that Atg7 silencing in acute myeloid leukemia enhanced the sensitivity to the genotoxic agents with alteration of Bcl-2 family proteins and up-regulation of PMAIP1/NOXA mRNA.	('Atg7', 'Gene', (11, 15))	('Atg7', 'Gene', '10533', (11, 15))	('silencing', 'Var', (16, 25))	('Bcl-2', 'molecular_function', 'GO:0015283', ('120', '125'))	('NOXA', 'Gene', '5366', (170, 174))	('acute myeloid leukemia', 'Disease', (29, 51))	('sensitivity to the genotoxic agents', 'MPA', (65, 100))	('NOXA', 'Gene', (170, 174))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (29, 51))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (35, 51))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (29, 51))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('Bcl-2', 'Gene', (120, 125))	('PMAIP1', 'Gene', (163, 169))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('alteration', 'Reg', (106, 116))	('up-regulation', 'PosReg', (146, 159))	('PMAIP1', 'Gene', '5366', (163, 169))	('enhanced', 'PosReg', (52, 60))	('Bcl-2', 'Gene', '596', (120, 125))
61404	28938696	showed that miRNA-30a knockdown activated Beclin 1- mediated autophagy for osteosarcoma chemoresistance.	('osteosarcoma', 'Disease', (75, 87))	('Beclin 1', 'Gene', (42, 50))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('autophagy', 'biological_process', 'GO:0016236', ('61', '70'))	('miRNA-30a', 'Gene', (12, 21))	('activated', 'PosReg', (32, 41))	('Beclin 1', 'Gene', '8678', (42, 50))	('autophagy', 'biological_process', 'GO:0006914', ('61', '70'))	('knockdown', 'Var', (22, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
61416	28938696	demonstrated that NNK increased chemoresistance in colorectal cancer via up-regulation of Snail, CD133, Nanog, Oct4, and drug-resistant genes.	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('CD133', 'Gene', (97, 102))	('up-regulation', 'PosReg', (73, 86))	('Nanog', 'Gene', '79923', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Nanog', 'Gene', (104, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('chemoresistance', 'CPA', (32, 47))	('CD133', 'Gene', '8842', (97, 102))	('Oct4', 'Gene', (111, 115))	('increased', 'PosReg', (22, 31))	('colorectal cancer', 'Disease', (51, 68))	('Snail', 'Gene', (90, 95))	('Snail', 'Gene', '6615', (90, 95))	('Oct4', 'Gene', '5460', (111, 115))	('NNK', 'Var', (18, 21))
61421	28938696	miR-138, miR-145 and miR-489 suppressed chemoresistance and EMT in lung, hepatocellular and breast cancers by targeting Zeb2 and Smad3 respectively.	('miR-145', 'Gene', (9, 16))	('miR-489', 'Gene', (21, 28))	('miR-138', 'Var', (0, 7))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('EMT', 'CPA', (60, 63))	('suppressed', 'NegReg', (29, 39))	('Zeb2', 'Gene', '9839', (120, 124))	('hepatocellular', 'Disease', (73, 87))	('Zeb2', 'Gene', (120, 124))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('Smad3', 'Gene', '4088', (129, 134))	('miR-489', 'Gene', '574442', (21, 28))	('miR-145', 'Gene', '406937', (9, 16))	('Smad3', 'Gene', (129, 134))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('chemoresistance', 'CPA', (40, 55))	('lung', 'Disease', (67, 71))	('targeting', 'Reg', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
61423	28938696	showed that LncRNA SLC25A25-AS1 knockdown remarkably promoted the drug resistance and EMT of colorectal cancer cells through Erk and p38 activation.	('AS1', 'Gene', '5729', (28, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))	('SLC25A25', 'Gene', (19, 27))	('Erk', 'molecular_function', 'GO:0004707', ('125', '128'))	('p38', 'Gene', '5594', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('drug resistance', 'Phenotype', 'HP:0020174', (66, 81))	('activation', 'PosReg', (137, 147))	('drug resistance', 'biological_process', 'GO:0009315', ('66', '81'))	('AS1', 'Gene', (28, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('drug resistance', 'biological_process', 'GO:0042493', ('66', '81'))	('promoted', 'PosReg', (53, 61))	('SLC25A25', 'Gene', '114789', (19, 27))	('colorectal cancer', 'Disease', (93, 110))	('Erk', 'Gene', (125, 128))	('drug resistance', 'CPA', (66, 81))	('knockdown', 'Var', (32, 41))	('p38', 'Gene', (133, 136))	('Erk', 'Gene', '5594', (125, 128))	('EMT of', 'CPA', (86, 92))
61430	28938696	Reportedly, CD133+ colorectal cancer cells had chemoresistance to 5-FU via survivin and ABCG2 expression, and ABCG2 knockdown inhibited the self-renewal capacity of these cells, and enhanced chemotherapy-induced apoptosis.	('chemotherapy-induced apoptosis', 'CPA', (191, 221))	('knockdown', 'Var', (116, 125))	('chemoresistance', 'CPA', (47, 62))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('ABCG2', 'Gene', (88, 93))	('ABCG2', 'Gene', '9429', (88, 93))	('enhanced', 'PosReg', (182, 190))	('apoptosis', 'biological_process', 'GO:0097194', ('212', '221'))	('survivin', 'Protein', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('212', '221'))	('inhibited', 'NegReg', (126, 135))	('ABCG2', 'Gene', (110, 115))	('CD133', 'Gene', (12, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('ABCG2', 'Gene', '9429', (110, 115))	('CD133', 'Gene', '8842', (12, 17))	('self-renewal capacity of', 'CPA', (140, 164))	('colorectal cancer', 'Disease', (19, 36))
61435	28938696	DOT1L knockdown blocked the expression of DOT1L, miR-10b, RhoGTPase and survival protein, and reduced cancer invasion and chemoresistance in CSCs.	('blocked', 'NegReg', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CSCs', 'Disease', (141, 145))	('reduced', 'NegReg', (94, 101))	('miR-10b', 'Gene', '406903', (49, 56))	('expression', 'MPA', (28, 38))	('survival protein', 'Protein', (72, 88))	('DOT1L', 'Gene', (0, 5))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('DOT1L', 'Gene', (42, 47))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('miR-10b', 'Gene', (49, 56))	('knockdown', 'Var', (6, 15))	('DOT1L', 'Gene', '84444', (42, 47))	('DOT1L', 'Gene', '84444', (0, 5))	('chemoresistance', 'CPA', (122, 137))	('RhoGTPase', 'Gene', (58, 67))
61449	28938696	However, cisplatin uptake by cancer cells and exosomal cisplatin content was markedly impaired by low pH conditions or PPI (proton pump inhibitor) treatments.	('uptake', 'biological_process', 'GO:0098657', ('19', '25'))	('exosomal cisplatin content', 'MPA', (46, 72))	('cancer', 'Disease', (29, 35))	('PPI', 'biological_process', 'GO:0060134', ('119', '122'))	('impaired', 'NegReg', (86, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('PPI', 'Var', (119, 122))	('proton pump', 'cellular_component', 'GO:0005889', ('124', '135'))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('proton pump', 'Gene', (124, 135))	('cisplatin uptake', 'MPA', (9, 25))	('uptake', 'biological_process', 'GO:0098739', ('19', '25'))	('proton pump', 'Gene', '495', (124, 135))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
61465	27960087	DNA repair defects in breast cancer associated genes 1 and 2 (BRCA1/2) yielded hypersensitivity to PARP inhibition and caused a rush to develop new PARP inhibitors for targeted therapy in these rare (~5%) hereditary breast and ovarian cancers.	('hypersensitivity', 'biological_process', 'GO:0002524', ('79', '95'))	('defects', 'Var', (11, 18))	('DNA repair', 'biological_process', 'GO:0006281', ('0', '10'))	('breast cancer', 'Disease', (22, 35))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (205, 242))	('BRCA1/2', 'Gene', '672;675', (62, 69))	('hypersensitivity', 'Disease', (79, 95))	('hypersensitivity', 'Disease', 'MESH:D004342', (79, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('ovarian cancer', 'Phenotype', 'HP:0100615', (227, 241))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('ovarian cancers', 'Phenotype', 'HP:0100615', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('BRCA1/2', 'Gene', (62, 69))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
61480	27960087	We hypothesized that inhibiting PARP activity prior to beta-lap exposure would enhance both agents, extending NQO1-medialed ROS production and inhibiting PARP-driven DNA repair in a tumor-selective manner.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('inhibiting', 'Var', (21, 31))	('tumor', 'Disease', (182, 187))	('DNA repair', 'biological_process', 'GO:0006281', ('166', '176'))	('NQO1', 'molecular_function', 'GO:0003955', ('110', '114'))	('extending', 'PosReg', (100, 109))	('inhibiting', 'NegReg', (143, 153))	('PARP-driven DNA repair', 'MPA', (154, 176))	('eta', 'Gene', '1909', (56, 59))	('eta', 'Gene', (56, 59))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('lap', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('lap', 'Gene', '7939', (60, 63))	('NQO1-medialed ROS production', 'MPA', (110, 138))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
61490	27960087	Elevated NQO1 levels were greater in high vs low grade PDAs (Figure S1E).	('PD', 'Disease', 'MESH:D010300', (55, 57))	('high', 'Var', (37, 41))	('NQO1 levels', 'MPA', (9, 20))	('NQO1', 'molecular_function', 'GO:0003955', ('9', '13'))
61494	27960087	LD50 values for beta-lap-treated NSCLC cell lines ranged between 1-4 microM, 2 hr, regardless of oncogenic or passenger mutations or deletions.	('lap', 'Gene', (21, 24))	('lap', 'Gene', '7939', (21, 24))	('deletions', 'Var', (133, 142))	('eta', 'Gene', (17, 20))	('NSCLC', 'Disease', (33, 38))	('LD50', 'MPA', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('eta', 'Gene', '1909', (17, 20))
61495	27960087	At least one wild-type NQO1 allele was sufficient for efficient cell killing by beta-lap, as heterozygous *2 or *3 NQO1 single nucleotide polymorphism (SNP) cells were killed with equal efficacy as homozygous wild-type cancer cells.	('NQO1', 'molecular_function', 'GO:0003955', ('115', '119'))	('cell killing', 'CPA', (64, 76))	('NQO1', 'Gene', (115, 119))	('single nucleotide polymorphism', 'Var', (120, 150))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('lap', 'Gene', '7939', (85, 88))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('eta', 'Gene', '1909', (81, 84))	('cancer', 'Disease', (219, 225))	('cell killing', 'biological_process', 'GO:0001906', ('64', '76'))	('lap', 'Gene', (85, 88))	('NQO1', 'molecular_function', 'GO:0003955', ('23', '27'))	('eta', 'Gene', (81, 84))
61503	27960087	We theorized that inhibiting PARP1 would enhance ROS formation due to continuous NQO1 futile redox cycling of beta-lap and generate greater DNA damage that, in turn, would not be repaired due to concomitant PARP inhibition.	('NQO1', 'molecular_function', 'GO:0003955', ('81', '85'))	('enhance', 'PosReg', (41, 48))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('lap', 'Gene', (115, 118))	('eta', 'Gene', '1909', (111, 114))	('ROS formation', 'MPA', (49, 62))	('inhibiting', 'Var', (18, 28))	('PARP1', 'Gene', (29, 34))	('DNA damage', 'MPA', (140, 150))	('lap', 'Gene', '7939', (115, 118))	('ROS formation', 'biological_process', 'GO:1903409', ('49', '62'))	('eta', 'Gene', (111, 114))	('NQO1', 'MPA', (81, 85))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))
61512	27960087	We examined NSCLC, PDA, and breast cancer cells that were reconstituted or knocked down for NQO1 expression, +- dicoumarol (Figures 4A-4H).	('knocked down', 'Var', (75, 87))	('NQO1', 'Gene', (92, 96))	('PD', 'Disease', 'MESH:D010300', (19, 21))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('NSCLC', 'Disease', (12, 17))	('breast cancer', 'Disease', (28, 41))	('NQO1', 'molecular_function', 'GO:0003955', ('92', '96'))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('+- dicoumarol', 'Chemical', 'MESH:D001728', (109, 122))
61513	27960087	H596 NSCLC cells that lack NQO1 expression due to a *2 NQO1 polymorphism, were reconstituted for NQO1 and sensitized to Rucaparib + beta-lap.	('lap', 'Gene', '7939', (137, 140))	('NQO1', 'molecular_function', 'GO:0003955', ('27', '31'))	('Rucaparib', 'Chemical', 'MESH:C531549', (120, 129))	('NQO1', 'molecular_function', 'GO:0003955', ('97', '101'))	('NSCLC', 'Disease', 'MESH:D002289', (5, 10))	('polymorphism', 'Var', (60, 72))	('NQO1', 'molecular_function', 'GO:0003955', ('55', '59'))	('NSCLC', 'Disease', (5, 10))	('NQO1', 'Gene', (55, 59))	('eta', 'Gene', '1909', (133, 136))	('eta', 'Gene', (133, 136))	('lap', 'Gene', (137, 140))
61517	27960087	Similarly, beta-lap-, chemo-, and radio- resistant Suit-2 (S2-013) PDA cancer cells that lack NQO1 expression due to a *2 polymorphism, were rendered hypersensitive to beta-lap + Rucaparib treatments with re-expression of wild-type NQO1.	('expression', 'MPA', (99, 109))	('lap', 'Gene', (16, 19))	('NQO1', 'molecular_function', 'GO:0003955', ('232', '236'))	('NQO1', 'molecular_function', 'GO:0003955', ('94', '98'))	('eta', 'Gene', (169, 172))	('lap', 'Gene', '7939', (16, 19))	('hypersensitive', 'Disease', (150, 164))	('NQO1', 'Gene', (94, 98))	('cancer', 'Disease', (71, 77))	('lap', 'Gene', (173, 176))	('lap', 'Gene', '7939', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('polymorphism', 'Var', (122, 134))	('lack', 'NegReg', (89, 93))	('Rucaparib', 'Chemical', 'MESH:C531549', (179, 188))	('eta', 'Gene', '1909', (12, 15))	('hypersensitive', 'Disease', 'MESH:D004342', (150, 164))	('PD', 'Disease', 'MESH:D010300', (67, 69))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('eta', 'Gene', '1909', (169, 172))	('eta', 'Gene', (12, 15))
61535	27960087	PARP1 knockdown caused a dramatic increase in lethality in beta-lap-treated stable shPARP1 knockdown MCF-7 cells (Figure S4E), with resistance to ATP losses (Figure S4F).	('shPARP1', 'Gene', (83, 90))	('knockdown', 'Var', (91, 100))	('lap', 'Gene', '7939', (64, 67))	('knockdown', 'Var', (6, 15))	('MCF-7', 'CellLine', 'CVCL:0031', (101, 106))	('lap', 'Gene', (64, 67))	('increase', 'PosReg', (34, 42))	('eta', 'Gene', '1909', (60, 63))	('eta', 'Gene', (60, 63))	('ATP', 'Chemical', 'MESH:D000255', (146, 149))	('PARP1', 'Gene', (0, 5))	('lethality', 'MPA', (46, 55))
61536	27960087	The lethal effects of beta-lap, with or without PARP1 inhibition or knockdown, were NQO1-dependent and blocked by dicoumarol (Figure S4E).	('lap', 'Gene', (27, 30))	('lap', 'Gene', '7939', (27, 30))	('PARP1', 'Gene', (48, 53))	('dicoumarol', 'Chemical', 'MESH:D001728', (114, 124))	('knockdown', 'Var', (68, 77))	('NQO1', 'molecular_function', 'GO:0003955', ('84', '88'))	('eta', 'Gene', '1909', (23, 26))	('eta', 'Gene', (23, 26))
61554	27960087	Since similar ROS levels were noted with the combination therapy vs individual exposures of A549 cells to low doses of beta-lap alone (Figure 6A), our data strongly suggest that inhibiting PARP activity by Rucaparib significantly impeded the repair of initial beta-lap-induced DNA lesions (DNA base, SSBs), culminating in conversion of initial lesions to more lethal non-repairable DSBs noted 24 hr later (Figure 7B).	('DNA', 'cellular_component', 'GO:0005574', ('290', '293'))	('eta', 'Gene', '1909', (120, 123))	('eta', 'Gene', '1909', (261, 264))	('impeded', 'NegReg', (230, 237))	('Rucaparib', 'Chemical', 'MESH:C531549', (206, 215))	('eta', 'Gene', (120, 123))	('lap', 'Gene', (124, 127))	('eta', 'Gene', (261, 264))	('SSBs', 'Chemical', 'MESH:C016118', (300, 304))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('repair', 'MPA', (242, 248))	('lap', 'Gene', '7939', (124, 127))	('DSBs', 'Chemical', 'MESH:C007563', (382, 386))	('PARP', 'Protein', (189, 193))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('inhibiting', 'Var', (178, 188))	('DNA', 'cellular_component', 'GO:0005574', ('277', '280'))	('lap', 'Gene', (265, 268))	('lap', 'Gene', '7939', (265, 268))	('activity', 'MPA', (194, 202))
61592	27960087	Here, we show that combining PARP inhibitors with the highly tumor-specific DNA damaging agent, beta-lap, results in synergy at nontoxic doses of both drugs in NQO1+ over-expressing non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDA) and breast cancers, including TNBC.	('pancreatic ductal adenocarcinoma', 'Disease', (211, 243))	('NQO1+', 'Var', (160, 165))	('eta', 'Gene', '1909', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (211, 243))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('eta', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('over-expressing', 'PosReg', (166, 181))	('PD', 'Disease', 'MESH:D010300', (245, 247))	('NSCLC', 'Disease', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('lap', 'Gene', (101, 104))	('breast cancers', 'Disease', 'MESH:D001943', (254, 268))	('breast cancers', 'Disease', (254, 268))	('TNBC', 'Disease', (280, 284))	('lap', 'Gene', '7939', (101, 104))	('non-small cell lung', 'Disease', (182, 201))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('breast cancers', 'Phenotype', 'HP:0003002', (254, 268))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (211, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('synergy', 'MPA', (117, 124))	('NQO1', 'molecular_function', 'GO:0003955', ('160', '164'))	('tumor', 'Disease', (61, 66))
61594	27960087	Combining a PARP inhibitor with beta-lap results in robust, NQO1-dependent, tumor-selective SSBs, DSBs and apoptosis in vitro and in vivo, with synergistic antitumor efficacy in mice bearing NQO1+ pancreatic or NSCLC orthotopic xenografts.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('inhibitor', 'Var', (17, 26))	('NQO1-dependent', 'Gene', (60, 74))	('tumor', 'Disease', (76, 81))	('pancreatic', 'Disease', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('eta', 'Gene', '1909', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('NQO1', 'molecular_function', 'GO:0003955', ('191', '195'))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('apoptosis', 'CPA', (107, 116))	('eta', 'Gene', (33, 36))	('PARP', 'Gene', (12, 16))	('DSBs', 'Chemical', 'MESH:C007563', (98, 102))	('mice', 'Species', '10090', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('NQO1', 'molecular_function', 'GO:0003955', ('60', '64'))	('SSBs', 'Chemical', 'MESH:C016118', (92, 96))	('NSCLC', 'Disease', (211, 216))	('lap', 'Gene', (37, 40))	('lap', 'Gene', '7939', (37, 40))	('tumor', 'Disease', (160, 165))	('pancreatic', 'Disease', 'MESH:D010195', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))
61602	27960087	Analyses of NSCLCs growing >140 days post-Rucaparib + beta-lap revealed NQO1+ and no NQO1- cancers, suggesting an effect of insufficient drug levels rather than resistance.	('lap', 'Gene', (59, 62))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('lap', 'Gene', '7939', (59, 62))	('eta', 'Gene', '1909', (55, 58))	('eta', 'Gene', (55, 58))	('NQO1- cancers', 'Disease', 'MESH:D009369', (85, 98))	('NSCLC', 'Disease', (12, 17))	('NQO1', 'molecular_function', 'GO:0003955', ('72', '76'))	('Rucaparib', 'Chemical', 'MESH:C531549', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('NQO1+', 'Var', (72, 77))	('NQO1', 'molecular_function', 'GO:0003955', ('85', '89'))	('NQO1- cancers', 'Disease', (85, 98))
61609	27960087	PARP inhibitors prevented NAD+ loss, sustained NQO1 futile cycling of beta-lap, caused elevated ROS/H2O2 levels with enhanced DNA damage (e.g., DSBs), whose repair was suppressed by PARP inhibition.	('H2O2', 'Chemical', 'MESH:D006861', (100, 104))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('eta', 'Gene', '1909', (71, 74))	('DSBs', 'Disease', (144, 148))	('NQO1 futile cycling', 'MPA', (47, 66))	('NQO1', 'molecular_function', 'GO:0003955', ('47', '51'))	('prevented', 'NegReg', (16, 25))	('NAD+', 'Chemical', 'MESH:D009243', (26, 30))	('NAD+', 'MPA', (26, 30))	('eta', 'Gene', (71, 74))	('lap', 'Gene', (75, 78))	('enhanced', 'PosReg', (117, 125))	('DNA damage', 'MPA', (126, 136))	('lap', 'Gene', '7939', (75, 78))	('ROS/H2O2 levels', 'MPA', (96, 111))	('elevated', 'PosReg', (87, 95))	('DSBs', 'Chemical', 'MESH:C007563', (144, 148))	('PARP', 'Gene', (0, 4))	('inhibitors', 'Var', (5, 15))	('elevated ROS/H2O2 levels', 'Phenotype', 'HP:0025464', (87, 111))
61615	27960087	MCF-7 and MDA-MB-231 cells were equally sensitized by Rucaparib + beta-lap, yet these cells have wild-type vs mutant p53 and estrogen receptor+ vs triple-negative (estrogen receptor-, Heregulin receptor 2- and progesterone receptor-) growth statuses, respectively.	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('p53', 'Gene', (117, 120))	('mutant', 'Var', (110, 116))	('eta', 'Gene', '1909', (67, 70))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (10, 20))	('lap', 'Gene', (71, 74))	('lap', 'Gene', '7939', (71, 74))	('eta', 'Gene', (67, 70))	('Rucaparib', 'Chemical', 'MESH:C531549', (54, 63))
61616	27960087	The drug combination retains NQO1-dependency, where synergy was noted in >90% mutant KRAS PDAs, but also equally effective against >80% NSCLC, >60% breast, >60% prostate, >45% head and neck and >60% colon cancers, where NQO1 is elevated.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('NQO1', 'molecular_function', 'GO:0003955', ('29', '33'))	('colon cancers', 'Disease', 'MESH:D015179', (199, 212))	('colon cancers', 'Disease', (199, 212))	('KRAS', 'Gene', '3845', (85, 89))	('prostate', 'Disease', (161, 169))	('breast', 'Disease', (148, 154))	('eta', 'Gene', '1909', (22, 25))	('eta', 'Gene', (22, 25))	('PD', 'Disease', 'MESH:D010300', (90, 92))	('KRAS', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('NQO1', 'molecular_function', 'GO:0003955', ('220', '224'))	('NSCLC', 'Disease', (136, 141))	('mutant', 'Var', (78, 84))	('neck', 'cellular_component', 'GO:0044326', ('185', '189'))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('colon cancers', 'Phenotype', 'HP:0003003', (199, 212))
61619	27960087	However, overall cell death is still triggered by PARP inhibitors + beta-lap by excessive levels of H2O2, at doses not likely to elicit resistance.	('H2O2', 'Chemical', 'MESH:D006861', (100, 104))	('inhibitors +', 'Var', (55, 67))	('eta', 'Gene', '1909', (69, 72))	('lap', 'Gene', (73, 76))	('cell death', 'CPA', (17, 27))	('lap', 'Gene', '7939', (73, 76))	('eta', 'Gene', (69, 72))	('PARP', 'Gene', (50, 54))	('H2O2', 'MPA', (100, 104))	('cell death', 'biological_process', 'GO:0008219', ('17', '27'))	('triggered', 'Reg', (37, 46))
61652	27960087	Inhibitors of poly(ADP-ribose) polymerase (PARP) activity, similar to other DNA repair blockers, lack tumor-selectivity, are typically toxic to normal tissue and are only efficacious against a small subset of vulnerable (e.g., BRCA1/2 deficient) cancers by synthetic lethality.	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('DNA repair', 'biological_process', 'GO:0006281', ('76', '86'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Inhibitors', 'Var', (0, 10))	('lack', 'NegReg', (97, 101))	('poly(ADP-ribose) polymerase', 'Gene', '142', (14, 41))	('poly(ADP-ribose) polymerase', 'Gene', (14, 41))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('BRCA1/2 deficient) cancers', 'Disease', 'OMIM:612555', (227, 253))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
61658	27960087	PARP inhibitors + beta-lap induce DNA lesions, block repair, and cause apoptosis.	('apoptosis', 'CPA', (71, 80))	('PARP', 'Gene', (0, 4))	('repair', 'MPA', (53, 59))	('induce', 'Reg', (27, 33))	('DNA lesions', 'MPA', (34, 45))	('cause', 'Reg', (65, 70))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('inhibitors +', 'Var', (5, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('eta', 'Gene', '1909', (19, 22))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('lap', 'Gene', (23, 26))	('lap', 'Gene', '7939', (23, 26))	('block', 'NegReg', (47, 52))	('eta', 'Gene', (19, 22))
61714	27273134	The cumulative incidence of VTE at 3, 6, 12, and 24 months were 5.2%, 6.2%, 7,2%, and 10.3% for high KRS and 5.1%, 6.3%, 7.4%, and 9.2% for intermediate KRS (Table 2).	('VTE', 'Disease', 'MESH:D054556', (28, 31))	('VTE', 'Disease', (28, 31))	('high KRS', 'Var', (96, 104))
61720	27273134	Among patients with NSCLC, there was no significant association of a high KRS and VTE.	('VTE', 'Disease', 'MESH:D054556', (82, 85))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('VTE', 'Disease', (82, 85))	('patients', 'Species', '9606', (6, 14))	('high', 'Var', (69, 73))	('NSCLC', 'Disease', (20, 25))
61721	27273134	KRS was a predictor of mortality (HR 1.7 95% CI 1.4 - 2.2) in this cohort of patients with lung cancer (Figure 2).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('KRS', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('patients', 'Species', '9606', (77, 85))	('lung cancer', 'Disease', (91, 102))
61723	27273134	In this prospectively maintained cohort of patients with lung cancer and retrospectively adjudicated VTE events, a high KRS was not predictive of thrombotic events but was independently associated with all-cause mortality.	('all-cause mortality', 'MPA', (202, 221))	('thrombotic events', 'Phenotype', 'HP:0001907', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (43, 51))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('thrombotic', 'Disease', 'MESH:D013927', (146, 156))	('VTE', 'Disease', 'MESH:D054556', (101, 104))	('VTE', 'Disease', (101, 104))	('associated with', 'Reg', (186, 201))	('high KRS', 'Var', (115, 123))	('thrombotic', 'Disease', (146, 156))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
61738	27273134	In a study of patients with pancreatic cancer, patients with a high KRS were more likely to die within 6 months (HR 2.5; 95%CI 1.1 - 2.1).	('pancreatic cancer', 'Disease', (28, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('patients', 'Species', '9606', (47, 55))	('high KRS', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('patients', 'Species', '9606', (14, 22))
61753	27273134	A high KRS was not predictive of VTE but was independently associated with all-cause mortality.	('VTE', 'Disease', (33, 36))	('high KRS', 'Var', (2, 10))	('associated with', 'Reg', (59, 74))	('all-cause mortality', 'MPA', (75, 94))	('VTE', 'Disease', 'MESH:D054556', (33, 36))
61760	33509252	Beyond this "classical" pathway, ADCs can induce tumor cell death through the so-called bystander effect, which occurs when the cytotoxic warhead diffuses across the cell membrane to neighboring cells, thus inducing their apoptosis.	('ADCs', 'Var', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cell membrane', 'cellular_component', 'GO:0005886', ('164', '177'))	('apoptosis', 'biological_process', 'GO:0097194', ('220', '229'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('induce', 'Reg', (42, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('220', '229'))	('apoptosis', 'CPA', (222, 231))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))	('tumor', 'Disease', (49, 54))	('inducing', 'Reg', (207, 215))
61773	33509252	Conversely, conjugation into ADC hides the cytotoxic drug in the bloodstream to convey it directly into tumor cells, thus significantly reducing toxicity of these potent agents.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('reducing', 'NegReg', (136, 144))	('conjugation', 'biological_process', 'GO:0000746', ('12', '23'))	('tumor', 'Disease', (104, 109))	('ADC', 'Gene', (29, 32))	('conjugation', 'Var', (12, 23))	('toxicity', 'Disease', 'MESH:D064420', (145, 153))	('toxicity', 'Disease', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
61779	33509252	Maytansinoids (DM1 and DM4) are synthetic derivatives of maytansine that also act by inhibiting microtubule polymerization.	('Maytansinoids', 'Chemical', '-', (0, 13))	('DM1', 'Gene', (15, 18))	('microtubule', 'cellular_component', 'GO:0005874', ('96', '107'))	('inhibiting', 'NegReg', (85, 95))	('DM1', 'Gene', '28509', (15, 18))	('microtubule polymerization', 'MPA', (96, 122))	('microtubule polymerization', 'biological_process', 'GO:0046785', ('96', '122'))	('DM4', 'Chemical', 'MESH:D008453', (23, 26))	('DM4', 'Var', (23, 26))	('maytansine', 'Chemical', 'MESH:D008453', (57, 67))
61795	33509252	Given the rarity of these mutations, their role as oncogenic drivers has been questioned for many years, and only recent studies proved their tumorigenic role along with their sensitivity to anti-HER2 agents.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('HER2', 'Gene', (196, 200))	('mutations', 'Var', (26, 35))	('HER2', 'Gene', '2064', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
61796	33509252	Bladder cancer has the highest prevalence of HER2 mutations (9-18%), followed by uterine cervix (6%), colorectal (5.8%), lung (4%) and breast cancer (4%).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('uterine cervix', 'Disease', (81, 95))	('lung', 'Disease', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('uterine cervix', 'Phenotype', 'HP:0030160', (81, 95))	('colorectal', 'Disease', (102, 112))	('HER2', 'Gene', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('HER2', 'Gene', '2064', (45, 49))	('breast cancer', 'Disease', (135, 148))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', (142, 148))
61801	33509252	Trastuzumab deruxtecan (DS-8201a; T-DXd) is an anti-HER2 ADC in which trastuzumab is conjugated with DXd, a novel topoisomerase I inhibitor payload.	('topoisomerase', 'molecular_function', 'GO:0003918', ('114', '127'))	('deruxtecan', 'Chemical', '-', (12, 22))	('HER2', 'Gene', '2064', (52, 56))	('DS-8201a', 'Var', (24, 32))	('trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('topoisomerase', 'molecular_function', 'GO:0003917', ('114', '127'))	('HER2', 'Gene', (52, 56))
61818	33509252	This gap has mainly been attributed to tumor heterogeneity of HER2-expression in GC/GEJC, eventual co-occurrence of HER2 amplification with other oncogenic mutations and to mechanisms of primary and secondary resistance to anti-HER2 treatments.	('amplification', 'Var', (121, 134))	('HER2', 'Gene', '2064', (62, 66))	('HER2', 'Gene', (228, 232))	('GC/GEJC', 'Disease', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('HER2', 'Gene', '2064', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('HER2', 'Gene', (116, 120))	('co-occurrence', 'Reg', (99, 112))	('tumor', 'Disease', (39, 44))	('HER2', 'Gene', '2064', (116, 120))	('HER2', 'Gene', (62, 66))
61820	33509252	The trial met its primary endpoint, with an ORR of 51% in patients in the T-DXd group, as compared to 14% in the control arm (P < 0.001).	('met', 'Gene', (10, 13))	('T-DXd', 'Var', (74, 79))	('met', 'Gene', '79811', (10, 13))	('patients', 'Species', '9606', (58, 66))
61830	33509252	Noteworthy, many other anti-HER2 ADCs are under evaluation, including A166, XMT-1522, MEDI-4276, ARX788, RC48-ADC, BAT8001 and PF-06804103.	('HER2', 'Gene', '2064', (28, 32))	('PF-06804103', 'Var', (127, 138))	('BAT8001', 'Var', (115, 122))	('HER2', 'Gene', (28, 32))	('A166', 'Var', (70, 74))
61859	33509252	This ADC is characterized by a high drug-to-antibody ratio (7.5-8), allowed by the significantly better toxicity profile of SN-38 than irinotecan, its prodrug.	('SN-38', 'Chemical', 'MESH:D000077146', (124, 129))	('antibody', 'cellular_component', 'GO:0042571', ('44', '52'))	('antibody', 'cellular_component', 'GO:0019814', ('44', '52'))	('toxicity', 'Disease', 'MESH:D064420', (104, 112))	('antibody', 'molecular_function', 'GO:0003823', ('44', '52'))	('antibody', 'cellular_component', 'GO:0019815', ('44', '52'))	('toxicity', 'Disease', (104, 112))	('better', 'PosReg', (97, 103))	('SN-38', 'Var', (124, 129))	('irinotecan', 'Chemical', 'MESH:D000077146', (135, 145))
61882	33509252	The TROPiCS-03 (NCT03964727) is a multi-cohort, open-label, phase 2 study that is currently open to enrollment for patients with metastatic solid tumors, presently NSCLC (adenocarcinoma and squamous cell carcinoma), head and neck squamous cell carcinoma, and endometrial cancer, all selected for Trop-2 overexpression by a validated IHC assay.	('met', 'Gene', (129, 132))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (225, 253))	('neck', 'cellular_component', 'GO:0044326', ('225', '229'))	('Trop-2', 'Gene', '4070', (296, 302))	('endometrial cancer', 'Phenotype', 'HP:0012114', (259, 277))	('met', 'Gene', '79811', (263, 266))	('met', 'Gene', (263, 266))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('Trop-2', 'Gene', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('solid tumors', 'Disease', (140, 152))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('endometrial cancer', 'Disease', (259, 277))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('endometrial cancer', 'Disease', 'MESH:D016889', (259, 277))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (216, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('NSCLC', 'Disease', (164, 169))	('patients', 'Species', '9606', (115, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('NCT03964727', 'Var', (16, 27))	('overexpression', 'PosReg', (303, 317))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 213))	('neck squamous cell carcinoma', 'Disease', (225, 253))	('met', 'Gene', '79811', (129, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
61903	33509252	SAR408701 is an ADC in which an anti-CEACAM5 antibody is conjugated to DM4, a maytansinoid cytotoxic agent.	('SAR408701', 'Chemical', '-', (0, 9))	('CEACAM5', 'Gene', (37, 44))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('CEACAM5', 'Gene', '1048', (37, 44))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('DM4', 'Chemical', 'MESH:D008453', (71, 74))	('conjugated', 'Interaction', (57, 67))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('SAR408701', 'Var', (0, 9))
61908	33509252	Given the manageable tolerability profile, SAR408701 was then subsequently investigated in three expansion cohorts, enrolling patients with CRC, lung cancers (both small-cell lung cancer and non-squamous NSCLC) and GC.	('small-cell lung cancer', 'Disease', 'MESH:D055752', (164, 186))	('small-cell lung cancer', 'Disease', (164, 186))	('non-squamous NSCLC', 'Disease', (191, 209))	('CRC', 'Disease', (140, 143))	('patients', 'Species', '9606', (126, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('lung cancers', 'Disease', 'MESH:D008175', (145, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('lung cancers', 'Disease', (145, 157))	('SAR408701', 'Var', (43, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('SAR408701', 'Chemical', '-', (43, 52))	('lung cancers', 'Phenotype', 'HP:0100526', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (191, 209))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('CR', 'Chemical', '-', (140, 142))
61909	33509252	Most promising data came from the non-squamous NSCLC cohort, where a high antitumor activity was shown particularly in patients with high expression of CEACAM5 (>= 50%; ORR 20.3%, SD 42.2%), while responses were reduced in moderate expressors (1-49%; ORR 7.1%).	('high expression', 'Var', (133, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (34, 52))	('tumor', 'Disease', (78, 83))	('CEACAM5', 'Gene', (152, 159))	('non-squamous NSCLC', 'Disease', (34, 52))	('CEACAM5', 'Gene', '1048', (152, 159))
61910	33509252	Accordingly, subsequent development of SAR408701 was mainly focused on patients with CEACAM5-positive non-squamous NSCLC, and three ongoing trials are investigating it as monotherapy (CARMEN-LC03), in association with ramucirumab (CARMEN-LC04) or as first-line therapy in combination with PD-1 (CARMEN-LC05) are ongoing (Table 2).	('ramucirumab', 'Chemical', 'MESH:C543333', (218, 229))	('CEACAM5', 'Gene', '1048', (85, 92))	('CEACAM5', 'Gene', (85, 92))	('patients', 'Species', '9606', (71, 79))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (102, 120))	('PD-1', 'Gene', '5133', (289, 293))	('PD-1', 'Gene', (289, 293))	('SAR408701', 'Var', (39, 48))	('non-squamous NSCLC', 'Disease', (102, 120))	('SAR408701', 'Chemical', '-', (39, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
61911	33509252	Of note, despite the high expression of CEACAM5 by colorectal cancer cells, development of SAR408701 was discontinued in this subtype because of its low sensitivity to microtubule-inhibitors payload.	('SAR408701', 'Chemical', '-', (91, 100))	('CEACAM5', 'Gene', '1048', (40, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('sensitivity to microtubule-inhibitors payload', 'MPA', (153, 198))	('microtubule', 'cellular_component', 'GO:0005874', ('168', '179'))	('colorectal cancer', 'Disease', (51, 68))	('SAR408701', 'Var', (91, 100))	('CEACAM5', 'Gene', (40, 47))
61931	33509252	A phase I trial then investigated this ADC in EGFR-mutated NSCLC progressing to first generation EGFR-TKIs and negative for T790M mutation, or after osimertinib failure.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', '1956', (46, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('EGFR', 'Gene', (97, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('T790M mutation', 'Var', (124, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('osimertinib failure', 'Disease', (149, 168))	('NSCLC', 'Disease', (59, 64))	('T790M', 'Mutation', 'rs121434569', (124, 129))	('osimertinib failure', 'Disease', 'MESH:D006333', (149, 168))
61934	33509252	Antitumor activity was seen regardless of the specific mechanism of resistance to EGFR-TKI (EGFR mutations, amplifications of non-EGFR mutations/fusions).	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', (82, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('amplifications', 'Var', (108, 122))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
61958	33509252	Others anti-mesothelin ADCs, like DMOT4039A, RC88 and BMS-986148, are under clinical evaluation (Table 2).	('DMOT4039A', 'Var', (34, 43))	('MS', 'Chemical', 'MESH:C000607289', (55, 57))	('mesothelin', 'Gene', (12, 22))	('mesothelin', 'Gene', '10232', (12, 22))
61962	33509252	Physiologically, c-Met is primarily implicated in processes of cell motility occurring during embryogenesis and wound repair, while its pathological activation throughout mutation, amplification or overexpression has been detected in different cancer types.	('embryogenesis', 'biological_process', 'GO:0009790', ('94', '107'))	('mutation', 'Var', (171, 179))	('cancer', 'Disease', (244, 250))	('c-Met', 'Gene', '4233', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('implicated', 'Reg', (36, 46))	('cell motility', 'biological_process', 'GO:0048870', ('63', '76'))	('embryogenesis', 'biological_process', 'GO:0009793', ('94', '107'))	('cell motility', 'CPA', (63, 76))	('embryogenesis', 'biological_process', 'GO:0009792', ('94', '107'))	('activation', 'PosReg', (149, 159))	('c-Met', 'Gene', (17, 22))
61963	33509252	Aberrations of c-Met have been described as both primary events, leading to cancer cell transformation, and secondary events, responsible for cancer progression and treatment resistance.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('c-Met', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('c-Met', 'Gene', '4233', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', (76, 82))	('leading to', 'Reg', (65, 75))	('cancer', 'Disease', (142, 148))
61980	33509252	Conversely, data from LUNG-MAP sub-study S1400K evaluating teliso-V in squamous NSCLC in ICI-refractory or ICI-naive patients were disappointing, with a ORR of 9% (2/23) and 7 high-grade events (3 G5 and 4 G3), leading to S1400K closure.	('S1400K', 'Mutation', 'p.S1400K', (222, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('squamous NSCLC', 'Disease', (71, 85))	('MAP', 'molecular_function', 'GO:0004239', ('27', '30'))	('S1400K', 'Mutation', 'p.S1400K', (41, 47))	('squamous NSCLC', 'Disease', 'MESH:D002294', (71, 85))	('S1400K', 'Var', (222, 228))	('patients', 'Species', '9606', (117, 125))
61981	33509252	A phase II study (NCT03539536) investigating teliso-V in both squamous and non-squamous (EGFR mutated and wt) c-Met-positive NSCLC is open to enrollment, with data expected in 2021.	('mutated', 'Var', (94, 101))	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', (125, 130))	('c-Met', 'Gene', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('c-Met', 'Gene', '4233', (110, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('EGFR', 'Gene', '1956', (89, 93))
62033	33509252	Centyrins are small (~ 10 kDa) cysteine-free scaffolds based on the type-III fibronectin domain of human Tenascin C. These alternative scaffolds possess excellent biophysical properties, which allow for mutation and conjugation at one or even multiple positions and are easily internalized by tumor.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('Tenascin C', 'Gene', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('conjugation', 'MPA', (216, 227))	('Tenascin C', 'Gene', '3371', (105, 115))	('Tenascin C', 'cellular_component', 'GO:0090733', ('105', '115'))	('mutation', 'Var', (203, 211))	('tumor', 'Disease', (293, 298))	('conjugation', 'biological_process', 'GO:0000746', ('216', '227'))	('cysteine', 'Chemical', 'MESH:D003545', (31, 39))	('human', 'Species', '9606', (99, 104))
62039	33509252	Trastuzumab deruxtecan has been associated with development of grade 5 interstitial lung diseases (ILDs) across several tumor types, while maytansinoids or auristatins-based ADCs have been linked to high-grade ocular or neurological toxicities, not always reversible.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('auristatins', 'Chemical', 'MESH:C543533', (156, 167))	('neurological toxicities', 'Disease', 'MESH:D009422', (220, 243))	('ILDs', 'Phenotype', 'HP:0006530', (99, 103))	('deruxtecan', 'Var', (12, 22))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (71, 96))	('associated with', 'Reg', (32, 47))	('lung diseases', 'Disease', 'MESH:D008171', (84, 97))	('ILD', 'Disease', 'MESH:D017563', (99, 102))	('lung diseases', 'Phenotype', 'HP:0002088', (84, 97))	('tumor', 'Disease', (120, 125))	('ILD', 'Phenotype', 'HP:0006530', (99, 102))	('maytansinoids', 'Chemical', '-', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('lung diseases', 'Disease', (84, 97))	('ILD', 'Disease', (99, 102))	('deruxtecan', 'Chemical', '-', (12, 22))	('lung disease', 'Phenotype', 'HP:0002088', (84, 96))	('neurological toxicities', 'Disease', (220, 243))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('interstitial lung diseases', 'Phenotype', 'HP:0006530', (71, 97))
62055	33472858	MAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (28, 33))	('MAMs', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mouse', 'Species', '10090', (100, 105))	('mice', 'Species', '10090', (58, 62))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('E0771-LG', 'Var', (91, 99))
62070	33472858	In this study, we identified that NK cell cytotoxicity is suppressed by metastasis-associated macrophages (MAMs) via transforming growth factor beta (TGF-beta) and that depletion of MAMs or blockade of TGF-beta signaling enhances efficacy of infused NK cells in suppressing early metastatic tumor outgrowth (online supplemental file 1).	('TGF-beta', 'Gene', '21802', (150, 158))	('depletion', 'Var', (169, 178))	('TGF-beta', 'Gene', (202, 210))	('enhances', 'PosReg', (221, 229))	('TGF-beta', 'Gene', '21802', (202, 210))	('MAMs', 'Chemical', '-', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('signaling', 'biological_process', 'GO:0023052', ('211', '220'))	('MAMs', 'Chemical', '-', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('117', '148'))	('suppressing', 'NegReg', (262, 273))	('tumor', 'Disease', (291, 296))	('TGF-beta', 'Gene', (150, 158))	('blockade', 'Var', (190, 198))
62075	33472858	E0771-LG cells, a highly metastatic derivative of E0771 mouse mammary adenocarcinoma cells that originated from a medullary cancer in C57BL/6 mice, were manipulated to express firefly luciferase (E0771-LG:Fluc) and a nuclear localized red fluorescent protein mKate2 (E0771-LG:Fluc_NLR) as previously described.	('cancer', 'Disease', (124, 130))	('E0771-LG', 'Var', (196, 204))	('mouse', 'Species', '10090', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mice', 'Species', '10090', (142, 146))	('adenocarcinoma', 'Disease', (70, 84))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
62079	33472858	1x106 of E0771-LG:Fluc cells were injected into the tail vein of syngeneic C57BL/6JCrl or Csf1r-cKO mice (7-12-week-old females).	('Csf1', 'molecular_function', 'GO:0005011', ('90', '94'))	('mice', 'Species', '10090', (100, 104))	('Csf1r', 'Gene', (90, 95))	('Csf1r', 'Gene', '12978', (90, 95))	('E0771-LG', 'Var', (9, 17))
62086	33472858	To block TGF-beta signaling, a selective TGF-beta receptor antagonist LY346947 (Seleckchem, 0.2 mg/20 g mouse) was injected into the peritoneum every 2 days from day 4 after tumor injection.	('tumor', 'Disease', (174, 179))	('TGF-beta', 'Gene', '21802', (41, 49))	('mouse', 'Species', '10090', (104, 109))	('TGF-beta', 'Gene', (9, 17))	('LY346947', 'Var', (70, 78))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('TGF-beta', 'Gene', '21802', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('LY346947', 'Chemical', '-', (70, 78))	('TGF-beta', 'Gene', (41, 49))
62094	33472858	1x103 target cells (E0771-LG:Fluc_NLR cells), 4x103 effector cells (splenic NK cells), and/or 3x103 suppressor cells (macrophages or MDSCs isolated from the lung containing E0771-LG metastatic tumors) were seeded into 96-well plates (Nunc) precoated with basement membrane extract (Geltrex, Gibco).	('E0771-LG', 'Var', (173, 181))	('basement membrane', 'cellular_component', 'GO:0005604', ('255', '272'))	('tumors', 'Disease', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (193, 199))
62111	33472858	In this model, numbers of M-MDSCs and MAMs, but not lung RMACs, were significantly increased in the lung containing metastatic tumors established by E0771-LG:Fluc cells (online supplemental figure 1 and figure 1A).	('E0771-LG:Fluc', 'Var', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MAMs', 'Chemical', '-', (38, 42))	('increased', 'PosReg', (83, 92))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('RMACs', 'Chemical', '-', (57, 62))
62120	33472858	It is reported that the gene expression profile of GM-BMMs is closer to that of macrophages than to dendritic cells and is clearly distinct from that of M-BMMs.	('GM-BMMs', 'Var', (51, 58))	('gene expression', 'biological_process', 'GO:0010467', ('24', '39'))	('gene expression profile', 'MPA', (24, 47))	('GM', 'Chemical', 'MESH:D005839', (51, 53))
62121	33472858	The phenotype of GM-BMMs (F4/80+CD11bLowCD11cHigh) is also distinguishable from that of M-BMMs (F4/80+CD11bHigh CD11cLow) (online supplemental figure 2), which represent RMACs and MAMs in the metastatic lung, respectively.	('CD11c', 'Gene', '16411', (112, 117))	('CD11c', 'Gene', (112, 117))	('CD11c', 'Gene', (40, 45))	('CD11bLowCD11cHigh', 'Gene', (32, 49))	('CD11c', 'Gene', '16411', (40, 45))	('F4/80+CD11bHigh', 'Var', (96, 111))	('RMACs', 'Chemical', '-', (170, 175))	('MAMs', 'Chemical', '-', (180, 184))	('GM', 'Chemical', 'MESH:D005839', (17, 19))	('CD11bLowCD11cHigh', 'Gene', '12479', (32, 49))
62124	33472858	We further performed the NK cell cytotoxicity assay in "non-contact" conditions where M-BMMs were placed in a Transwell chamber to physically separate them from tumor and NK cells, and found that M-BMMs under this condition did not reduce the apoptotic fraction of tumor cells cultured with NK cells (figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('rat', 'Species', '10116', (146, 149))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('apoptotic fraction', 'CPA', (243, 261))	('tumor', 'Disease', (161, 166))	('M-BMMs', 'Var', (196, 202))
62127	33472858	We thus hypothesized that M-BMMs might suppress NK cell cytotoxicity via H2-Kb and/or H2-Db.	('H2-Db', 'Protein', (86, 91))	('H2-Kb', 'Gene', '14972', (73, 78))	('H2-Db', 'Chemical', '-', (86, 91))	('suppress NK cell cytotoxicity', 'Phenotype', 'HP:0040218', (39, 68))	('M-BMMs', 'Var', (26, 32))	('NK cell cytotoxicity', 'CPA', (48, 68))	('suppress', 'NegReg', (39, 47))	('H2-Kb', 'Gene', (73, 78))
62128	33472858	However, blocking antibodies against H2-Kb, H-2Db, or their receptors Ly49C/I did not rescue the suppression of NK cell cytotoxicity caused by M-BMMs (figure 2D).	('Ly49C', 'Gene', '16634', (70, 75))	('NK cell cytotoxicity', 'CPA', (112, 132))	('H-2Db', 'Protein', (44, 49))	('Ly49C', 'Gene', (70, 75))	('H2-Kb', 'Gene', '14972', (37, 42))	('M-BMMs', 'Var', (143, 149))	('H2-Kb', 'Gene', (37, 42))
62131	33472858	We found that mb-TGF-beta expression was significantly higher in NK suppressive M-BMMs compared with non-suppressive GM-BMMs (figure 2E, F).	('TGF-beta', 'Gene', (17, 25))	('expression', 'MPA', (26, 36))	('TGF-beta', 'Gene', '21802', (17, 25))	('suppressive', 'Var', (68, 79))	('GM', 'Chemical', 'MESH:D005839', (117, 119))	('higher', 'PosReg', (55, 61))
62136	33472858	To investigate the effects of MAMs on NK cell phenotype and functions in the metastatic tumor microenvironment, we used CSF-1 receptor conditional knockout (Csf1r-cKO) mice in which floxed CSF-1 receptor genes (Csf1rF/F) are deleted and thereby certain macrophage populations are ablated on doxycycline treatment.	('Csf1r', 'Gene', (157, 162))	('CSF-1 receptor', 'Gene', '12978', (120, 134))	('MAMs', 'Chemical', '-', (30, 34))	('CSF-1 receptor', 'Gene', (120, 134))	('Csf1', 'molecular_function', 'GO:0005011', ('211', '215'))	('deleted', 'Var', (225, 232))	('Csf1r', 'Gene', '12978', (211, 216))	('Csf1', 'molecular_function', 'GO:0005011', ('157', '161'))	('CSF-1 receptor', 'Gene', '12978', (189, 203))	('CSF-1 receptor', 'Gene', (189, 203))	('CSF-1', 'molecular_function', 'GO:0005011', ('189', '194'))	('tumor', 'Disease', (88, 93))	('Csf1r', 'Gene', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Csf1r', 'Gene', '12978', (157, 162))	('mice', 'Species', '10090', (168, 172))	('doxycycline', 'Chemical', 'MESH:D004318', (291, 302))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CSF-1', 'molecular_function', 'GO:0005011', ('120', '125'))
62137	33472858	We injected E0771-LG tumor cells into the tail vein of Csf1r-cKO mice and treated with either doxycycline or vehicle from day 4 after tumor cell injection, a time point when tumor cells develop micro-metastases within the lung (figure 3A).	('tumor', 'Disease', (174, 179))	('Csf1', 'molecular_function', 'GO:0005011', ('55', '59'))	('metastases', 'Disease', (200, 210))	('tumor', 'Disease', (21, 26))	('metastases', 'Disease', 'MESH:D009362', (200, 210))	('mice', 'Species', '10090', (65, 69))	('Csf1r', 'Gene', (55, 60))	('Csf1r', 'Gene', '12978', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('E0771-LG', 'Var', (12, 20))	('doxycycline', 'Chemical', 'MESH:D004318', (94, 105))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
62140	33472858	In contrast, the ratio of CD69 expressing NK cells in the tumor-bearing lung was significantly increased in doxycycline treated mice compared with vehicle treated mice (figure 3C).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('doxycycline', 'Chemical', 'MESH:D004318', (108, 119))	('CD69', 'Gene', (26, 30))	('doxycycline', 'Var', (108, 119))	('mice', 'Species', '10090', (128, 132))	('mice', 'Species', '10090', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('rat', 'Species', '10116', (17, 20))	('increased', 'PosReg', (95, 104))
62142	33472858	Therefore, the increase in CD69+ NK cells by MAM depletion is likely to be caused by enhanced activation of tumor-infiltrating NK cells rather than accumulation of tissue resident NK cells within the metastatic lung.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MAM', 'cellular_component', 'GO:0044233', ('45', '48'))	('CD69+', 'MPA', (27, 32))	('increase', 'PosReg', (15, 23))	('tumor', 'Disease', (108, 113))	('rat', 'Species', '10116', (136, 139))	('rat', 'Species', '10116', (120, 123))	('depletion', 'Var', (49, 58))	('activation', 'PosReg', (94, 104))
62151	33472858	In the metastatic lung of doxycycline treated mice, the percentage of "immature" NK cells (CD11b-CD27- and CD11b-CD27+) was significantly reduced and the ratio of the most mature NK subset (CD11b+CD27-) was concomitantly increased (figure 3E).	('reduced', 'NegReg', (138, 145))	('increased', 'PosReg', (221, 230))	('CD11b-CD27-', 'Var', (91, 102))	('rat', 'Species', '10116', (154, 157))	('doxycycline', 'Chemical', 'MESH:D004318', (26, 37))	('mice', 'Species', '10090', (46, 50))	('CD11b+CD27-', 'Var', (190, 201))	('CD11b-CD27+', 'Var', (107, 118))
62156	33472858	In contrast, the number of NK cells within the tumor area was significantly higher in doxycycline treated mice compared with vehicle treated animals (figure 3H, I).	('mice', 'Species', '10090', (106, 110))	('doxycycline treated', 'Var', (86, 105))	('higher', 'PosReg', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NK cells', 'CPA', (27, 35))	('tumor', 'Disease', (47, 52))	('doxycycline', 'Chemical', 'MESH:D004318', (86, 97))
62159	33472858	We thus hypothesized that depletion of MAMs would suppress metastatic tumor outgrowth by promoting NK cell functions.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NK cell functions', 'CPA', (99, 116))	('depletion', 'Var', (26, 35))	('tumor', 'Disease', (70, 75))	('suppress', 'NegReg', (50, 58))	('MAMs', 'Chemical', '-', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('promoting', 'PosReg', (89, 98))
62166	33472858	The average tumor load at day 10 in Csf1r-cKO mice treated with IgG was also lower than that of control C57BL/6 mice, although this was not statistically significant.	('lower', 'NegReg', (77, 82))	('Csf1r', 'Gene', '12978', (36, 41))	('Csf1', 'molecular_function', 'GO:0005011', ('36', '40'))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (112, 116))	('IgG', 'Var', (64, 67))	('tumor', 'Disease', (12, 17))	('Csf1r', 'Gene', (36, 41))
62171	33472858	Importantly, adoptive transfer of NK cells significantly reduced the metastatic tumor load at day 10 in doxycycline treated mice, but not in vehicle treated mice (figure 5B, C).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('doxycycline', 'Chemical', 'MESH:D004318', (104, 115))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Disease', (80, 85))	('reduced', 'NegReg', (57, 64))	('doxycycline treated', 'Var', (104, 123))
62172	33472858	Therefore, the depletion of MAMs not only enhances intrinsic NK cell activity but also improves the efficacy of transferred NK cells, which can suppress metastatic tumor expansion.	('depletion', 'Var', (15, 24))	('tumor', 'Disease', (164, 169))	('MAMs', 'Chemical', '-', (28, 32))	('intrinsic NK cell activity', 'CPA', (51, 77))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('enhances', 'PosReg', (42, 50))	('efficacy', 'MPA', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('improves', 'PosReg', (87, 95))	('suppress', 'NegReg', (144, 152))
62175	33472858	We then adoptively transferred NK cells into a cohort of mice on days 7 and 10 and found that NK cell infusion in combination with LY364947 treatment significantly reduced metastatic tumor load at day 10 after tumor injection (figure 6C).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('LY364947', 'Var', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('LY364947', 'Chemical', 'MESH:C520284', (131, 139))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('reduced', 'NegReg', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
62177	33472858	In this model, NK cell injection with LY364947 treatment or macrophage depletion did not significantly suppress the late metastatic tumor growth from day 10 to day 14 (figure 6C, D).	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('suppress', 'NegReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('LY364947', 'Var', (38, 46))	('LY364947', 'Chemical', 'MESH:C520284', (38, 46))
62178	33472858	Collectively, these data demonstrate that MAM targeting (eg, depletion of MAM or blockade of TGF-beta signal transmission by MAMs) promotes NK cell cytotoxicity and thereby enhances efficacy of NK cell infusion in suppressing "early" metastatic tumor expansion, whereas further improvement of NK cell efficacy is required to suppress "late" stage of metastatic tumor growth.	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('depletion', 'Var', (61, 70))	('enhances', 'PosReg', (173, 181))	('rat', 'Species', '10116', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('TGF-beta', 'Gene', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('blockade', 'Var', (81, 89))	('NK cell cytotoxicity', 'CPA', (140, 160))	('TGF-beta', 'Gene', '21802', (93, 101))	('tumor', 'Disease', (361, 366))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('MAMs', 'Chemical', '-', (125, 129))	('MAM', 'cellular_component', 'GO:0044233', ('74', '77'))	('tumor', 'Disease', (245, 250))	('signal transmission', 'biological_process', 'GO:0023060', ('102', '121'))	('MAM', 'cellular_component', 'GO:0044233', ('42', '45'))	('promotes', 'PosReg', (131, 139))
62188	33472858	In this study, we have shown that depletion of MAMs can inhibit metastatic expansion of breast cancer cells not only by restricting pro-metastatic tumor cell functions but also by promoting NK cell mediated antitumor immune reactions in the metastatic site.	('MAMs', 'Chemical', '-', (47, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('promoting', 'PosReg', (180, 189))	('metastatic expansion', 'CPA', (64, 84))	('depletion', 'Var', (34, 43))	('breast cancer', 'Disease', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('restricting', 'NegReg', (120, 131))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('inhibit', 'NegReg', (56, 63))
62202	33472858	The enhancement of NK cell recruitment into the parenchyma of metastatic lungs by MAM depletion also suggests the existence of additional mechanisms other than the mb-TGF-beta dependent NK cell suppression.	('enhancement', 'PosReg', (4, 15))	('TGF-beta', 'Gene', '21802', (167, 175))	('MAM', 'cellular_component', 'GO:0044233', ('82', '85'))	('NK cell recruitment', 'CPA', (19, 38))	('depletion', 'Var', (86, 95))	('TGF-beta', 'Gene', (167, 175))
62207	33472858	Since CD27low NK cells demonstrate lower cytotoxicity against target cells compared with CD27high NK cells, these results suggest that prevention of NK cell maturation within the metastatic site may be another mechanism behind MAM mediated suppression of intrinsic NK cells in vivo.	('NK cell maturation', 'CPA', (149, 167))	('cytotoxicity', 'MPA', (41, 53))	('rat', 'Species', '10116', (30, 33))	('lower', 'NegReg', (35, 40))	('cell maturation', 'biological_process', 'GO:0048469', ('152', '167'))	('rat', 'Species', '10116', (161, 164))	('CD27low', 'Var', (6, 13))	('MAM', 'cellular_component', 'GO:0044233', ('227', '230'))
62210	33472858	Since PMN-MDSC but not M-MDSC subset inhibits the activation of NK cells in an in vitro model of vaccinia virus infection, it is possible that PMN-MDSCs rather than M-MDSCs play major roles in NK cell suppression in the particular tumor microenvironment.	('activation', 'MPA', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('PMN', 'biological_process', 'GO:0034727', ('143', '146'))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('vaccinia virus infection', 'Disease', 'MESH:D014615', (97, 121))	('rat', 'Species', '10116', (153, 156))	('tumor', 'Disease', (231, 236))	('vaccinia virus infection', 'Disease', (97, 121))	('PMN', 'biological_process', 'GO:0034727', ('6', '9'))	('PMN-MDSC', 'Var', (6, 14))	('inhibits', 'NegReg', (37, 45))
62211	33472858	In line with this notion, blockade of PMN-MDSC recruitment enhances therapeutic efficacy of transferred NK cells in a mouse model of oral cancer.	('cancer', 'Disease', (138, 144))	('PMN-MDSC', 'Gene', (38, 46))	('therapeutic efficacy', 'CPA', (68, 88))	('blockade', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mouse', 'Species', '10090', (118, 123))	('enhances', 'PosReg', (59, 67))	('PMN', 'biological_process', 'GO:0034727', ('38', '41'))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
62212	33472858	However, depletion of Ly6G+ cells did not alter the number of metastatic foci developed by E0771-LG cells in the lung,suggesting minor contribution of PMN-MDSCs in metastatic formation in our model.	('PMN', 'biological_process', 'GO:0034727', ('151', '154'))	('Ly6G', 'Gene', (22, 26))	('Ly6G', 'Gene', '546644', (22, 26))	('E0771-LG', 'Var', (91, 99))	('formation', 'biological_process', 'GO:0009058', ('175', '184'))
62214	33472858	In our experimental metastasis model, intravenously transplanted E0771-LG cells extravasate and colonize in the lung by day 4 after tumor injection, form small metastatic foci by day 7, and develop into lethal macro-metastatic lesions by day 14.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('colonize', 'CPA', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('E0771-LG', 'Var', (65, 73))	('tumor', 'Disease', (132, 137))	('extravasate', 'CPA', (80, 91))	('develop', 'Reg', (190, 197))
62280	32850691	Among those, GO:0048568 Embryonic organ development, GO:0061458 Reproductive system development, GO:0007389 Pattern specification process, GO:0043062 Extracellular structure organization, GO:0002009 Morphogenesis of an epithelium, and GO:0048732 Gland development were related to tissue or organ morphogenesis.	('GO:0002009', 'Var', (188, 198))	('Embryonic organ', 'Disease', (24, 39))	('GO:0048568', 'Var', (13, 23))	('Pattern specification process', 'biological_process', 'GO:0007389', ('108', '137'))	('GO:0048732', 'Var', (235, 245))	('Embryonic organ development', 'biological_process', 'GO:0048568', ('24', '51'))	('Extracellular structure organization', 'biological_process', 'GO:0043062', ('150', '186'))	('Reproductive system development', 'biological_process', 'GO:0061458', ('64', '95'))	('GO:0043062', 'Var', (139, 149))	('GO:0007389', 'Var', (97, 107))	('Morphogenesis of an epithelium', 'biological_process', 'GO:0002009', ('199', '229'))	('Pattern specification', 'CPA', (108, 129))	('Extracellular structure', 'cellular_component', 'GO:0044421', ('150', '173'))	('Gland development', 'biological_process', 'GO:0048732', ('246', '263'))	('morphogenesis', 'biological_process', 'GO:0009653', ('296', '309'))	('GO:0061458', 'Var', (53, 63))	('Reproductive system development', 'CPA', (64, 95))	('Gland development', 'CPA', (246, 263))	('Embryonic organ', 'Disease', 'MESH:D019965', (24, 39))
62297	32850691	Additionally, the deregulated expression of KLKs has been utilized in designing novel therapeutic targets for prostate cancer.	('KLKs', 'Gene', (44, 48))	('expression', 'MPA', (30, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('prostate cancer', 'Disease', (110, 125))	('deregulated', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
62320	32536347	Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease.	('adaptive metabolic re-programming', 'CPA', (480, 513))	('tumour', 'Disease', (267, 273))	('tumor', 'Disease', (282, 287))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('282', '298'))	('epithelial to mesenchymal transition', 'CPA', (515, 551))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('splicing', 'biological_process', 'GO:0045292', ('28', '36'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('282', '298'))	('tumour', 'Phenotype', 'HP:0002664', (313, 319))	('angiogenesis', 'CPA', (342, 354))	('promote', 'PosReg', (611, 618))	('tumour', 'Disease', 'MESH:D009369', (440, 446))	('immune response', 'biological_process', 'GO:0006955', ('421', '436'))	('programmed cell death', 'biological_process', 'GO:0012501', ('379', '400'))	('genetic instability', 'Var', (566, 585))	('tumour', 'Disease', 'MESH:D009369', (313, 319))	('tumour growth', 'Disease', (267, 280))	('tumour', 'Disease', (440, 446))	('tumour', 'Disease', 'MESH:D009369', (414, 420))	('tumour', 'Disease', (313, 319))	('metastatic disease', 'Disease', (619, 637))	('tumour', 'Disease', (414, 420))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('Hypoxia', 'Disease', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('inflammatory response', 'biological_process', 'GO:0006954', ('457', '478'))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('autonomous tumour', 'Disease', (256, 273))	('tumour', 'Disease', (135, 141))	('tumour', 'Phenotype', 'HP:0002664', (356, 362))	('autonomous tumour', 'Disease', 'MESH:D009423', (256, 273))	('angiogenesis', 'biological_process', 'GO:0001525', ('342', '354'))	('tumour', 'Disease', 'MESH:D009369', (356, 362))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Disease', (356, 362))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('515', '551'))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('invasion', 'CPA', (553, 561))	('tumour', 'Disease', 'MESH:D009369', (267, 273))	('tumour', 'Disease', (70, 76))	('tumour growth', 'Disease', 'MESH:D006130', (267, 280))
62335	32536347	In humans, alternative splicing accounts for   100,000 different proteins, is largely responsible for proteomic complexity that cannot be explained by gene numbers alone and is tightly regulated in order to provide sufficient adaptive flexibility to gene expression, whilst limiting the potential for chaos.	('gene expression', 'biological_process', 'GO:0010467', ('250', '265'))	('proteins', 'Protein', (65, 73))	('humans', 'Species', '9606', (3, 9))	('alternative splicing', 'Var', (11, 31))	('responsible', 'Reg', (86, 97))	('splicing', 'biological_process', 'GO:0045292', ('23', '31'))
62341	32536347	hnRNPA1 promotes distal 5' spice site activation by looping out an internal exon), which results in   4% of alternative splicing events.	('splicing', 'biological_process', 'GO:0045292', ('120', '128'))	("distal 5' spice site activation", 'MPA', (17, 48))	('results in', 'Reg', (89, 99))	('alternative splicing events', 'MPA', (108, 135))	('hnRNPA1', 'Gene', (0, 7))	('promotes', 'PosReg', (8, 16))	('looping', 'Var', (52, 59))	('hnRNPA1', 'Gene', '3178', (0, 7))
62345	32536347	In general, SR proteins bound to exons upstream of the 5' splice site activate splicing but repress splicing when bound to introns downstream of 5' splice sites, with alternative splicing promoted by alterations in splice site trans-acting SR and hnRNP protein expression.	('repress', 'NegReg', (92, 99))	('hnRNP', 'Gene', '3183', (247, 252))	('splicing', 'biological_process', 'GO:0045292', ('79', '87'))	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('alterations', 'Var', (200, 211))	('promoted', 'PosReg', (188, 196))	('activate', 'PosReg', (70, 78))	('splicing', 'MPA', (100, 108))	('hnRNP', 'cellular_component', 'GO:0030530', ('247', '252'))	('splicing', 'biological_process', 'GO:0045292', ('179', '187'))	('splicing', 'MPA', (79, 87))	('SR protein', 'Gene', (12, 22))	('hnRNP', 'Gene', (247, 252))	('hnRNP', 'molecular_function', 'GO:0008436', ('247', '252'))	('SR protein', 'Gene', '10921', (12, 22))
62348	32536347	2'-O-methyl, pseudo-uridine and trimethylated guanosine cap (m3G) modifications in U2 SnRNAs are critical for splicing reactions and nuclear U-snRNP importation, post-transcriptional m6A modifications in pre-mRNAs influence secondary structure, altering single-strand RNAs and RNA binding motif accessibility, and adenosine deaminase conversion of adenosine to inosine creates novel splice sites by converting AA dinucleotides to AI dinucleotides that promote alternative splicing.	('modifications', 'Var', (66, 79))	('inosine', 'Chemical', 'MESH:D007288', (361, 368))	('single-strand RNAs', 'MPA', (254, 272))	('adenosine', 'Chemical', 'MESH:D000241', (314, 323))	('snRNP', 'cellular_component', 'GO:0030532', ('143', '148'))	('alternative splicing', 'MPA', (460, 480))	('influence', 'Reg', (214, 223))	('adenosine deaminase', 'Gene', (314, 333))	('guanosine', 'Chemical', 'MESH:D006151', (46, 55))	('snRNP', 'molecular_function', 'GO:0003734', ('143', '148'))	('RNA', 'cellular_component', 'GO:0005562', ('277', '280'))	('dinucleotides', 'Chemical', 'MESH:D015226', (413, 426))	('AA dinucleotides', 'MPA', (410, 426))	('accessibility', 'MPA', (295, 308))	("2'-O-methyl", 'Chemical', '-', (0, 11))	('promote', 'PosReg', (452, 459))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('RNA binding', 'molecular_function', 'GO:0003723', ('277', '288'))	('dinucleotides', 'Chemical', 'MESH:D015226', (433, 446))	('pre', 'molecular_function', 'GO:0003904', ('204', '207'))	('secondary structure', 'MPA', (224, 243))	('adenosine deaminase', 'Gene', '100', (314, 333))	('modifications', 'Var', (187, 200))	('adenosine', 'Chemical', 'MESH:D000241', (348, 357))	('snRNP', 'Gene', (143, 148))	('splicing', 'biological_process', 'GO:0045292', ('472', '480'))	('snRNP', 'Gene', '57819', (143, 148))	('pseudo-uridine', 'Chemical', 'MESH:D011560', (13, 27))	('altering', 'Reg', (245, 253))
62354	32536347	Hypoxia inhibits PHD activity resulting in the accumulation, stabilization and activation of HIF transcription factors, that promote HIF-target gene expression, alternative splicing of HIF-target and non-HIF target genes and also induce 4E-BP1 phosphorylation-dependent inhibition of capped non-HIF target gene mRNA translation, also inhibited by the hypoxia-induced RNA binding protein EVLAV1 (HuR) that regulates the expression of translation initiating factor 4E nuclear import factor 1 (Eif4enif1).	('HIF', 'Gene', (295, 298))	('HuR', 'Gene', '1994', (395, 398))	('HIF', 'Gene', '405;9915', (295, 298))	('4E-BP1', 'Gene', '1978', (237, 243))	('inhibition', 'NegReg', (270, 280))	('hypoxia', 'Disease', (351, 358))	('HIF', 'Gene', (133, 136))	('gene expression', 'biological_process', 'GO:0010467', ('144', '159'))	('splicing', 'biological_process', 'GO:0045292', ('173', '181'))	('HIF', 'Gene', '405;9915', (133, 136))	('mRNA translation', 'MPA', (311, 327))	('HIF', 'Gene', (93, 96))	('alternative splicing', 'Var', (161, 181))	('PHD', 'molecular_function', 'GO:0050175', ('17', '20'))	('translation', 'biological_process', 'GO:0006412', ('316', '327'))	('HIF', 'Gene', '405;9915', (93, 96))	('4E-BP1', 'Gene', (237, 243))	('hypoxia', 'Disease', 'MESH:D000860', (351, 358))	('HIF', 'Gene', (204, 207))	('phosphorylation-dependent', 'MPA', (244, 269))	('RNA', 'cellular_component', 'GO:0005562', ('367', '370'))	('translation', 'biological_process', 'GO:0006412', ('433', '444'))	('HIF', 'Gene', '405;9915', (204, 207))	('Hypoxia inhibits PHD', 'Disease', (0, 20))	('Eif4enif1', 'Gene', '56478', (491, 500))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('promote', 'PosReg', (125, 132))	('Hypoxia inhibits PHD', 'Disease', 'MESH:D000860', (0, 20))	('HuR', 'Gene', (395, 398))	('nuclear import', 'biological_process', 'GO:0051170', ('466', '480'))	('phosphorylation', 'biological_process', 'GO:0016310', ('244', '259'))	('HIF', 'Gene', (185, 188))	('protein', 'cellular_component', 'GO:0003675', ('379', '386'))	('RNA binding', 'molecular_function', 'GO:0003723', ('367', '378'))	('HIF', 'Gene', '405;9915', (185, 188))	('Eif4', 'cellular_component', 'GO:0008304', ('491', '495'))	('Eif4enif1', 'Gene', (491, 500))
62369	32536347	Hypoxia sensitive signal transduction pathways also regulate alternative splicing, resulting in tumour promoting VEGF, FGF, HGF and TGFbeta signaling, ligand-independent EGFR signaling, myogenic to mitogenic conversion of insulin growth factor signaling and also specify signaling pathways use.	('signal transduction', 'biological_process', 'GO:0007165', ('18', '37'))	('EGFR', 'molecular_function', 'GO:0005006', ('170', '174'))	('EGFR', 'Gene', (170, 174))	('alternative splicing', 'Var', (61, 81))	('VEGF', 'Gene', '7422', (113, 117))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('VEGF', 'Gene', (113, 117))	('myogenic to mitogenic conversion', 'CPA', (186, 218))	('TGFbeta', 'Gene', (132, 139))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('ligand-independent', 'MPA', (151, 169))	('EGFR', 'Gene', '1956', (170, 174))	('TGFbeta', 'Gene', '7039', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('HGF', 'Gene', '3082', (124, 127))	('tumour', 'Disease', (96, 102))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('FGF', 'MPA', (119, 122))	('signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('insulin', 'molecular_function', 'GO:0016088', ('222', '229'))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('resulting in', 'Reg', (83, 95))	('HGF', 'Gene', (124, 127))	('ligand', 'molecular_function', 'GO:0005488', ('151', '157'))
62378	32536347	Tumour initiation is determined by a combination of oncogene activation and tumour suppressor inactivation, resulting in the acquisition of autonomous neoplastic growth that is promoted either by autocrine growth factor activity caused by coincidental tumour cell growth factor and growth factor receptor expression or by proliferation-promoting oncogenes damage-activated by oncoviruses, gene amplification, mutation, chromosomal translocation or alternative/aberrant pre-mRNA splicing.	('promoted', 'PosReg', (177, 185))	('tumour', 'Disease', (252, 258))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('gene amplification', 'Var', (389, 407))	('mutation', 'Var', (409, 417))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('inactivation', 'Var', (94, 106))	('autonomous neoplastic growth', 'CPA', (140, 168))	('tumour', 'Disease', (76, 82))	('growth factor activity', 'molecular_function', 'GO:0008083', ('206', '228'))	('autocrine', 'MPA', (196, 205))	('Tumour initiation', 'Disease', (0, 17))	('alternative/aberrant pre-mRNA splicing', 'Var', (448, 486))	('cell growth', 'biological_process', 'GO:0016049', ('259', '270'))	('pre', 'molecular_function', 'GO:0003904', ('469', '472'))	('chromosomal translocation', 'Var', (419, 444))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('469', '486'))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('Tumour initiation', 'Disease', 'MESH:D009369', (0, 17))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
62382	32536347	TrkAIII is expressed by advanced stage primary human neuroblastomas, glioblastomas, melanomas and Merkel cell carcinomas, is characterized by cassette exon 6, 7 and 9 skipping, exhibits constitutive activation, transforms NIH3T3 cells, exhibits oncogenic activity in neuroblastoma models and prevents neural-related progenitor cell death induced by the development-regulated NF-YA alternative splice variant NF-YAx, expressed during mouse developmental stages associated with neuroblast culling and neuroblastoma suppression, suggesting potential roles in neuroblastoma initiation and hypoxia-dependent progression.	('melanomas', 'Disease', (84, 93))	('neuroblastoma', 'Disease', (556, 569))	('cell death', 'biological_process', 'GO:0008219', ('327', '337'))	('TrkA', 'Gene', '4914', (0, 4))	('neuroblastoma', 'Phenotype', 'HP:0003006', (556, 569))	('glioblastomas', 'Disease', (69, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('Merkel cell carcinomas', 'Disease', 'MESH:D015266', (98, 120))	('neuroblastomas', 'Phenotype', 'HP:0003006', (53, 67))	('neuroblastoma', 'Disease', 'MESH:D009447', (556, 569))	('oncogenic activity', 'CPA', (245, 263))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('neuroblastomas', 'Disease', (53, 67))	('glioblastomas', 'Disease', 'MESH:D005909', (69, 82))	('NIH3T3', 'CellLine', 'CVCL:0594', (222, 228))	('neuroblastoma suppression', 'Disease', 'MESH:D009447', (499, 524))	('human', 'Species', '9606', (47, 52))	('NF-YAx', 'Gene', (408, 414))	('Merkel cell carcinomas', 'Disease', (98, 120))	('neuroblastoma', 'Disease', (499, 512))	('neuroblastomas', 'Disease', 'MESH:D009447', (53, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('mouse', 'Species', '10090', (433, 438))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('neuroblastoma', 'Phenotype', 'HP:0003006', (499, 512))	('neuroblastoma', 'Disease', (267, 280))	('neuroblastoma', 'Disease', (53, 66))	('neuroblastoma', 'Phenotype', 'HP:0003006', (267, 280))	('neuroblastoma', 'Phenotype', 'HP:0003006', (53, 66))	('TrkA', 'Gene', (0, 4))	('neuroblastoma', 'Disease', 'MESH:D009447', (499, 512))	('hypoxia', 'Disease', (585, 592))	('neuroblastoma', 'Disease', 'MESH:D009447', (53, 66))	('neural-related progenitor cell death', 'CPA', (301, 337))	('neuroblastoma initiation', 'Disease', 'MESH:D009447', (556, 580))	('neuroblastoma', 'Disease', 'MESH:D009447', (267, 280))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('neuroblastoma initiation', 'Disease', (556, 580))	('glioblastomas', 'Phenotype', 'HP:0012174', (69, 82))	('neuroblastoma suppression', 'Disease', (499, 524))	('hypoxia', 'Disease', 'MESH:D000860', (585, 592))	('skipping', 'Var', (167, 175))
62384	32536347	Hypoxia reduces the KRAS 4A to 4B (exon 4a skipped) alternative splice ratio, helping to explain predominant mutation-activated KRAS4B splice variant oncogene expression in colon tumours and cancer stem cells, and induces predominant short form MXIs alternative splicing reducing MIX1 antagonism of Nmyc-dependent proliferation of relevance to aggressive autonomous Nmyc amplified neuroblastoma growth.	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('Nmyc', 'Gene', (299, 303))	('splicing', 'biological_process', 'GO:0045292', ('262', '270'))	('mutation-activated', 'Var', (109, 127))	('Nmyc', 'Gene', '4613', (366, 370))	('cancer', 'Disease', (191, 197))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('KRAS4B', 'Gene', (128, 134))	('reduces', 'NegReg', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('KRAS 4A to 4B', 'Gene', '3845', (20, 33))	('neuroblastoma', 'Disease', (381, 394))	('Nmyc', 'Gene', '4613', (299, 303))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('neuroblastoma', 'Phenotype', 'HP:0003006', (381, 394))	('Hypoxia', 'Disease', (0, 7))	('colon tumours', 'Disease', (173, 186))	('KRAS4B', 'Gene', '3845', (128, 134))	('neuroblastoma', 'Disease', 'MESH:D009447', (381, 394))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Nmyc', 'Gene', (366, 370))	('colon tumours', 'Disease', 'MESH:D003110', (173, 186))	('KRAS 4A to 4B', 'Gene', (20, 33))
62387	32536347	In breast cancer cells, hypoxia induces alternative APP splicing linked to breast cancer cell proliferation and tumorigenicity and in non-small cell lung cancer cells, promotes Clk1-dependent Srp55 splicing factor phosphorylation, resulting in alternative VEGFA165b splicing and autonomous growth of VEGFR2 and neuropilin-1 receptor expressing tumour cells.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (134, 160))	('Clk1', 'molecular_function', 'GO:0004712', ('177', '181'))	('splicing', 'biological_process', 'GO:0045292', ('198', '206'))	('Srp', 'cellular_component', 'GO:0005786', ('192', '195'))	('autonomous growth', 'CPA', (279, 296))	('phosphorylation', 'biological_process', 'GO:0016310', ('214', '229'))	('VEGFA', 'Gene', (256, 261))	('lung cancer', 'Disease', (149, 160))	('Srp55', 'Gene', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('alternative', 'Var', (40, 51))	('Clk1', 'Gene', (177, 181))	('Clk1', 'Gene', '1195', (177, 181))	('tumour', 'Phenotype', 'HP:0002664', (344, 350))	('tumor', 'Disease', (112, 117))	('splicing factor', 'Gene', (198, 213))	('hypoxia', 'Disease', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (344, 350))	('tumour', 'Disease', (344, 350))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('VEGFA', 'Gene', '7422', (256, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Srp55', 'Gene', '6431', (192, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('VEGFR2', 'Gene', (300, 306))	('hypoxia', 'Disease', 'MESH:D000860', (24, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('alternative', 'Var', (244, 255))	('splicing factor', 'Gene', '10569', (198, 213))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('VEGFR2', 'Gene', '3791', (300, 306))	('splicing', 'biological_process', 'GO:0045292', ('266', '274'))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('promotes', 'PosReg', (168, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (138, 160))
62392	32536347	Alternative RON splicing is complex and results in RONDelta170, Delta165, Delta160, Delta155, Delta110, Delta90 and Deltai55 isoforms, several of which exhibit constitutive oncogenic activation, differences in localization, opposing functions and associate with tumour progression and disease stage.	('Delta155', 'Mutation', 'c.del155', (84, 92))	('tumour', 'Disease', (262, 268))	('Delta155', 'Var', (84, 92))	('Delta165', 'Var', (64, 72))	('Delta160', 'Mutation', 'c.del160', (74, 82))	('Delta90', 'Mutation', 'c.del90', (104, 111))	('Delta165', 'Mutation', 'c.del165', (64, 72))	('activation', 'PosReg', (183, 193))	('splicing', 'biological_process', 'GO:0045292', ('16', '24'))	('Delta90', 'Var', (104, 111))	('results in', 'Reg', (40, 50))	('Delta110', 'Mutation', 'c.del110', (94, 102))	('Delta160', 'Var', (74, 82))	('Delta110', 'Var', (94, 102))	('Deltai55', 'Var', (116, 124))	('localization', 'biological_process', 'GO:0051179', ('210', '222'))	('RONDelta170', 'Var', (51, 62))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('oncogenic', 'CPA', (173, 182))	('tumour', 'Disease', 'MESH:D009369', (262, 268))	('associate', 'Reg', (247, 256))
62402	32536347	Tumourigenesis also depends upon tumour suppressor inactivation to overcome oncogene-induced senescence.	('tumour', 'Disease', (33, 39))	('inactivation', 'Var', (51, 63))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('senescence', 'biological_process', 'GO:0010149', ('93', '103'))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Tumourigenesis', 'CPA', (0, 14))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
62407	32536347	In colon cancer cells, hypoxia also reduces TP53 function by promoting inhibitory alternative HDAC6 intron-retention splicing, de-regulating the unfolded protein response (UPR), protein aggregate processing, altering the cell response to cytotoxic stress, reducing HDAC6-dependent TP53 binding protein-1 expression, repressing expression of the p53 target gene P21/Waf1 cell cycle inhibitor and impairing recognition of H4K20me2 and H2AK15ub histone marks induced by DNA double strand breaks and DNA repair.	('H4K20me2', 'Var', (420, 428))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('DNA', 'cellular_component', 'GO:0005574', ('496', '499'))	('promoting', 'PosReg', (61, 70))	('TP53', 'Gene', (44, 48))	('expression', 'MPA', (304, 314))	('P21', 'Gene', '1026', (361, 364))	('recognition', 'MPA', (405, 416))	('reducing', 'NegReg', (256, 264))	('P21', 'Gene', (361, 364))	('binding', 'molecular_function', 'GO:0005488', ('286', '293'))	('unfolded protein response', 'MPA', (145, 170))	('HDAC6', 'Gene', '10013', (265, 270))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('HDAC6', 'Gene', (94, 99))	('expression', 'MPA', (327, 337))	('impairing', 'NegReg', (395, 404))	('de-regulating', 'NegReg', (127, 140))	('TP53', 'Gene', (281, 285))	('cell', 'MPA', (221, 225))	('Waf1', 'Gene', (365, 369))	('repressing', 'PosReg', (316, 326))	('DNA', 'cellular_component', 'GO:0005574', ('467', '470'))	('H2AK15ub', 'Var', (433, 441))	('hypoxia', 'Disease', (23, 30))	('retention', 'biological_process', 'GO:0051235', ('107', '116'))	('DNA repair', 'biological_process', 'GO:0006281', ('496', '506'))	('splicing', 'biological_process', 'GO:0045292', ('117', '125'))	('TP53', 'Gene', '7157', (44, 48))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('altering', 'Reg', (208, 216))	('colon cancer', 'Disease', (3, 15))	('Waf1', 'Gene', '1026', (365, 369))	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))	('protein', 'cellular_component', 'GO:0003675', ('294', '301'))	('HDAC6', 'Gene', (265, 270))	('HDAC6', 'Gene', '10013', (94, 99))	('reduces', 'NegReg', (36, 43))	('cell cycle', 'biological_process', 'GO:0007049', ('370', '380'))	('TP53', 'Gene', '7157', (281, 285))
62418	32536347	Hypoxia inactivation of PHD results is dissociation of HIFalpha/pVHL complexes, resulting in HIF-1alpha and HIF-2alpha accumulation and stabilization, nuclear translocation, heterodimerization with nuclear ARNT subunits to form HIF-1alpha/ARNT (HIF-1) and HIF-2alpha/ARNT (HIF2) transcription factors and the induction of HIF-dependent pro-angiogenic alternative VEGFA and VEGFR receptor expression and splicing.	('ARNT', 'Gene', (239, 243))	('splicing', 'MPA', (403, 411))	('VEGFR', 'Gene', '3791', (373, 378))	('ARNT', 'Gene', (206, 210))	('HIF', 'Gene', (55, 58))	('stabilization', 'MPA', (136, 149))	('HIF-1alpha', 'Gene', (228, 238))	('HIF', 'Gene', '405;9915', (55, 58))	('VEGFR', 'Gene', (373, 378))	('HIF-2alpha', 'Gene', '2034', (256, 266))	('HIF', 'Gene', (228, 231))	('HIF', 'Gene', (245, 248))	('transcription', 'biological_process', 'GO:0006351', ('279', '292'))	('HIF-2alpha', 'Gene', (108, 118))	('HIF', 'Gene', '405;9915', (228, 231))	('HIF', 'Gene', '405;9915', (245, 248))	('HIF-1alpha', 'Gene', (93, 103))	('HIF-1', 'Gene', '3091', (245, 250))	('ARNT', 'Gene', '405', (267, 271))	('HIF', 'Gene', (93, 96))	('VEGFA', 'Gene', (363, 368))	('HIF', 'Gene', (108, 111))	('HIF-1', 'Gene', (245, 250))	('HIF', 'Gene', '405;9915', (93, 96))	('ARNT', 'Gene', (267, 271))	('HIF', 'Gene', '405;9915', (108, 111))	('accumulation', 'PosReg', (119, 131))	('HIFalpha', 'Disease', (55, 63))	('HIF', 'Gene', (322, 325))	('HIF-1', 'Gene', '3091', (93, 98))	('HIFalpha', 'Disease', 'None', (55, 63))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('expression', 'MPA', (388, 398))	('Hypoxia', 'Disease', (0, 7))	('HIF', 'Gene', '405;9915', (322, 325))	('HIF-1', 'Gene', '3091', (228, 233))	('PHD', 'molecular_function', 'GO:0050175', ('24', '27'))	('HIF-1', 'Gene', (93, 98))	('HIF-2alpha', 'Gene', (256, 266))	('inactivation', 'Var', (8, 20))	('HIF-1', 'Gene', (228, 233))	('PHD', 'Disease', (24, 27))	('heterodimerization', 'MPA', (174, 192))	('HIF', 'Gene', (256, 259))	('nuclear translocation', 'MPA', (151, 172))	('HIF', 'Gene', (273, 276))	('VEGFA', 'Gene', '7422', (363, 368))	('HIF-1alpha', 'Gene', '3091', (228, 238))	('HIF', 'Gene', '405;9915', (256, 259))	('splicing', 'biological_process', 'GO:0045292', ('403', '411'))	('HIF', 'Gene', '405;9915', (273, 276))	('ARNT', 'Gene', '405', (239, 243))	('PHD', 'Disease', 'MESH:D011547', (24, 27))	('HIF-2alpha', 'Gene', '2034', (108, 118))	('pVHL', 'Gene', '7428', (64, 68))	('pVHL', 'Gene', (64, 68))	('ARNT', 'Gene', '405', (206, 210))	('HIF-1alpha', 'Gene', '3091', (93, 103))
62422	32536347	Alternative VEGFA splice variants derived from exon 8 alternative splicing also include angiogenesis promoting VEGFAxxxa and inhibiting VEGFAxxxb isoforms, both of which bind VEGFR2 but only the VEGFAxxxa isoform activates angiogenic signaling.	('VEGFA', 'Gene', '7422', (12, 17))	('VEGFR2', 'Gene', (175, 181))	('VEGFA', 'Gene', (111, 116))	('bind', 'Interaction', (170, 174))	('alternative splicing', 'Var', (54, 74))	('VEGFA', 'Gene', '7422', (136, 141))	('angiogenesis', 'CPA', (88, 100))	('promoting', 'PosReg', (101, 110))	('VEGFA', 'Gene', '7422', (195, 200))	('angiogenesis', 'biological_process', 'GO:0001525', ('88', '100'))	('signaling', 'biological_process', 'GO:0023052', ('234', '243'))	('VEGFA', 'Gene', (12, 17))	('inhibiting', 'NegReg', (125, 135))	('VEGFR2', 'Gene', '3791', (175, 181))	('VEGFA', 'Gene', '7422', (111, 116))	('VEGFA', 'Gene', (136, 141))	('VEGFA', 'Gene', (195, 200))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))
62435	32536347	Although a direct role for hypoxia in sVEGFR-2 and soluble s-neuropilin VEGF co-receptor alternative splicing has not been reported, the sVEGFR-2 isoform is induced by inflammatory cytokines IL-8 and IL-12 in human benign prostate hypertrophy tissue microvascular endothelial cells, suggesting an indirect role for hypoxia-induced inflammation in down-regulating angiogenesis in benign prostate tumours through alternative sVEGFR2 splicing.	('human', 'Species', '9606', (209, 214))	('inflammation', 'Disease', 'MESH:D007249', (331, 343))	('splicing', 'biological_process', 'GO:0045292', ('101', '109'))	('tumour', 'Phenotype', 'HP:0002664', (395, 401))	('VEGFR2', 'Gene', '3791', (424, 430))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('VEGF', 'Gene', '7422', (138, 142))	('benign prostate hypertrophy', 'Phenotype', 'HP:0008711', (215, 242))	('inflammation', 'biological_process', 'GO:0006954', ('331', '343'))	('benign prostate tumours', 'Disease', (379, 402))	('VEGF', 'Gene', '7422', (424, 428))	('IL-8', 'Gene', (191, 195))	('VEGF', 'Gene', (138, 142))	('benign prostate hypertrophy', 'Disease', 'MESH:D011470', (215, 242))	('VEGFR-2', 'Gene', (39, 46))	('VEGFR-2', 'Gene', '3791', (138, 145))	('VEGF', 'Gene', (424, 428))	('inflammation', 'Disease', (331, 343))	('splicing', 'biological_process', 'GO:0045292', ('431', '439'))	('hypoxia', 'Disease', (315, 322))	('angiogenesis', 'CPA', (363, 375))	('VEGFR-2', 'Gene', (138, 145))	('benign prostate tumours', 'Disease', 'MESH:D011471', (379, 402))	('VEGF', 'Gene', '7422', (72, 76))	('IL-8', 'Gene', '3576', (191, 195))	('IL-12', 'molecular_function', 'GO:0005143', ('200', '205'))	('alternative', 'Var', (411, 422))	('down-regulating', 'NegReg', (347, 362))	('VEGF', 'Gene', '7422', (39, 43))	('soluble', 'cellular_component', 'GO:0005625', ('51', '58'))	('benign prostate hypertrophy', 'Disease', (215, 242))	('angiogenesis', 'biological_process', 'GO:0001525', ('363', '375'))	('VEGF', 'Gene', (72, 76))	('hypoxia', 'Disease', 'MESH:D000860', (315, 322))	('IL-8', 'molecular_function', 'GO:0005153', ('191', '195'))	('tumours', 'Phenotype', 'HP:0002664', (395, 402))	('VEGF', 'Gene', (39, 43))	('hypoxia', 'Disease', (27, 34))	('VEGFR-2', 'Gene', '3791', (39, 46))	('VEGFR2', 'Gene', (424, 430))
62437	32536347	The VHL HIF1alpha inactivator and tumour suppressor also exhibits hypoxia-regulated alternative splicing, characterized by inactivating mutations in the cryptic exon (E1) deep in intron 1 that promotes excessive E1 retention and VHL protein repression, within the context of pre-neoplastic von Hippel Landau disease, leading to aberrant HIF activation (Fig.	('VHL', 'Gene', (229, 232))	('neoplastic von Hippel Landau disease', 'Disease', 'MESH:D006623', (279, 315))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('inactivating mutations', 'Var', (123, 145))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('VHL', 'Gene', '7428', (229, 232))	('E1 retention', 'Protein', (212, 224))	('tumour', 'Disease', (34, 40))	('VHL', 'Gene', (4, 7))	('splicing', 'biological_process', 'GO:0045292', ('96', '104'))	('promotes', 'PosReg', (193, 201))	('protein', 'cellular_component', 'GO:0003675', ('233', '240'))	('HIF', 'Gene', (337, 340))	('pre', 'molecular_function', 'GO:0003904', ('275', '278'))	('VHL', 'Gene', '7428', (4, 7))	('HIF', 'Gene', '405;9915', (337, 340))	('retention', 'biological_process', 'GO:0051235', ('215', '224'))	('hypoxia', 'Disease', (66, 73))	('HIF', 'Gene', (8, 11))	('neoplastic von Hippel Landau disease', 'Disease', (279, 315))	('HIF', 'Gene', '405;9915', (8, 11))
62447	32536347	With respect to the impact of hypoxia-induced alternative splicing on apoptosis, in breast cancer cells, chronic hypoxia promotes alternative intron 1-retention splicing in the TNF family member TNFSF13, resulting in suppression of TNFSF13 anti-apoptotic activity, implicating hypoxia-induced TNFSF13 alternative splicing in tumour suppression.	('TNF', 'Gene', (195, 198))	('tumour suppression', 'Disease', 'MESH:D009369', (325, 343))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('hypoxia', 'Disease', (113, 120))	('TNF', 'Gene', (232, 235))	('TNF', 'Gene', (177, 180))	('TNFSF13', 'Gene', (293, 300))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('anti-apoptotic activity', 'CPA', (240, 263))	('tumour suppression', 'Disease', (325, 343))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('TNF', 'Gene', '7124', (195, 198))	('TNFSF13', 'Gene', '8741', (195, 202))	('TNF', 'Gene', '7124', (232, 235))	('TNF', 'Gene', '7124', (177, 180))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('splicing', 'biological_process', 'GO:0045292', ('313', '321'))	('TNFSF13', 'Gene', '8741', (232, 239))	('breast cancer', 'Disease', (84, 97))	('splicing', 'biological_process', 'GO:0045292', ('58', '66'))	('splicing', 'biological_process', 'GO:0045292', ('161', '169'))	('hypoxia', 'Disease', (30, 37))	('TNFSF13', 'Gene', (195, 202))	('hypoxia', 'Disease', (277, 284))	('TNF', 'Gene', (293, 296))	('TNFSF13', 'Gene', (232, 239))	('suppression', 'NegReg', (217, 228))	('retention', 'biological_process', 'GO:0051235', ('151', '160'))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))	('hypoxia', 'Disease', 'MESH:D000860', (30, 37))	('hypoxia', 'Disease', 'MESH:D000860', (277, 284))	('TNF', 'Gene', '7124', (293, 296))	('alternative intron 1-retention splicing', 'Var', (130, 169))	('TNFSF13', 'Gene', '8741', (293, 300))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
62451	32536347	In breast cancer cells, hypoxia-sensitive hnRNPs also induce alternative Mcl1 splicing, lncRNA LUCAT-1 expression, LUCAT-1 complexing with PTPB1 splice factor promoting survival and therapeutic-resistance and alternative intron retention splicing and NMD inactivation of TP53, resulting in evasion of TP53 and BAX-dependent apoptosis.	('survival', 'CPA', (169, 177))	('hypoxia-sensitive hnRNPs', 'Disease', (24, 48))	('alternative intron retention splicing', 'Var', (209, 246))	('therapeutic-resistance', 'CPA', (182, 204))	('hypoxia-sensitive hnRNPs', 'Disease', 'MESH:D000860', (24, 48))	('alternative', 'MPA', (61, 72))	('PB', 'Chemical', 'MESH:D007854', (141, 143))	('inactivation', 'NegReg', (255, 267))	('splicing', 'biological_process', 'GO:0045292', ('238', '246'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('TP53', 'Gene', '7157', (301, 305))	('LUCAT-1', 'Gene', (115, 122))	('LUCAT-1', 'Gene', '100505994', (115, 122))	('BAX', 'Gene', (310, 313))	('BAX', 'Gene', '581', (310, 313))	('apoptosis', 'biological_process', 'GO:0097194', ('324', '333'))	('apoptosis', 'biological_process', 'GO:0006915', ('324', '333'))	('Mcl1', 'Gene', (73, 77))	('TP53', 'Gene', (271, 275))	('splicing', 'biological_process', 'GO:0045292', ('78', '86'))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('induce', 'Reg', (54, 60))	('Mcl1', 'Gene', '4170', (73, 77))	('retention', 'biological_process', 'GO:0051235', ('228', '237'))	('LUCAT-1', 'Gene', (95, 102))	('LUCAT-1', 'Gene', '100505994', (95, 102))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('promoting', 'PosReg', (159, 168))	('evasion', 'MPA', (290, 297))	('TP53', 'Gene', '7157', (271, 275))	('TP53', 'Gene', (301, 305))
62454	32536347	Consistent with a role for HIFs in cancer cell survival, UPR activation also promotes cooperation between XBP1s and HIF-1alpha increasing survival.	('HIFs', 'Disease', (27, 31))	('HIF-1alpha', 'Gene', '3091', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('XBP1', 'Gene', '7494', (106, 110))	('increasing', 'PosReg', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('HIFs', 'Disease', 'None', (27, 31))	('survival', 'CPA', (138, 146))	('UPR', 'Var', (57, 60))	('HIF-1alpha', 'Gene', (116, 126))	('cooperation', 'Interaction', (86, 97))	('cancer', 'Disease', (35, 41))	('XBP1', 'Gene', (106, 110))
62456	32536347	E1F2B5epsilon is overexpressed in head and neck cancers, implicating hypoxia-induced E1F2B5epsilon splicing in reducing protein expression and promoting survival during periods of hypoxia-induced acute and chronic ER stress.	('protein expression', 'MPA', (120, 138))	('promoting', 'PosReg', (143, 152))	('neck cancers', 'Disease', 'MESH:D006258', (43, 55))	('E1F2B5epsilon splicing', 'Var', (85, 107))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('splicing', 'biological_process', 'GO:0045292', ('99', '107'))	('hypoxia', 'Disease', 'MESH:D000860', (69, 76))	('hypoxia', 'Disease', 'MESH:D000860', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('neck', 'cellular_component', 'GO:0044326', ('43', '47'))	('head and neck cancers', 'Phenotype', 'HP:0012288', (34, 55))	('reducing', 'NegReg', (111, 119))	('hypoxia', 'Disease', (69, 76))	('survival', 'CPA', (153, 161))	('neck cancers', 'Disease', (43, 55))	('hypoxia', 'Disease', (180, 187))
62462	32536347	Hypoxia induces alternative splicing of the co-stimulatory TNFR family member CD137, reported in a variety of tumour cell types, results in the expression of soluble sCD137 that binds CD137L, inhibiting interaction with wtCD137 and preventing T-lymphocyte activation.	('CD137L', 'Gene', (184, 190))	('T-lymphocyte activation', 'biological_process', 'GO:0042110', ('243', '266'))	('binds', 'Interaction', (178, 183))	('splicing', 'biological_process', 'GO:0045292', ('28', '36'))	('results in', 'Reg', (129, 139))	('soluble', 'cellular_component', 'GO:0005625', ('158', '165'))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('alternative splicing', 'Var', (16, 36))	('interaction', 'Interaction', (203, 214))	('Hypoxia', 'Disease', (0, 7))	('inhibiting', 'NegReg', (192, 202))	('CD137', 'Gene', (184, 189))	('CD137', 'Gene', '3604', (184, 189))	('preventing', 'NegReg', (232, 242))	('T-lymphocyte activation', 'CPA', (243, 266))	('CD137', 'Gene', (167, 172))	('CD137', 'Gene', '3604', (167, 172))	('TNFR', 'Gene', '7132', (59, 63))	('CD137L', 'Gene', '8744', (184, 190))	('CD137', 'Gene', (78, 83))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('CD137', 'Gene', (222, 227))	('CD137', 'Gene', '3604', (222, 227))	('CD137', 'Gene', '3604', (78, 83))	('TNFR', 'Gene', (59, 63))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
62463	32536347	Hypoxia promotes alternative splicing of HLA-G human leukocyte antigen G, a non-classical major histocompatibility complex (MHC) class I immune checkpoint molecule, resulting in expression of 4 membrane bound (HLA-G1-G4) and 3 soluble (HLA-G5-G7) isoforms in melanoma, choriocarcinoma, lymphoma, glioma and other cancer cell types, that attenuate NK, cytotoxic T-cell and antigen presenting cell activity.	('melanoma', 'Disease', 'MESH:D008545', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('alternative', 'Var', (17, 28))	('glioma', 'Disease', (296, 302))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('attenuate', 'NegReg', (337, 346))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('90', '122'))	('human', 'Species', '9606', (47, 52))	('choriocarcinoma', 'Disease', 'MESH:D002822', (269, 284))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('lymphoma', 'Phenotype', 'HP:0002665', (286, 294))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('soluble', 'cellular_component', 'GO:0005625', ('227', '234'))	('Hypoxia', 'Disease', (0, 7))	('choriocarcinoma', 'Disease', (269, 284))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('melanoma', 'Disease', (259, 267))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('membrane', 'cellular_component', 'GO:0016020', ('194', '202'))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (269, 284))	('lymphoma', 'Disease', (286, 294))	('lymphoma', 'Disease', 'MESH:D008223', (286, 294))	('cancer', 'Disease', (313, 319))
62465	32536347	The hypoxia-regulated PDL1 suppressor of adaptive immunity is also expressed as 2 soluble alternative splice variants in human non-small cell lung carcinoma, in association with mutation of TDP-43 splicing factor, which regulates PD-L1 expression and splicing.	('splicing', 'biological_process', 'GO:0045292', ('251', '259'))	('lung carcinoma', 'Disease', (142, 156))	('mutation', 'Var', (178, 186))	('PD-L1', 'Gene', (230, 235))	('hypoxia', 'Disease', 'MESH:D000860', (4, 11))	('human', 'Species', '9606', (121, 126))	('splicing', 'biological_process', 'GO:0045292', ('197', '205'))	('PD-L1', 'Gene', '29126', (230, 235))	('soluble', 'cellular_component', 'GO:0005625', ('82', '89'))	('PDL1', 'Gene', (22, 26))	('splicing factor', 'Gene', (197, 212))	('PDL1', 'Gene', '29126', (22, 26))	('lung carcinoma', 'Disease', 'MESH:D008175', (142, 156))	('TDP-43', 'Gene', (190, 196))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (127, 156))	('TDP-43', 'Gene', '23435', (190, 196))	('splicing factor', 'Gene', '10569', (197, 212))	('hypoxia', 'Disease', (4, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (131, 156))
62473	32536347	PKM1 and PKM2 represents alternative splice variants of the same 12 exon transcript, in which exons 9 and 10 are mutually exclusive.	('PKM1', 'Var', (0, 4))	('PKM2', 'Gene', '5315', (9, 13))	('PKM2', 'Gene', (9, 13))
62474	32536347	Hypoxia promotes HIF-1-dependent PK expression and alternative PKM2 splicing.	('Hypoxia promotes HIF-1-dependent PK', 'Disease', 'MESH:D000860', (0, 35))	('alternative', 'Var', (51, 62))	('PKM2', 'Gene', (63, 67))	('PKM2', 'Gene', '5315', (63, 67))	('Hypoxia promotes HIF-1-dependent PK', 'Disease', (0, 35))	('splicing', 'biological_process', 'GO:0045292', ('68', '76'))
62484	32536347	The hypoxia-regulated alternative TrkAIII splice variant also promotes stress-induced metabolic reprogramming in human neuroblastoma cells, by localizing to mitochondria under non-stressed conditions in inactive form, where it exhibits mitochondrial internalization and cleavage-dependent activation under conditions of ER stress, resulting in tyrosine phosphorylation of pyruvate dehydrogenase kinase (PDK1) and glycolytic metabolic re-programming.	('PDK1', 'molecular_function', 'GO:0004740', ('403', '407'))	('hypoxia', 'Disease', 'MESH:D000860', (4, 11))	('promotes', 'PosReg', (62, 70))	('variant', 'Var', (49, 56))	('human', 'Species', '9606', (113, 118))	('PDK1', 'Gene', (403, 407))	('mitochondria', 'cellular_component', 'GO:0005739', ('157', '169'))	('tyrosine phosphorylation', 'MPA', (344, 368))	('phosphorylation', 'biological_process', 'GO:0016310', ('353', '368'))	('neuroblastoma', 'Disease', (119, 132))	('TrkA', 'Gene', (34, 38))	('neuroblastoma', 'Phenotype', 'HP:0003006', (119, 132))	('tyrosine', 'Chemical', 'MESH:D014443', (344, 352))	('glycolytic metabolic re-programming', 'CPA', (413, 448))	('stress-induced metabolic reprogramming', 'CPA', (71, 109))	('neuroblastoma', 'Disease', 'MESH:D009447', (119, 132))	('pyruvate', 'Chemical', 'MESH:D019289', (372, 380))	('PDK1', 'Gene', '5163', (403, 407))	('TrkA', 'Gene', '4914', (34, 38))	('hypoxia', 'Disease', (4, 11))
62488	32536347	This process is facilitated by the accumulation of genetic mutations and is promoted by hypoxia and hypoxia-induced alternative splicing.	('genetic mutations', 'Var', (51, 68))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('facilitated', 'PosReg', (16, 27))	('hypoxia', 'Disease', (88, 95))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('splicing', 'biological_process', 'GO:0045292', ('128', '136'))	('promoted', 'PosReg', (76, 84))	('hypoxia', 'Disease', (100, 107))
62491	32536347	In hepato-carcinoma cells, hypoxia induces alternative splicing of the membrane and actin-associated protein Supervillin, involved in actin filament assembly, cell spreading, lamellipodia extension and regulation of focal adhesions, resulting in V4 and V5 alternatively spliced isoforms that promote RhoA/ROCK-ERK/p38-dependent EMT.	('Supervillin', 'Gene', '6840', (109, 120))	('actin filament', 'cellular_component', 'GO:0005884', ('134', '148'))	('hepato-carcinoma', 'Disease', (3, 19))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('hepato-carcinoma', 'Disease', 'MESH:D020065', (3, 19))	('RhoA', 'Gene', (300, 304))	('EMT', 'biological_process', 'GO:0001837', ('328', '331'))	('p38', 'Gene', (314, 317))	('alternative splicing', 'Var', (43, 63))	('promote', 'PosReg', (292, 299))	('ERK', 'Gene', '5594', (310, 313))	('RhoA', 'Gene', '387', (300, 304))	('regulation', 'biological_process', 'GO:0065007', ('202', '212'))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('ERK', 'molecular_function', 'GO:0004707', ('310', '313'))	('p38', 'Gene', '5594', (314, 317))	('ERK', 'Gene', (310, 313))	('hepato-carcinoma', 'Phenotype', 'HP:0001402', (3, 19))	('hypoxia', 'Disease', (27, 34))	('membrane', 'cellular_component', 'GO:0016020', ('71', '79'))	('Supervillin', 'Gene', (109, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
62497	32536347	Hypoxia induced oncogenic alternative RON splicing and activation promotes CLK1-medited SF2/ASF splice factor phosphorylation-dependent reduction in E-cadherin expression, and promotes actin reorganization and vimentin expression, resulting in EMT, invasion and metastasis.	('vimentin', 'Gene', (210, 218))	('cadherin', 'molecular_function', 'GO:0008014', ('151', '159'))	('vimentin', 'cellular_component', 'GO:0045098', ('210', '218'))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))	('SF2/ASF splice factor', 'Gene', '6426', (88, 109))	('EMT', 'CPA', (244, 247))	('invasion', 'CPA', (249, 257))	('CLK1', 'molecular_function', 'GO:0004712', ('75', '79'))	('EMT', 'biological_process', 'GO:0001837', ('244', '247'))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('CLK1', 'Gene', (75, 79))	('Hypoxia', 'Disease', (0, 7))	('SF2/ASF splice factor', 'Gene', (88, 109))	('alternative RON splicing', 'Var', (26, 50))	('vimentin', 'cellular_component', 'GO:0045099', ('210', '218'))	('reduction', 'NegReg', (136, 145))	('promotes', 'PosReg', (176, 184))	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('expression', 'MPA', (219, 229))	('actin', 'MPA', (185, 190))	('metastasis', 'CPA', (262, 272))	('CLK1', 'Gene', '1195', (75, 79))	('vimentin', 'Gene', '7431', (210, 218))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
62512	32536347	Genetic instability underpins all stages of cancer, from tumour initiation to metastatic disease, and is both directly and indirectly influenced by tumour hypoxia-induced alternative splicing.	('tumour initiation to metastatic disease', 'Disease', (57, 96))	('tumour hypoxia', 'Disease', 'MESH:D000860', (148, 162))	('tumour hypoxia', 'Disease', (148, 162))	('Genetic instability', 'Var', (0, 19))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('splicing', 'biological_process', 'GO:0045292', ('183', '191'))	('underpins', 'Reg', (20, 29))	('influenced', 'Reg', (134, 144))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumour initiation to metastatic disease', 'Disease', 'MESH:D018223', (57, 96))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
62516	32536347	Hypoxia also promotes cytoplasmic stress granule sequestration of the spliceosome component MFAP1, reducing nuclear MFAP1 levels, resulting in alternative splicing of DNA damage response and DNA repair genes that results in genomic instability.	('reducing', 'NegReg', (99, 107))	('promotes', 'PosReg', (13, 21))	('DNA repair', 'biological_process', 'GO:0006281', ('191', '201'))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('spliceosome', 'cellular_component', 'GO:0005681', ('70', '81'))	('DNA repair genes', 'Gene', (191, 207))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('DNA damage response', 'biological_process', 'GO:0006974', ('167', '186'))	('MFAP1', 'Gene', '4236', (92, 97))	('MFAP1', 'Gene', '4236', (116, 121))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('results in', 'Reg', (213, 223))	('alternative splicing', 'Var', (143, 163))	('cytoplasmic stress granule', 'cellular_component', 'GO:0010494', ('22', '48'))	('cytoplasmic', 'MPA', (22, 33))	('splicing', 'biological_process', 'GO:0045292', ('155', '163'))	('genomic', 'MPA', (224, 231))	('MFAP1', 'Gene', (92, 97))	('DNA damage response', 'Gene', (167, 186))	('MFAP1', 'Gene', (116, 121))
62517	32536347	Additional mechanisms by which hypoxia-regulated alternative splicing promotes genetic instability, include induction of LUCAT1 expression and complexing with PTBP1, resulting in inhibitory alternative DNA damage-related gene splicing, and inhibitory intron-retention alternative splicing of DNA damage and DNA repair pathway genes in human colorectal and breast cancer cells.	('PTBP1', 'Gene', '5725', (159, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (356, 369))	('complexing', 'Var', (143, 153))	('promotes', 'PosReg', (70, 78))	('DNA repair', 'biological_process', 'GO:0006281', ('307', '317'))	('human', 'Species', '9606', (335, 340))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('PTBP1', 'Gene', (159, 164))	('genetic instability', 'MPA', (79, 98))	('hypoxia', 'Disease', (31, 38))	('expression', 'MPA', (128, 138))	('DNA', 'cellular_component', 'GO:0005574', ('292', '295'))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (341, 369))	('inhibitory', 'NegReg', (179, 189))	('splicing', 'biological_process', 'GO:0045292', ('226', '234'))	('splicing', 'biological_process', 'GO:0045292', ('280', '288'))	('hypoxia', 'Disease', 'MESH:D000860', (31, 38))	('inhibitory', 'Var', (240, 250))	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('induction', 'Reg', (108, 117))	('retention', 'biological_process', 'GO:0051235', ('258', '267'))	('DNA', 'cellular_component', 'GO:0005574', ('307', '310'))	('LUCAT1', 'Gene', '100505994', (121, 127))	('LUCAT1', 'Gene', (121, 127))
62521	32536347	Between 10 and 30% of solid tumours are characterized by fluctuating acute and chronic hypoxia, resulting in cellular hypoxic responses that include alternative pre-mRNA splicing and the expression of novel protein isoforms that promote tumour progression and impact therapeutic efficacy.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('protein', 'Protein', (207, 214))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', (28, 34))	('therapeutic efficacy', 'CPA', (267, 287))	('solid tumours', 'Disease', (22, 35))	('cellular', 'MPA', (109, 117))	('hypoxia', 'Disease', (87, 94))	('promote', 'PosReg', (229, 236))	('alternative', 'Var', (149, 160))	('pre', 'molecular_function', 'GO:0003904', ('161', '164'))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('161', '178'))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('impact', 'Reg', (260, 266))	('solid tumours', 'Disease', 'MESH:D009369', (22, 35))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('tumour', 'Disease', (237, 243))	('expression', 'MPA', (187, 197))
62525	32536347	Therapeutic efficacy can be enhanced by interfering with or reprogramming the hypoxic tumour niche to improve drug efficacy.	('hypoxic tumour niche', 'Disease', (78, 98))	('improve drug efficacy', 'Phenotype', 'HP:0020173', (102, 123))	('improve', 'PosReg', (102, 109))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('reprogramming', 'Var', (60, 73))	('enhanced', 'PosReg', (28, 36))	('hypoxic tumour niche', 'Disease', 'MESH:D009369', (78, 98))	('interfering', 'NegReg', (40, 51))	('drug efficacy', 'MPA', (110, 123))	('Therapeutic', 'MPA', (0, 11))
62533	32536347	PHD2 inhibition also promotes tumour vascular "normalization", restoring tumor oxygenation, normalizing the vascular endothelium and inhibiting metastatic progression (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('metastatic progression', 'CPA', (144, 166))	('inhibition', 'Var', (5, 15))	('inhibiting', 'NegReg', (133, 143))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PHD', 'molecular_function', 'GO:0050175', ('0', '3'))	('tumour', 'Disease', (30, 36))	('promotes', 'PosReg', (21, 29))	('oxygen', 'Chemical', 'MESH:D010100', (79, 85))	('normalizing', 'NegReg', (92, 103))	('tumor', 'Disease', (73, 78))	('PHD2', 'Gene', '54583', (0, 4))	('PHD2', 'Gene', (0, 4))	('vascular endothelium', 'MPA', (108, 128))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('restoring', 'PosReg', (63, 72))
62536	32536347	Hypoxia inactivation of PHD proline hydroxylase, results in dissociation of HIFalpha/VHL-VEC complexes, HIFalpha stabilization, nuclear translocation and hetero-dimerization with ARNT/HIFbeta components, identifying many relevant therapeutic targets.	('HIFalpha', 'Disease', 'None', (76, 84))	('HIFalpha', 'Disease', (76, 84))	('VHL', 'Gene', (85, 88))	('dissociation', 'MPA', (60, 72))	('HIFalpha', 'Disease', 'None', (104, 112))	('HIFalpha', 'Disease', (104, 112))	('HIFbeta', 'Disease', (184, 191))	('proline', 'Chemical', 'MESH:D011392', (28, 35))	('VHL', 'Gene', '7428', (85, 88))	('ARNT', 'Gene', '405', (179, 183))	('HIFbeta', 'Disease', 'None', (184, 191))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('ARNT', 'Gene', (179, 183))	('PHD', 'molecular_function', 'GO:0050175', ('24', '27'))	('Hypoxia', 'Disease', (0, 7))	('nuclear translocation', 'MPA', (128, 149))	('inactivation', 'Var', (8, 20))	('PHD', 'Disease', (24, 27))	('hetero-dimerization', 'MPA', (154, 173))	('PHD', 'Disease', 'MESH:D011547', (24, 27))
62543	32536347	HIF transcriptional Inhibitors, include: chetomin dithio-diketopiperizine that impedes HIF-1alpha interaction with its transcriptional activating histone acetyltransferase p300 co-factor and increases the radiosensitivity of human fibrosarcoma cells; idenopyrasole 21 that inhibits HIF-1 transcriptional activity but not HIF-1alpha accumulation or dimerization; YC-1 platelet aggregation inhibitor that disassociates HIF-1alpha/p300 complexes, represses HIF transcriptional activity and reduces HIF-1alpha protein accumulation; FM19G11 that inhibits HIF transcriptional activation by impairing interaction with p300; small molecule NSC-607097 that inhibits HIF-1 transcriptional activity, and IDF-11774 that prevents HIF-1alpha accumulation, regulates cancer metabolism, suppresses tumour growth in vitro and in vivo and is a clinical cancer therapy candidate.	('HIF-1alpha', 'Gene', '3091', (321, 331))	('platelet aggregation', 'Phenotype', 'HP:0003540', (367, 387))	('HIF', 'Gene', (0, 3))	('HIF-1', 'Gene', (495, 500))	('HIF', 'Gene', '405;9915', (0, 3))	('regulates', 'Reg', (742, 751))	('HIF-1', 'Gene', '3091', (87, 92))	('p300', 'Gene', (611, 615))	('fibrosarcoma', 'Disease', 'MESH:D005354', (231, 243))	('tumour', 'Phenotype', 'HP:0002664', (782, 788))	('HIF', 'Gene', (417, 420))	('HIF', 'Gene', '405;9915', (417, 420))	('HIF', 'Gene', (321, 324))	('platelet aggregation', 'Disease', 'MESH:D001791', (367, 387))	('HIF-1alpha', 'Gene', (495, 505))	('HIF', 'Gene', '405;9915', (321, 324))	('p300', 'Gene', '2033', (428, 432))	('HIF-1', 'Gene', '3091', (657, 662))	('HIF', 'Gene', '405;9915', (282, 285))	('HIF-1', 'Gene', '3091', (417, 422))	('YC-1', 'Gene', (362, 366))	('platelet aggregation', 'Disease', (367, 387))	('HIF-1', 'Gene', (321, 326))	('p300', 'Gene', '2033', (172, 176))	('cancer', 'Disease', (835, 841))	('IDF-11774', 'Var', (693, 702))	('HIF-1alpha', 'Gene', (87, 97))	('tumour growth', 'Disease', 'MESH:D006130', (782, 795))	('HIF-1alpha', 'Gene', '3091', (717, 727))	('cancer', 'Disease', (752, 758))	('fibrosarcoma', 'Disease', (231, 243))	('tumour growth', 'Disease', (782, 795))	('platelet aggregation', 'biological_process', 'GO:0070527', ('367', '387'))	('HIF', 'Gene', (282, 285))	('YC-1', 'Gene', '5937', (362, 366))	('prevents', 'NegReg', (708, 716))	('HIF-1', 'Gene', '3091', (282, 287))	('HIF', 'Gene', (717, 720))	('FM19G11', 'Var', (528, 535))	('HIF', 'Gene', '405;9915', (717, 720))	('HIF-1', 'Gene', '3091', (717, 722))	('human', 'Species', '9606', (225, 230))	('inhibits', 'NegReg', (541, 549))	('HIF-1', 'Gene', '3091', (495, 500))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (231, 243))	('cancer', 'Phenotype', 'HP:0002664', (835, 841))	('HIF-1alpha', 'Gene', '3091', (495, 505))	('HIF', 'Gene', (657, 660))	('HIF', 'Gene', '405;9915', (657, 660))	('HIF-1', 'Gene', (87, 92))	('HIF-1alpha', 'Gene', (417, 427))	('suppresses', 'NegReg', (771, 781))	('p300', 'Gene', '2033', (611, 615))	('HIF-1alpha', 'Gene', (321, 331))	('p300', 'Gene', (428, 432))	('inhibits', 'NegReg', (648, 656))	('cancer', 'Phenotype', 'HP:0002664', (752, 758))	('HIF', 'Gene', (495, 498))	('HIF', 'Gene', (550, 553))	('HIF-1', 'Gene', (657, 662))	('HIF', 'Gene', '405;9915', (495, 498))	('HIF', 'Gene', '405;9915', (550, 553))	('HIF-1', 'Gene', '3091', (321, 326))	('p300', 'Gene', (172, 176))	('HIF-1', 'Gene', (417, 422))	('protein', 'cellular_component', 'GO:0003675', ('506', '513'))	('HIF', 'Gene', (87, 90))	('HIF', 'Gene', '405;9915', (87, 90))	('interaction', 'Interaction', (594, 605))	('cancer', 'Disease', 'MESH:D009369', (835, 841))	('metabolism', 'biological_process', 'GO:0008152', ('759', '769'))	('impairing', 'NegReg', (584, 593))	('HIF-1alpha', 'Gene', (717, 727))	('HIF-1alpha', 'Gene', '3091', (87, 97))	('HIF-1', 'Gene', (282, 287))	('HIF', 'Gene', (454, 457))	('cancer', 'Disease', 'MESH:D009369', (752, 758))	('HIF', 'Gene', '405;9915', (454, 457))	('HIF-1', 'Gene', (717, 722))	('HIF-1alpha', 'Gene', '3091', (417, 427))
62546	32536347	Bacterial products that bind the SF3B component of U2 snRNP and interrupt spliceosome assembly, include: the spliceostatins, spliceostatin A, FD-895 and the derivatives FR901463, FR901464 and FR901465; sudemycins, from pseudomonas; herboxidienes, from streptomyces A7847, and pladienolide B and its E7017 analogue, from streptomyces platensis Mer-11,107.	('FD-895', 'Var', (142, 148))	('streptomyces', 'Species', '58346', (252, 264))	('snRNP', 'Gene', (54, 59))	('spliceosome', 'cellular_component', 'GO:0005681', ('74', '85'))	('interrupt', 'NegReg', (64, 73))	('snRNP', 'Gene', '57819', (54, 59))	('streptomyces platensis', 'Species', '58346', (320, 342))	('spliceosome assembly', 'biological_process', 'GO:0000245', ('74', '94'))	('FR901465', 'Chemical', 'MESH:C104487', (192, 200))	('herboxidienes', 'Chemical', 'MESH:C076087', (232, 245))	('FR901463', 'Chemical', 'MESH:C104485', (169, 177))	('streptomyces', 'Species', '58346', (320, 332))	('E7017', 'Chemical', '-', (299, 304))	('FR901463', 'Var', (169, 177))	('snRNP', 'molecular_function', 'GO:0003734', ('54', '59'))	('pladienolide', 'Chemical', '-', (276, 288))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('51', '59'))	('sudemycins', 'Chemical', '-', (202, 212))	('FR901465', 'Var', (192, 200))	('FR901464', 'Var', (179, 187))	('spliceosome assembly', 'MPA', (74, 94))	('pseudomonas', 'Species', '306', (219, 230))
62547	32536347	These inhibitors induce cell cycle arrest, cytotoxicity and inhibit  10% of canonical splicing events, suggesting that only weaker splice sites are influenced by spliceosome inhibitors.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('inhibit', 'NegReg', (60, 67))	('cytotoxicity', 'Disease', (43, 55))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('24', '41'))	('arrest', 'Disease', (35, 41))	('inhibitors', 'Var', (6, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('splicing', 'biological_process', 'GO:0045292', ('86', '94'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (24, 41))	('spliceosome', 'cellular_component', 'GO:0005681', ('162', '173'))	('canonical splicing events', 'MPA', (76, 101))
62548	32536347	E7017, spliceostatin A and sudemycin D6/K exhibit improved stability and lower inhibitory IC50 concentrations, making them more suitable for therapy.	('stability', 'MPA', (59, 68))	('E7017', 'Var', (0, 5))	('inhibitory IC50 concentrations', 'MPA', (79, 109))	('improved', 'PosReg', (50, 58))	('E7017', 'Chemical', '-', (0, 5))	('lower', 'NegReg', (73, 78))	('sudemycin', 'Chemical', '-', (27, 36))
62558	32536347	Phosphorodiamidate linkages in morpholino oligonucleotides further increases specificity and lowers toxicity but these ASOs must be conjugated with a delivery moiety for in vivo targeting.	('toxicity', 'Disease', 'MESH:D064420', (100, 108))	('toxicity', 'Disease', (100, 108))	('Phosphorodiamidate', 'Var', (0, 18))	('ASO', 'Chemical', 'MESH:D016376', (119, 122))	('lowers', 'NegReg', (93, 99))	('increases', 'PosReg', (67, 76))	('morpholino oligonucleotides', 'Chemical', 'MESH:D060172', (31, 58))	('Phosphorodiamidate', 'Chemical', '-', (0, 18))	('specificity', 'MPA', (77, 88))
62573	32536347	HnRNPB1 expression correlates with lung cancer development and siRNA HnRNPB1 knockdown promotes A549 lung cancer cell apoptosis, and several potential inhibitory small HnRNPB1 binding molecules have also recently been identified amongst lung cancer drugs.	('HnRNPB1', 'Gene', '3181', (0, 7))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('knockdown', 'Var', (77, 86))	('lung cancer', 'Disease', (237, 248))	('HnRNPB1', 'Gene', (69, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('binding', 'molecular_function', 'GO:0005488', ('176', '183'))	('HnRNPB1', 'Gene', '3181', (69, 76))	('lung cancer', 'Disease', 'MESH:D008175', (237, 248))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('lung cancer', 'Disease', (101, 112))	('HnRNPB1', 'Gene', (168, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('lung cancer', 'Disease', (35, 46))	('promotes', 'PosReg', (87, 95))	('HnRNPB1', 'Gene', '3181', (168, 175))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('HnRNPB1', 'Gene', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
62576	32536347	SiRNA hnRNPA1 knockdown inhibits HepG2 hepatocellular carcinoma cell proliferation, migration, promotes alternative PKM2 splicing and induces glycolysis, which influences glucose-dependent HnRNPA1 acetylation, de-acetylated under glucose starvation conditions by SIRT1 and SIRT6 sirtuins, which inhibit glycolysis by reducing PKM2 and increasing PMK1 expression, implicating an adaptive hnRNPA1 acetylation-regulated metabolic reprogramming mechanism for HCC metabolic adaptation, proliferation and tumourigenesis, within nutrient-deprived tumour microenvironments (Fig.	('HnRNPA1', 'Gene', (189, 196))	('SIRT6', 'Gene', '51548', (273, 278))	('HepG2', 'CellLine', 'CVCL:0027', (33, 38))	('PKM2', 'Gene', '5315', (326, 330))	('inhibits', 'NegReg', (24, 32))	('splicing', 'biological_process', 'GO:0045292', ('121', '129'))	('expression', 'MPA', (351, 361))	('glycolysis', 'biological_process', 'GO:0006096', ('303', '313'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('inhibit', 'NegReg', (295, 302))	('SIRT1', 'Gene', '23411', (263, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('migration', 'CPA', (84, 93))	('reducing', 'NegReg', (317, 325))	('hnRNPA1', 'Gene', (387, 394))	('hnRNPA1', 'Gene', (6, 13))	('tumour', 'Disease', 'MESH:D009369', (499, 505))	('glucose', 'Chemical', 'MESH:D005947', (171, 178))	('hepatocellular carcinoma', 'Disease', (39, 63))	('glycolysis', 'biological_process', 'GO:0006096', ('142', '152'))	('PKM2', 'Gene', (116, 120))	('PKM2', 'Gene', '5315', (116, 120))	('SIRT1', 'Gene', (263, 268))	('tumour', 'Phenotype', 'HP:0002664', (540, 546))	('hnRNPA1', 'Gene', '3178', (387, 394))	('tumour', 'Disease', 'MESH:D009369', (540, 546))	('promotes', 'PosReg', (95, 103))	('hnRNPA1', 'Gene', '3178', (6, 13))	('tumour', 'Disease', (540, 546))	('HnRNPA1', 'Gene', '3178', (189, 196))	('PMK1', 'Enzyme', (346, 350))	('tumour', 'Disease', (499, 505))	('SIRT6', 'Gene', (273, 278))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('tumour', 'Phenotype', 'HP:0002664', (499, 505))	('increasing', 'PosReg', (335, 345))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('HepG2', 'Gene', (33, 38))	('knockdown', 'Var', (14, 23))	('glucose', 'Chemical', 'MESH:D005947', (230, 237))	('PKM2', 'Gene', (326, 330))	('induces', 'Reg', (134, 141))
62577	32536347	Therapeutic targeting of splice factor kinases, which modulate splice factor involvement in spliceosome assembly, splice factor binding to splice sites and subsequently alternative splicing may also reduce the expression and activity of hypoxia-induced alternatively spliced tumour promoting protein isoforms.	('spliceosome assembly', 'biological_process', 'GO:0000245', ('92', '112'))	('modulate', 'Reg', (54, 62))	('splicing', 'biological_process', 'GO:0045292', ('181', '189'))	('binding', 'molecular_function', 'GO:0005488', ('128', '135'))	('expression', 'MPA', (210, 220))	('hypoxia', 'Disease', (237, 244))	('hypoxia', 'Disease', 'MESH:D000860', (237, 244))	('reduce', 'NegReg', (199, 205))	('activity', 'MPA', (225, 233))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('tumour', 'Disease', 'MESH:D009369', (275, 281))	('protein', 'cellular_component', 'GO:0003675', ('292', '299'))	('spliceosome', 'cellular_component', 'GO:0005681', ('92', '103'))	('tumour', 'Disease', (275, 281))	('alternative splicing', 'Var', (169, 189))
62579	32536347	The small molecular nanomolar casein kinase-2 inhibitor CX-4945 inhibits CLKs1-4 and exhibits anti-proliferative, anti-angiogenic and anti-tumour activity in mouse tumor xenograft models, inhibits PI3K/Akt signaling and HIF1alpha transcription, and is currently in clinical trials for bile duct cholangiocarcinoma, with gemcetibine and cisplatin.	('CLKs1-4', 'Gene', '12747;12748;102414;12750', (73, 80))	('tumor', 'Disease', (164, 169))	('transcription', 'MPA', (230, 243))	('bile duct cholangiocarcinoma', 'Disease', (285, 313))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('CX-4945', 'Chemical', 'MESH:C555142', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('inhibits', 'NegReg', (188, 196))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('anti-angiogenic', 'CPA', (114, 129))	('tumour', 'Disease', (139, 145))	('mouse', 'Species', '10090', (158, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (295, 313))	('PI3K', 'molecular_function', 'GO:0016303', ('197', '201'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PI3', 'Gene', '5266', (197, 200))	('gemcetibine', 'Chemical', '-', (320, 331))	('CLKs1-4', 'Gene', (73, 80))	('transcription', 'biological_process', 'GO:0006351', ('230', '243'))	('CX-4945', 'Var', (56, 63))	('bile duct cholangiocarcinoma', 'Disease', 'MESH:D001650', (285, 313))	('HIF1alpha', 'Gene', (220, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('PI3', 'Gene', (197, 200))	('Akt signaling', 'biological_process', 'GO:0043491', ('202', '215'))	('cisplatin', 'Chemical', 'MESH:D002945', (336, 345))	('inhibits', 'NegReg', (64, 72))	('anti-proliferative', 'CPA', (94, 112))
62581	32536347	The small molecule Wnt signaling pathway inhibitor SM08502 also inhibits CLKs (CLK3 and DRYKs) and oral SM08502 administration exhibits anti-tumor effects in mouse GI tumour xenograft models, inhibits SRSF phosphorylation, induces DVL2, TCFJ, ERBB2 and LRP5 alternative intron retention splicing and NMD, implicating alternative splicing in Wnt pathway signaling.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CLK3', 'Gene', '102414', (79, 83))	('ERBB2', 'Gene', '13866', (243, 248))	('DVL2', 'Gene', (231, 235))	('CLK3', 'Gene', (79, 83))	('CLKs', 'Disease', 'None', (73, 77))	('LRP5', 'Gene', (253, 257))	('CLKs', 'Disease', (73, 77))	('SM08502', 'Chemical', '-', (104, 111))	('SM08502', 'Var', (104, 111))	('splicing', 'biological_process', 'GO:0045292', ('329', '337'))	('NMD', 'MPA', (300, 303))	('LRP5', 'Gene', '16973', (253, 257))	('mouse', 'Species', '10090', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('induces', 'PosReg', (223, 230))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('19', '40'))	('splicing', 'biological_process', 'GO:0045292', ('287', '295'))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('phosphorylation', 'biological_process', 'GO:0016310', ('206', '221'))	('GI tumour', 'Phenotype', 'HP:0007378', (164, 173))	('retention', 'biological_process', 'GO:0051235', ('277', '286'))	('GI tumour', 'Disease', 'MESH:D009369', (164, 173))	('GI tumour', 'Disease', (164, 173))	('inhibits', 'NegReg', (192, 200))	('DVL2', 'Gene', '13543', (231, 235))	('tumor', 'Disease', (141, 146))	('TCFJ', 'Gene', (237, 241))	('ERBB2', 'Gene', (243, 248))	('SM08502', 'Chemical', '-', (51, 58))	('SM08502', 'Var', (51, 58))	('SRSF phosphorylation', 'MPA', (201, 221))	('inhibits', 'NegReg', (64, 72))	('signaling', 'biological_process', 'GO:0023052', ('353', '362'))
62582	32536347	SM08508 inhibition of CLK2, CLK 3 and Wnt signaling is likely to disrupt spliceosomes, resulting in unstable alternative intron-retained splice transcripts, subsequently degraded by NMD.	('disrupt', 'Reg', (65, 72))	('CLK2', 'Gene', '1196', (22, 26))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('inhibition', 'NegReg', (8, 18))	('CLK 3', 'Gene', '1198', (28, 33))	('SM08508', 'Chemical', '-', (0, 7))	('SM08508', 'Var', (0, 7))	('CLK 3', 'Gene', (28, 33))	('alternative intron-retained splice transcripts', 'MPA', (109, 155))	('degraded', 'NegReg', (170, 178))	('CLK2', 'Gene', (22, 26))
62583	32536347	SM08508 also induces apoptosis regardless of the K-Ras or Wnt mutational status, permeates the nucleus and is in phase I clinical trials (NCT03355066) in patients with advanced stage solid tumours.	('solid tumours', 'Disease', 'MESH:D009369', (183, 196))	('induces', 'Reg', (13, 20))	('SM08508', 'Chemical', '-', (0, 7))	('SM08508', 'Var', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('patients', 'Species', '9606', (154, 162))	('solid tumours', 'Disease', (183, 196))	('apoptosis', 'biological_process', 'GO:0097194', ('21', '30'))	('permeates', 'CPA', (81, 90))	('apoptosis', 'CPA', (21, 30))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('K-Ras', 'Gene', '3845', (49, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('21', '30'))	('K-Ras', 'Gene', (49, 54))	('nucleus', 'cellular_component', 'GO:0005634', ('95', '102'))
62584	32536347	Amiloride, discovered in a screen of small molecule inhibitors of hepatocellular carcinoma Huh-7 cells, modulates oncogenic alternative splicing, devitalizes cancer cells, normalizes Bclx, HPK3 and RON/MISTR1 transcripts in association with SF2/ASF hypo-phosphorylation, reduces the expression of SRp20 and 2 other SR proteins, decreases AKT, ERK1/2 and PP1 phosphorylation and increases p38 and JNK phosphorylation, in association with global changes in alternative splicing, involving 584 exons in 551 ion transport, cell matrix formation, cytoskeletal remodeling and genome maintenance gene transcripts, reducing cellular invasion and migration, cell cycle disruption, cytokinesis and inducing cell death.	('increases', 'PosReg', (378, 387))	('SR protein', 'Gene', '10921', (315, 325))	('SF2', 'Gene', '6426', (241, 244))	('splicing', 'biological_process', 'GO:0045292', ('136', '144'))	('phosphorylation', 'biological_process', 'GO:0016310', ('400', '415'))	('ASF', 'Gene', (245, 248))	('p38', 'Gene', '5594', (388, 391))	('hepatocellular carcinoma', 'Disease', (66, 90))	('ERK1', 'molecular_function', 'GO:0004707', ('343', '347'))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('cell cycle disruption', 'CPA', (649, 670))	('Bclx', 'Gene', (183, 187))	('ERK1/2', 'Gene', (343, 349))	('cell cycle', 'biological_process', 'GO:0007049', ('649', '659'))	('ERK1/2', 'Gene', '5595;5594', (343, 349))	('SR protein', 'Gene', (315, 325))	('reduces', 'NegReg', (271, 278))	('changes', 'Reg', (444, 451))	('JNK', 'Gene', (396, 399))	('AKT', 'Gene', (338, 341))	('alternative splicing', 'Var', (455, 475))	('JNK', 'Gene', '5599', (396, 399))	('Amiloride', 'Chemical', 'MESH:D000584', (0, 9))	('cancer', 'Disease', (158, 164))	('cell death', 'biological_process', 'GO:0008219', ('697', '707'))	('cytokinesis', 'biological_process', 'GO:0000910', ('672', '683'))	('decreases', 'NegReg', (328, 337))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('254', '269'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('PP1', 'Gene', '5540', (354, 357))	('cell death', 'CPA', (697, 707))	('cytokinesis', 'CPA', (672, 683))	('formation', 'biological_process', 'GO:0009058', ('531', '540'))	('p38', 'Gene', (388, 391))	('expression', 'MPA', (283, 293))	('cellular invasion', 'CPA', (616, 633))	('inducing', 'Reg', (688, 696))	('AKT', 'Gene', '207', (338, 341))	('Bclx', 'Gene', '598', (183, 187))	('splicing', 'biological_process', 'GO:0045292', ('467', '475'))	('reducing', 'NegReg', (607, 615))	('ion transport', 'biological_process', 'GO:0006811', ('504', '517'))	('SRp', 'cellular_component', 'GO:0005786', ('297', '300'))	('PP1', 'Gene', (354, 357))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('Huh-7', 'CellLine', 'CVCL:0336', (91, 96))	('JNK', 'molecular_function', 'GO:0004705', ('396', '399'))	('SF2', 'Gene', (241, 244))	('SRp20 and 2', 'Gene', '6428', (297, 308))	('ASF', 'Gene', '6426', (245, 248))	('phosphorylation', 'biological_process', 'GO:0016310', ('358', '373'))
62599	31744829	In vivo epigenetic CRISPR screen identifies Asf1a as an immunotherapeutic target in Kras-mutant lung adenocarcinoma Despite substantial progress in lung cancer immunotherapy, the overall response rate in KRAS-mutant lung adenocarcinoma (ADC) patients remains low.	('lung adenocarcinoma', 'Disease', (96, 115))	('lung adenocarcinoma', 'Disease', (216, 235))	('KRAS-mutant', 'Var', (204, 215))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (216, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (96, 115))	('Kras', 'Gene', (84, 88))	('Kras', 'Gene', '16653', (84, 88))	('Asf1a', 'Gene', (44, 49))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('Asf1a', 'Gene', '66403', (44, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (216, 235))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('lung cancer', 'Disease', (148, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('patients', 'Species', '9606', (242, 250))
62600	31744829	Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses:such as epigenetic modulation of anti-tumor immunity:is therefore an attractive strategy.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('enhance', 'PosReg', (63, 70))	('tumor', 'Disease', (135, 140))	('epigenetic modulation', 'Var', (105, 126))	('adaptive immune responses', 'CPA', (71, 96))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
62602	31744829	Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment.	('loss', 'Var', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('histone chaperone', 'biological_process', 'GO:0006334', ('33', '50'))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('histone chaperone', 'biological_process', 'GO:0043486', ('33', '50'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Asf1a', 'Gene', (51, 56))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('sensitizes', 'Reg', (72, 82))
62603	31744829	Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T cell activation in combination with anti-PD-1.	('potentiated', 'PosReg', (187, 198))	('GM-CSF', 'Protein', (165, 171))	('macrophage differentiation', 'biological_process', 'GO:0030225', ('92', '118'))	('induced', 'Reg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('deficiency', 'Var', (61, 71))	('tumor', 'Disease', (34, 39))	('immunogenic macrophage differentiation', 'Disease', (80, 118))	('T cell activation', 'biological_process', 'GO:0042110', ('199', '216'))	('upregulating', 'PosReg', (152, 164))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('immunogenic macrophage differentiation', 'Disease', 'MESH:D055501', (80, 118))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (126, 131))	('potentiated T cell activation', 'Phenotype', 'HP:0005419', (187, 216))	('expression', 'MPA', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Asf1a', 'Gene', (55, 60))	('T cell activation', 'CPA', (199, 216))
62605	31744829	Molecular targeted therapy is a promising therapeutic modality for lung ADC patients compared to conventional chemotherapy or radiotherapy.	('lung ADC', 'Disease', (67, 75))	('patients', 'Species', '9606', (76, 84))	('Molecular targeted', 'Var', (0, 18))
62606	31744829	Lung ADC patients with EGFR mutations can benefit from EGFR tyrosine kinase inhibitors (TKI).	('patients', 'Species', '9606', (9, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('Lung ADC', 'Disease', (0, 8))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
62610	31744829	However, the immunotherapeutic response rate in KRAS-mutant patients remains unsatisfactory.	('KRAS-mutant', 'Gene', (48, 59))	('patients', 'Species', '9606', (60, 68))	('KRAS-mutant', 'Var', (48, 59))
62611	31744829	Epigenetic genes play important roles in cancer biology, and accumulating evidence indicates that epigenetic factors are involved in modulating the tumor immune microenvironment (TME) and regulating the anti-tumor immune response.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('immune response', 'biological_process', 'GO:0006955', ('214', '229'))	('regulating', 'Reg', (188, 198))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('epigenetic factors', 'Var', (98, 116))	('involved', 'Reg', (121, 129))	('tumor', 'Disease', (208, 213))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('modulating', 'Reg', (133, 143))
62629	31744829	There were four treatment groups: immunodeficient Rag1-/- mice treated with control IgG (ID-IgG) or anti-PD-1 (ID-PD1), and immunocompetent WT mice treated with control IgG (IC-IgG) or anti-PD-1 (IC-PD1).	('PD1', 'Gene', (199, 202))	('IgG', 'Gene', (92, 95))	('anti-PD-1', 'Var', (100, 109))	('IgG', 'Gene', (177, 180))	('IgG', 'Gene', (169, 172))	('PD1', 'Gene', '18566', (199, 202))	('Rag1', 'Gene', '19373', (50, 54))	('Rag1', 'Gene', (50, 54))	('PD1', 'Gene', (114, 117))	('immunodeficient', 'Disease', 'MESH:D007153', (34, 49))	('immunodeficient', 'Disease', (34, 49))	('mice', 'Species', '10090', (58, 62))	('IgG', 'Gene', '16059', (84, 87))	('IgG', 'Gene', '16059', (92, 95))	('mice', 'Species', '10090', (143, 147))	('IgG', 'Gene', '16059', (177, 180))	('IgG', 'Gene', '16059', (169, 172))	('PD1', 'Gene', '18566', (114, 117))	('IgG', 'Gene', (84, 87))
62630	31744829	Comparing sgRNAs recovered from tumors in B6 Rag1-/- and B6 WT mice treated with control IgG (ID-IgG VS IC-IgG), we identified epigenetic targets that, upon loss, modulated the anti-tumor immune response in the immunocompetent WT mice (Supplementary Fig.	('modulated', 'Reg', (163, 172))	('immune response', 'biological_process', 'GO:0006955', ('188', '203'))	('Rag1', 'Gene', '19373', (45, 49))	('IgG', 'Gene', '16059', (97, 100))	('Rag1', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('IgG', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('IgG', 'Gene', (89, 92))	('IgG', 'Gene', (97, 100))	('ID-IgG VS IC-IgG', 'Disease', 'MESH:D017099', (94, 110))	('ID-IgG VS IC-IgG', 'Disease', (94, 110))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Disease', (32, 37))	('epigenetic', 'Var', (127, 137))	('tumor', 'Disease', (182, 187))	('mice', 'Species', '10090', (230, 234))	('IgG', 'Gene', '16059', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mice', 'Species', '10090', (63, 67))	('IgG', 'Gene', '16059', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('loss', 'NegReg', (157, 161))
62636	31744829	1B), consistent with findings that beta-catenin or Mapk3 inhibition promotes sensitivity to ICB.	('beta-catenin', 'Gene', (35, 47))	('inhibition', 'Var', (57, 67))	('promotes', 'PosReg', (68, 76))	('sensitivity to ICB', 'MPA', (77, 95))	('beta-catenin', 'Gene', '12387', (35, 47))	('Mapk3', 'Gene', '26417', (51, 56))	('Mapk', 'molecular_function', 'GO:0004707', ('51', '55'))	('Mapk3', 'Gene', (51, 56))
62637	31744829	Of note, sgRNAs targeting the histone chaperone gene anti-silencing function protein 1 homolog A (Asf1a) were also significantly depleted in tumors treated with anti-PD-1 (Fig.	('anti-silencing function protein 1 homolog A', 'Gene', (53, 96))	('depleted', 'NegReg', (129, 137))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('histone chaperone', 'biological_process', 'GO:0006334', ('30', '47'))	('anti-silencing function protein 1 homolog A', 'Gene', '66403', (53, 96))	('histone chaperone', 'biological_process', 'GO:0043486', ('30', '47'))	('anti-PD-1', 'Var', (161, 170))
62638	31744829	Importantly, Asf1a sgRNAs were only depleted by anti-PD-1 treatment in WT but not Rag1-/- mice and were not depleted by control IgG, suggesting specificity of responsiveness to PD-1 based immunotherapy and an enhanced T cell response (Fig.	('Rag1', 'Gene', (82, 86))	('IgG', 'Gene', '16059', (128, 131))	('Rag1', 'Gene', '19373', (82, 86))	('enhanced T cell', 'Phenotype', 'HP:0100828', (209, 224))	('anti-PD-1', 'Var', (48, 57))	('enhanced', 'PosReg', (209, 217))	('T cell response', 'CPA', (218, 233))	('Asf1a', 'Gene', (13, 18))	('IgG', 'Gene', (128, 131))	('mice', 'Species', '10090', (90, 94))
62647	31744829	Using an inducible shRNA system, we further confirmed Asf1a knockdown (KD) exerted only a marginal effect on tumor cell proliferation (Supplementary Fig.	('Asf1a', 'Gene', (54, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('115', '133'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('knockdown', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
62648	31744829	5A-C); however, Asf1a KD in combination with anti-PD-1 treatment significantly inhibited tumor growth in WT mice (Supplementary Fig.	('Asf1a KD', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mice', 'Species', '10090', (108, 112))	('inhibited', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
62650	31744829	Additionally, we performed the treatment study in colon cancer model (MC38 allograft model), and found Asf1a KO significantly synergized with anti-PD-1 to inhibit MC38 allograft tumors (Supplementary Fig.	('colon cancer', 'Disease', 'MESH:D015179', (50, 62))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('colon cancer', 'Disease', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('inhibit', 'NegReg', (155, 162))	('MC38', 'Var', (163, 167))	('colon cancer', 'Phenotype', 'HP:0003003', (50, 62))
62651	31744829	To determine the mechanism by which loss of Asf1a enhances sensitivity to anti-PD-1, we evaluated the immune profile of orthotopic lung tumors following treatment (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('lung tumors', 'Disease', (131, 142))	('sensitivity to', 'MPA', (59, 73))	('enhances', 'PosReg', (50, 58))	('Asf1a', 'Gene', (44, 49))	('lung tumors', 'Phenotype', 'HP:0100526', (131, 142))	('loss', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('lung tumors', 'Disease', 'MESH:D008175', (131, 142))
62654	31744829	Moreover, Re-challenge experiment in MC38 allograft model showed re-challenged tumor cells grew more slowly in the Asf1a KO tumor bearing mice pretreated with anti-PD-1 comparing with Ctrl tumor bearing mice pretreated with anti-PD-1 (Supplementary Fig.	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (79, 84))	('slowly', 'NegReg', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mice', 'Species', '10090', (203, 207))	('tumor', 'Disease', (124, 129))	('mice', 'Species', '10090', (138, 142))	('anti-PD-1', 'Var', (159, 168))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('grew', 'CPA', (91, 95))	('Asf1a', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
62656	31744829	In addition, an ex vivo experiment showed that isolated pan T cells from the lungs of KP-Asf1a KO plus anti-PD-1 treatment group showed a stronger cytotoxicity to tumor cells when compared to those from spleens or lungs of Ctrl mice (Supplementary Fig.	('cytotoxicity to tumor', 'Disease', (147, 168))	('KP-Asf1a KO', 'Var', (86, 97))	('cytotoxicity to tumor', 'Disease', 'MESH:D064420', (147, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('stronger', 'PosReg', (138, 146))	('mice', 'Species', '10090', (228, 232))
62661	31744829	Furthermore, Asf1a KO in MC38 cells also significantly promoted GM-CSF transcription and increased the expression of M1 macrophage markers (IA/IE, CD80, CD86) in macrophages (Supplementary Fig.	('CD86', 'Gene', '12524', (153, 157))	('Asf1a KO', 'Var', (13, 21))	('CD80', 'Gene', (147, 151))	('expression', 'MPA', (103, 113))	('promoted', 'PosReg', (55, 63))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))	('CD80', 'Gene', '12519', (147, 151))	('increased', 'PosReg', (89, 98))	('GM-CSF transcription', 'Gene', (64, 84))	('CD86', 'Gene', (153, 157))
62664	31744829	Gene set enrichment analysis (GSEA) revealed that the genes related to the TNFA signaling via NFKB and inflammatory response pathways were significantly enriched in KP cells with Asf1a KO (Fig.	('TNFA', 'Gene', '21926', (75, 79))	('Asf1a KO', 'Var', (179, 187))	('inflammatory response', 'biological_process', 'GO:0006954', ('103', '124'))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('GSEA', 'Chemical', '-', (30, 34))	('NFKB', 'Gene', (94, 98))	('TNFA', 'Gene', (75, 79))
62665	31744829	In parallel, we compared ASF1A-low lung ADC samples with ASF1A-high lung ADC samples in TCGA, and found TNFA signaling via NFKB and inflammatory response pathways were also significantly enriched in the ASF1A-low lung ADC samples (Figure 4D, E; Supplementary Table 3).	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('TNFA', 'Gene', (104, 108))	('NFKB', 'Gene', (123, 127))	('TNFA', 'Gene', '21926', (104, 108))	('enriched', 'PosReg', (187, 195))	('inflammatory response pathways', 'Pathway', (132, 162))	('inflammatory response', 'biological_process', 'GO:0006954', ('132', '153'))	('ASF1A-low', 'Var', (203, 212))
62669	31744829	Caf-1 subunits (Chaf1a, Chaf1b) and Hira were included in our sgRNA library, but the knockout of Chaf1a, Chaf1b or Hira did not sensitize to anti-PD-1 therapy in the screen (Supplementary Table 2).	('Chaf1a', 'Gene', '27221', (97, 103))	('Caf-1', 'Gene', '110749', (0, 5))	('Chaf1a', 'Gene', '27221', (16, 22))	('Chaf1b', 'Gene', '110749', (105, 111))	('Chaf1b', 'Gene', (105, 111))	('Chaf1b', 'Gene', '110749', (24, 30))	('Chaf1b', 'Gene', (24, 30))	('Caf-1', 'Gene', (0, 5))	('Hira', 'Gene', (36, 40))	('knockout', 'Var', (85, 93))	('Hira', 'Gene', (115, 119))	('Chaf1a', 'Gene', (97, 103))	('Hira', 'Gene', '15260', (115, 119))	('Hira', 'Gene', '15260', (36, 40))	('Chaf1a', 'Gene', (16, 22))
62671	31744829	Accordingly, ASF1A knockdown in human lung cancer cell line NCI-H2009 increased GM-CSF expression (Supplementary Fig.	('NCI-H2009', 'CellLine', 'CVCL:1514', (60, 69))	('lung cancer', 'Disease', (38, 49))	('ASF1A', 'Gene', (13, 18))	('increased', 'PosReg', (70, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('knockdown', 'Var', (19, 28))	('GM-CSF', 'Gene', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('human', 'Species', '9606', (32, 37))
62672	31744829	To further evaluate how Asf1a deficiency in tumor cells promotes M1-like macrophage polarization, we co-cultured tumor cells with bone marrow macrophage precursors.	('tumor', 'Disease', (113, 118))	('macrophage polarization', 'biological_process', 'GO:0042116', ('73', '96'))	('deficiency', 'Var', (30, 40))	('M1-like macrophage polarization', 'CPA', (65, 96))	('Asf1a', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('promotes', 'PosReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (44, 49))
62676	31744829	Collectively, these data indicate that tumor cell intrinsic Asf1a deficiency enhances M1-like macrophage polarization and promotes T cell activation via up-regulating GM-CSF.	('M1-like macrophage polarization', 'CPA', (86, 117))	('Asf1a', 'Gene', (60, 65))	('up-regulating', 'PosReg', (153, 166))	('GM-CSF', 'CPA', (167, 173))	('promotes', 'PosReg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('macrophage polarization', 'biological_process', 'GO:0042116', ('94', '117'))	('enhances', 'PosReg', (77, 85))	('T cell activation', 'CPA', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('deficiency', 'Var', (66, 76))	('T cell activation', 'biological_process', 'GO:0042110', ('131', '148'))	('tumor', 'Disease', (39, 44))
62685	31744829	Consistent with our previous observations, there was an increase in the monocyte/macrophage cluster in tumors with Asf1a deficiency and/or anti-PD-1 treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increase', 'PosReg', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('deficiency', 'Var', (121, 131))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('Asf1a', 'Gene', (115, 120))	('monocyte/macrophage cluster', 'CPA', (72, 99))
62689	31744829	Asf1a deficiency and/or anti-PD1 treatment markedly expanded the cluster 2 population.	('Asf1a', 'Gene', (0, 5))	('expanded', 'PosReg', (52, 60))	('deficiency', 'Var', (6, 16))	('PD1', 'Gene', (29, 32))	('PD1', 'Gene', '18566', (29, 32))
62691	31744829	Consistent with our previous observations, Asf1a deficiency and/or anti-PD1 treatment reduced the cluster MM_5 population (Fig.	('cluster MM_5 population', 'CPA', (98, 121))	('reduced', 'NegReg', (86, 93))	('Asf1a', 'Gene', (43, 48))	('PD1', 'Gene', (72, 75))	('deficiency', 'Var', (49, 59))	('PD1', 'Gene', '18566', (72, 75))
62692	31744829	To assess how Asf1a deficiency and anti-PD-1 immunotherapy affect the transcriptome of tumor-infiltrating T cells, we also performed unbiased secondary clustering of the bulk T cell population and identified 10 distinct subpopulations (Fig.	('affect', 'Reg', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('deficiency', 'Var', (20, 30))	('tumor', 'Disease', (87, 92))	('Asf1a', 'Gene', (14, 19))	('transcriptome', 'MPA', (70, 83))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
62705	31744829	In summary, these results support the notion that Asf1a deficiency and anti-PD-1 combination therapy restrains tumor progression through promoting inflammatory M1-like macrophage polarization and T cell activation.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('T cell activation', 'biological_process', 'GO:0042110', ('196', '213'))	('restrains', 'NegReg', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Asf1a', 'Gene', (50, 55))	('macrophage polarization', 'biological_process', 'GO:0042116', ('168', '191'))	('tumor', 'Disease', (111, 116))	('deficiency', 'Var', (56, 66))	('inflammatory M1-like macrophage polarization', 'CPA', (147, 191))	('promoting', 'PosReg', (137, 146))	('T cell activation', 'CPA', (196, 213))
62715	31744829	Individual reports showed that ASF1A inhibition elicits DNA damage in cancer cells.	('inhibition', 'Var', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('elicits', 'Reg', (48, 55))	('ASF1A', 'Gene', (31, 36))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('DNA damage', 'MPA', (56, 66))
62716	31744829	While emerging evidence indicates that accumulated DNA damage may lead to increased inflammation through the cGAS-cGAMP-STING pathway, we found no significant difference in gammaH2AX levels in KP cells with or without Asf1a knockout, indicating that the enhanced inflammation in Asf1a knockout tumors might not be due to the DNA damage response.	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('gammaH2AX', 'Gene', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumors', 'Disease', (294, 300))	('DNA damage response', 'biological_process', 'GO:0006974', ('325', '344'))	('enhanced', 'PosReg', (254, 262))	('inflammation', 'Disease', (84, 96))	('increased', 'PosReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('gammaH2AX', 'Gene', '15270', (173, 182))	('inflammation', 'Disease', 'MESH:D007249', (263, 275))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cGAS-cGAMP-STING pathway', 'Pathway', (109, 133))	('Asf1a', 'Gene', (279, 284))	('knockout', 'Var', (285, 293))	('inflammation', 'biological_process', 'GO:0006954', ('263', '275'))	('inflammation', 'Disease', (263, 275))	('DNA', 'cellular_component', 'GO:0005574', ('325', '328'))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
62725	31744829	Interestingly, Asf1a deficiency alone did not robustly reduce tumor progression in our KP orthotopic allograft model, suggesting that increased M1-like macrophage differentiation may not be sufficient to achieve a sustained anti-tumor immune response.	('macrophage differentiation', 'biological_process', 'GO:0030225', ('152', '178'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (62, 67))	('deficiency', 'Var', (21, 31))	('tumor', 'Disease', (229, 234))	('immune response', 'biological_process', 'GO:0006955', ('235', '250'))	('M1-like macrophage differentiation', 'CPA', (144, 178))	('Asf1a', 'Gene', (15, 20))
62726	31744829	However, tumor cell-intrinsic Asf1a deficiency coupled with anti-PD-1 treatment substantially increased the anti-tumor immune response.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('immune response', 'biological_process', 'GO:0006955', ('119', '134'))	('Asf1a', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('increased', 'PosReg', (94, 103))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('deficiency', 'Var', (36, 46))
62727	31744829	In Asf1a-deficient tumors treated with anti-PD-1, we observed a decrease in CD62L expression coupled with an increase in CD69, 4-1BB, OX40 and ICOS expression on intratumoral T cells, suggesting the enhanced T cell activation in this context.	('T cell activation', 'biological_process', 'GO:0042110', ('208', '225'))	('OX40', 'Gene', (134, 138))	('increase', 'PosReg', (109, 117))	('OX40', 'Gene', '22163', (134, 138))	('enhanced T cell', 'Phenotype', 'HP:0100828', (199, 214))	('4-1BB', 'Gene', '21942', (127, 132))	('tumor', 'Disease', (19, 24))	('expression', 'MPA', (82, 92))	('enhanced', 'PosReg', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('4-1BB', 'Gene', (127, 132))	('CD69', 'Gene', (121, 125))	('deficient tumors', 'Disease', 'MESH:D009369', (9, 25))	('ICOS', 'Gene', '54167', (143, 147))	('tumor', 'Disease', (167, 172))	('CD69', 'Gene', '12515', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('ICOS', 'Gene', (143, 147))	('CD62L', 'Gene', (76, 81))	('deficient tumors', 'Disease', (9, 25))	('anti-PD-1', 'Var', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('decrease', 'NegReg', (64, 72))	('CD62L', 'Gene', '20343', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
62728	31744829	Our study focused on the macrophage population, but we could not exclude the possibility that the other immune populations, such as dendritic cells, neutrophils and natural killer cells, may also play important roles in the anti-tumor immune response in Asf1a-deficient tumors treated with anti-PD-1.	('anti-PD-1', 'Var', (290, 299))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('deficient tumors', 'Disease', (260, 276))	('deficient tumors', 'Disease', 'MESH:D009369', (260, 276))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumor', 'Disease', (229, 234))	('immune response', 'biological_process', 'GO:0006955', ('235', '250'))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('tumor', 'Disease', (270, 275))
62732	31744829	Thus, the mechanism of the enhanced anti-tumor immune response in Asf1a-deficient tumors treated with anti-PD-1 may involve multiple innate immune populations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (41, 46))	('immune response', 'biological_process', 'GO:0006955', ('47', '62'))	('enhanced', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('deficient tumors', 'Disease', (72, 88))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('deficient tumors', 'Disease', 'MESH:D009369', (72, 88))	('tumor', 'Disease', (82, 87))	('anti-PD-1', 'Var', (102, 111))
62735	31744829	As in the case of CDK4/6 inhibition, despite the fact that CDK4/6 inhibitors can cause cell cycle arrest even in some normal cell types and immune cells, they were still approved by the FDA for the treatment of certain patients with breast cancer.	('CDK', 'molecular_function', 'GO:0004693', ('59', '62'))	('arrest', 'Disease', (98, 104))	('cause', 'Reg', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('breast cancer', 'Disease', (233, 246))	('CDK4/6', 'Gene', '1019;1021', (59, 65))	('CDK4/6', 'Gene', '1019;1021', (18, 24))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('CDK', 'molecular_function', 'GO:0004693', ('18', '21'))	('patients', 'Species', '9606', (219, 227))	('inhibitors', 'Var', (66, 76))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('87', '104'))	('CDK4/6', 'Gene', (59, 65))	('CDK4/6', 'Gene', (18, 24))
62736	31744829	Besides causing cell cycle arrest, CDK4/6 inhibitors could also affect other aspects of cancer cell behavior such as enhancing anti-tumor immunity if dosing schedule is optimized as intermittent to bypass the cell cycle arrest, suggesting that CDK4/6 is still an attractive therapeutic target.	('cancer', 'Disease', (88, 94))	('CDK4/6', 'Gene', '1019;1021', (35, 41))	('tumor', 'Disease', (132, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('arrest', 'Disease', (220, 226))	('enhancing', 'PosReg', (117, 126))	('CDK4/6', 'Gene', (244, 250))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('209', '226'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('16', '33'))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('arrest', 'Disease', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (16, 33))	('arrest', 'Disease', 'MESH:D006323', (220, 226))	('CDK4/6', 'Gene', (35, 41))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('CDK', 'molecular_function', 'GO:0004693', ('244', '247'))	('CDK4/6', 'Gene', '1019;1021', (244, 250))	('inhibitors', 'Var', (42, 52))	('affect', 'Reg', (64, 70))	('arrest', 'Disease', 'MESH:D006323', (27, 33))
62737	31744829	Similarly, beyond the possible cell cycle arrest in some cell types, here we showed that ASF1A is a potential target and its inhibition can synergize with anti-PD-1 treatment to restrain cancer development with enhance anti-tumor immunity through both macrophage and T cells.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (31, 48))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('arrest', 'Disease', (42, 48))	('cancer', 'Disease', (187, 193))	('ASF1A', 'Gene', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumor', 'Disease', (224, 229))	('enhance', 'PosReg', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('restrain', 'NegReg', (178, 186))	('inhibition', 'Var', (125, 135))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('31', '48'))	('arrest', 'Disease', 'MESH:D006323', (42, 48))
62788	31744829	Whole lung was minced and digested in collagenase D (11088866001, Roche) and DNase I (10104159001, Roche) in Hank's Balanced Salt Solution at 37 C for 30 minutes.	('11088866001', 'Var', (53, 64))	('10104159001', 'Var', (86, 97))	("Hank's Balanced Salt Solution", 'Chemical', '-', (109, 138))	('DNase I', 'Gene', '13419', (77, 84))	('DNase I', 'molecular_function', 'GO:0004530', ('77', '84'))	('DNase I', 'Gene', (77, 84))
62799	31744829	Equivalent amounts of each sample were loaded on 4%-12% Bis-Tris gels (Invitrogen), transferred to nitrocellulose membranes, and immunoblotted with antibodies directed against Cas9 (MA1-202, ThermoFisher), Asf1a (2990s, Cell Signaling Technology), Asf1b (PA5-67639, Invitrogen), gammaH2AX (9718s, CST) and beta-actin (Ab8227, Abcam).	('PA5-67639', 'Var', (255, 264))	('Bis-Tris', 'Chemical', 'MESH:C026272', (56, 64))	('gammaH2AX', 'Gene', (279, 288))	('Cas', 'cellular_component', 'GO:0005650', ('176', '179'))	('Signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('9718s', 'Var', (290, 295))	('Bis', 'molecular_function', 'GO:0033815', ('56', '59'))	('beta-actin', 'Protein', (306, 316))	('gammaH2AX', 'Gene', '15270', (279, 288))
62806	31744829	B6 WT mice were intravenously injected with KP-Ctrl or KP-Asf1a KO cells, and tumor formation in the lung was indicated by MRI imaging.	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('KP-Asf1a', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mice', 'Species', '10090', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
62812	31744829	Following treatment, 1 million MC38-Ctrl cells were subcutaneously injected to the right flanks of pre-treated mice bearing MC38-Ctrl tumors or MC38-Asf1a KO tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('MC38-Ctrl', 'Var', (124, 133))	('mice', 'Species', '10090', (111, 115))	('pre', 'molecular_function', 'GO:0003904', ('99', '102'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('KO tumors', 'Disease', (155, 164))	('KO tumors', 'Disease', 'MESH:D009369', (155, 164))
62848	31835465	Deletion of MMP-1 leads to decreased vascular permeability and reduced transendothelial migration.	('MMP-1', 'molecular_function', 'GO:0004232', ('12', '17'))	('reduced', 'NegReg', (63, 70))	('decreased', 'NegReg', (27, 36))	('vascular permeability', 'MPA', (37, 58))	('transendothelial migration', 'CPA', (71, 97))	('MMP-1', 'Gene', '4312', (12, 17))	('MMP-1', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
62854	31835465	Genetic and pharmaceutical deletion of pericyte results in increased vascular leakage and intratumoral hypoxia, leading to EMT-driven metastasis.	('vascular leakage', 'CPA', (69, 85))	('EMT-driven metastasis', 'CPA', (123, 144))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('intratumoral hypoxia', 'Disease', 'MESH:D000860', (90, 110))	('pericyte', 'Gene', (39, 47))	('deletion', 'Var', (27, 35))	('intratumoral hypoxia', 'Disease', (90, 110))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('increased', 'PosReg', (59, 68))
62867	31835465	Inhibition of neutrophil infiltration by interleukin 8 (IL-8) neutralization leads to diminished tumor angiogenesis and intravasation.	('interleukin 8', 'Gene', '3576', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('intravasation', 'MPA', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('diminished', 'NegReg', (86, 96))	('IL-8', 'Gene', '3576', (56, 60))	('angiogenesis', 'biological_process', 'GO:0001525', ('103', '115'))	('neutralization', 'Var', (62, 76))	('interleukin 8', 'Gene', (41, 54))	('IL-8', 'Gene', (56, 60))	('IL-8', 'molecular_function', 'GO:0005153', ('56', '60'))
62930	31835465	Ang2 neutralization inhibits the recruitment of CCR2+Tie2- MAMs via blocking C-C motif chemokine ligand 2 (CCL2) and ICAM-1, leading to reduced metastases.	('ICAM-1', 'Gene', '3383', (117, 123))	('neutralization', 'Var', (5, 19))	('reduced', 'NegReg', (136, 143))	('ligand', 'molecular_function', 'GO:0005488', ('97', '103'))	('metastases', 'Disease', 'MESH:D009362', (144, 154))	('CCR', 'molecular_function', 'GO:0043880', ('48', '51'))	('CCL', 'molecular_function', 'GO:0044101', ('107', '110'))	('CCL2', 'Gene', (107, 111))	('Ang2', 'Gene', (0, 4))	('metastases', 'Disease', (144, 154))	('inhibits', 'NegReg', (20, 28))	('ICAM-1', 'Gene', (117, 123))	('Tie2', 'Gene', (53, 57))	('CCR2', 'Gene', (48, 52))	('CCL2', 'Gene', '6347', (107, 111))	('recruitment', 'MPA', (33, 44))	('C-C motif chemokine ligand 2', 'Gene', (77, 105))	('CCR2', 'Gene', '729230', (48, 52))	('C-C motif chemokine ligand 2', 'Gene', '6347', (77, 105))	('Tie2', 'Gene', '7010', (53, 57))	('blocking', 'NegReg', (68, 76))	('Ang2', 'Gene', '285', (0, 4))
62936	31835465	Tie1 deficiency leads to reduced angiogenesis and increased mural cell coverage with improved vessel perfusion via activating the Ang1/Tie2 signaling pathway.	('reduced', 'NegReg', (25, 32))	('improved', 'PosReg', (85, 93))	('deficiency', 'Var', (5, 15))	('vessel perfusion', 'CPA', (94, 110))	('signaling pathway', 'biological_process', 'GO:0007165', ('140', '157'))	('angiogenesis', 'CPA', (33, 45))	('Tie2', 'Gene', (135, 139))	('increased', 'PosReg', (50, 59))	('Tie1', 'Gene', '7075', (0, 4))	('activating', 'Reg', (115, 125))	('Ang1', 'Gene', '284', (130, 134))	('Tie2', 'Gene', '7010', (135, 139))	('Ang1', 'Gene', (130, 134))	('angiogenesis', 'biological_process', 'GO:0001525', ('33', '45'))	('Tie1', 'Gene', (0, 4))	('mural cell coverage', 'CPA', (60, 79))
62940	31835465	The genetic inhibition of the glycolytic activator PFKFB3 improves vessel perfusion and tightens the endothelial cell barrier.	('tightens', 'PosReg', (88, 96))	('genetic inhibition', 'Var', (4, 22))	('vessel perfusion', 'CPA', (67, 83))	('improves', 'PosReg', (58, 66))	('PFKFB3', 'Gene', (51, 57))	('endothelial cell barrier', 'CPA', (101, 125))	('PFKFB3', 'Gene', '5209', (51, 57))
62951	31835465	Anti-angiogenic agents, including DC101 (antibody against VEGFR-2) and sunitinib, promote local invasiveness and increase distant metastasis in the mouse models of pancreatic neuroendocrine cancer and glioblastoma multiforme.	('promote', 'PosReg', (82, 89))	('neuroendocrine cancer', 'Phenotype', 'HP:0100634', (175, 196))	('pancreatic neuroendocrine cancer', 'Disease', (164, 196))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))	('sunitinib', 'Chemical', 'MESH:C473478', (71, 80))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('mouse', 'Species', '10090', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('DC101', 'Var', (34, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (201, 213))	('VEGFR-2', 'Gene', (58, 65))	('increase', 'PosReg', (113, 121))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('glioblastoma multiforme', 'Disease', (201, 224))	('pancreatic neuroendocrine cancer', 'Disease', 'MESH:D010190', (164, 196))	('pancreatic neuroendocrine cancer', 'Phenotype', 'HP:0030405', (164, 196))	('distant metastasis', 'CPA', (122, 140))	('local invasiveness', 'CPA', (90, 108))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (201, 224))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))
62952	31835465	Mice treated with DC101 or sunitinib show severe hypoxia, especially in the micrometastases of distant organs, indicating the crucial role of hypoxia in promoting metastasis after anti-angiogenic therapy.	('metastasis', 'CPA', (163, 173))	('metastases', 'Disease', (81, 91))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('promoting', 'PosReg', (153, 162))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('Mice', 'Species', '10090', (0, 4))	('hypoxia', 'Disease', (49, 56))	('sunitinib', 'Chemical', 'MESH:C473478', (27, 36))	('hypoxia', 'Disease', (142, 149))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('DC101', 'Var', (18, 23))
62970	31835465	Fatty acid synthase (FASN) is a critical enzyme in lipogenesis, and blocking FASN inhibits tumor regrowth and metastasis after the withdrawal of sunitinib treatment.	('blocking', 'Var', (68, 76))	('FASN', 'Gene', (77, 81))	('sunitinib', 'Chemical', 'MESH:C473478', (145, 154))	('FASN', 'Gene', '2194', (77, 81))	('FASN', 'Gene', (21, 25))	('FASN', 'Gene', '2194', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lipogenesis', 'biological_process', 'GO:0008610', ('51', '62'))	('tumor', 'Disease', (91, 96))	('inhibits', 'NegReg', (82, 90))	('Fatty acid synthase', 'Gene', '2194', (0, 19))	('Fatty acid synthase', 'Gene', (0, 19))
62980	31835465	High TAM infiltration and variations in genes regulating TAM-related functions such as TBK1, CCL2, CCL18 and IRF3 predict poor outcome in metastatic patients treated with bevacizumab.	('TAM', 'Chemical', 'MESH:C419191', (57, 60))	('CCL2', 'Gene', '6347', (93, 97))	('patients', 'Species', '9606', (149, 157))	('predict', 'Reg', (114, 121))	('TBK1', 'Gene', (87, 91))	('CCL', 'molecular_function', 'GO:0044101', ('99', '102'))	('CCL2', 'Gene', (93, 97))	('CCL18', 'Gene', '6362', (99, 104))	('IRF3', 'Gene', (109, 113))	('IRF3', 'Gene', '3661', (109, 113))	('CCL', 'molecular_function', 'GO:0044101', ('93', '96'))	('TBK1', 'molecular_function', 'GO:0008384', ('87', '91'))	('CCL18', 'Gene', (99, 104))	('metastatic', 'Disease', (138, 148))	('TAM', 'Chemical', 'MESH:C419191', (5, 8))	('variations', 'Var', (26, 36))	('TBK1', 'Gene', '29110', (87, 91))
62998	31835465	Moreover, the combination of VEGFR-2 and PD-L1 antibodies induces high endothelial venules (HEVs) to facilitate IFNgamma+ CD4+ and IFNgamma+ CD8+ lymphocyte infiltration in breast cancer and pancreatic neuroendocrine tumors, finally leading to tumor cell apoptosis and necrosis.	('combination', 'Var', (14, 25))	('necrosis', 'biological_process', 'GO:0070265', ('269', '277'))	('necrosis', 'biological_process', 'GO:0019835', ('269', '277'))	('facilitate', 'PosReg', (101, 111))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (191, 223))	('CD8', 'Gene', '925', (141, 144))	('necrosis', 'biological_process', 'GO:0001906', ('269', '277'))	('PD-L1', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('tumor', 'Disease', (217, 222))	('PD-L1', 'Gene', '29126', (41, 46))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (202, 223))	('pancreatic neuroendocrine tumors', 'Disease', (191, 223))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('necrosis', 'Disease', 'MESH:D009336', (269, 277))	('VEGFR-2', 'Gene', (29, 36))	('breast cancer', 'Disease', (173, 186))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('antibodies', 'Var', (47, 57))	('IFNgamma', 'Gene', '3458', (131, 139))	('IFNgamma', 'Gene', (131, 139))	('CD4', 'Gene', '920', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('necrosis', 'Disease', (269, 277))	('necrosis', 'biological_process', 'GO:0008219', ('269', '277'))	('CD8', 'Gene', (141, 144))	('CD4', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (244, 249))	('IFNgamma', 'Gene', (112, 120))	('necrosis', 'biological_process', 'GO:0008220', ('269', '277'))	('IFNgamma', 'Gene', '3458', (112, 120))	('leading to', 'Reg', (233, 243))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
63012	31137841	Moreover, using cell lines and patient-derived xenograft models, we showed that inhibition of YAP1 enhances the efficacy of conventional therapies by attenuating CSC stemness features.	('CSC', 'Disease', (162, 165))	('efficacy', 'MPA', (112, 120))	('attenuating', 'NegReg', (150, 161))	('YAP1', 'Gene', (94, 98))	('YAP1', 'Gene', '10413', (94, 98))	('patient', 'Species', '9606', (31, 38))	('enhances', 'PosReg', (99, 107))	('inhibition', 'Var', (80, 90))
63043	31137841	Recently, treatment of breast CSCs with interferon-beta in vitro has been reported to limit stemness, migration, sphere-forming properties, and re-expression of CD24, and promote an epithelial-like morphology.	('stemness', 'CPA', (92, 100))	('promote', 'PosReg', (171, 178))	('limit', 'NegReg', (86, 91))	('re-expression', 'Var', (144, 157))	('CD24', 'Gene', (161, 165))	('CD24', 'Gene', '100133941', (161, 165))	('sphere-forming properties', 'CPA', (113, 138))	('interferon-beta', 'Gene', (40, 55))	('interferon-beta', 'Gene', '3456', (40, 55))	('migration', 'CPA', (102, 111))	('epithelial-like morphology', 'CPA', (182, 208))
63054	31137841	Moreover, CD133+ colorectal cancer cells have also been shown to be resistant to radiotherapy and chemotherapy, consistent with a CSC phenotype.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colorectal cancer', 'Disease', (17, 34))	('CD133+', 'Var', (10, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))
63069	31137841	CD133 has also been identified as a lung CSC marker; notably, CD133+ cells have sphere-forming and tumorigenic capabilities, are chemoresistant, and are a biomarker of poor prognosis in lung cancer patients.	('tumor', 'Disease', (99, 104))	('sphere-forming', 'CPA', (80, 94))	('patients', 'Species', '9606', (198, 206))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('CD133+', 'Var', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))
63076	31137841	Among the CSC-targeting strategies explored in lung cancer to date, genetic knockdown or pharmacological inhibition of ALDH1 has been shown to attenuate the proliferative and migratory capabilities of NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (201, 206))	('attenuate', 'NegReg', (143, 152))	('genetic knockdown', 'Var', (68, 85))	('lung cancer', 'Disease', (47, 58))	('pharmacological', 'Var', (89, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ALDH', 'molecular_function', 'GO:0004030', ('119', '123'))	('NSCLC', 'Disease', (201, 206))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('ALDH1', 'Gene', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('ALDH1', 'Gene', '216', (119, 124))
63087	31137841	CD133+ ovarian cancer cells have been shown to have a more proliferative phenotype than do CD133- cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (7, 21))	('CD133+', 'Var', (0, 6))	('ovarian cancer', 'Disease', 'MESH:D010051', (7, 21))	('ovarian cancer', 'Disease', (7, 21))	('proliferative', 'CPA', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
63088	31137841	A recent study showed that CD133+ CSCs induced CD133- cells to undergo the EMT and to display enhanced metastatic capacity via secretion of CCL5 and activation of NF-kappaB signaling.	('CCL', 'molecular_function', 'GO:0044101', ('140', '143'))	('CCL5', 'Gene', '6352', (140, 144))	('secretion', 'MPA', (127, 136))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('149', '172'))	('EMT', 'biological_process', 'GO:0001837', ('75', '78'))	('CD133+ CSCs', 'Var', (27, 38))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('EMT', 'CPA', (75, 78))	('enhanced', 'PosReg', (94, 102))	('metastatic capacity', 'CPA', (103, 122))	('CCL5', 'Gene', (140, 144))	('activation', 'PosReg', (149, 159))	('NF-kappaB signaling', 'Pathway', (163, 182))	('secretion', 'biological_process', 'GO:0046903', ('127', '136'))
63090	31137841	CD44 knockdown in CSCs suppressed their proliferation, migration/invasion, and sphere-forming abilities and increased their drug sensitivity.	('suppressed', 'NegReg', (23, 33))	('migration/invasion', 'CPA', (55, 73))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (108, 117))	('CD44', 'Gene', '960', (0, 4))	('sphere-forming abilities', 'CPA', (79, 103))	('drug sensitivity', 'CPA', (124, 140))	('CD44', 'Gene', (0, 4))	('drug sensitivity', 'Phenotype', 'HP:0020174', (124, 140))	('proliferation', 'CPA', (40, 53))
63095	31137841	The authors proposed that high ALDH1 alone may be insufficient to drive the ovarian CSC phenotype, but that ALDH1 and CD44 co-expression may trigger chemoresistance and poor clinical outcome.	('chemoresistance', 'CPA', (149, 164))	('ALDH', 'molecular_function', 'GO:0004030', ('31', '35'))	('CD44', 'Gene', '960', (118, 122))	('ovarian CSC', 'Disease', (76, 87))	('ALDH1', 'Gene', (31, 36))	('CD44', 'Gene', (118, 122))	('ovarian CSC', 'Disease', 'MESH:D010051', (76, 87))	('ALDH1', 'Gene', (108, 113))	('co-expression', 'Var', (123, 136))	('ALDH1', 'Gene', '216', (31, 36))	('ALDH1', 'Gene', '216', (108, 113))	('ALDH', 'molecular_function', 'GO:0004030', ('108', '112'))	('trigger', 'Reg', (141, 148))	('insufficient', 'Disease', 'MESH:D000309', (50, 62))	('insufficient', 'Disease', (50, 62))
63097	31137841	For example, miR-199a decreased CD44 expression, resulting in reduced tumorigenicity and increased chemotherapeutic sensitivity.	('chemotherapeutic sensitivity', 'CPA', (99, 127))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD44', 'Gene', (32, 36))	('tumor', 'Disease', (70, 75))	('miR-199a', 'Var', (13, 21))	('expression', 'MPA', (37, 47))	('increased', 'PosReg', (89, 98))	('CD44', 'Gene', '960', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('reduced', 'NegReg', (62, 69))	('decreased', 'NegReg', (22, 31))
63098	31137841	In this study, other stemness factors, such as NANOG, OCT4 and CD133, were also reduced by miR-199a overexpression.	('CD133', 'CPA', (63, 68))	('miR-199a', 'Var', (91, 99))	('NANOG', 'Gene', (47, 52))	('reduced', 'NegReg', (80, 87))	('stemness factors', 'CPA', (21, 37))	('OCT4', 'Gene', '5460', (54, 58))	('OCT4', 'Gene', (54, 58))	('overexpression', 'PosReg', (100, 114))	('NANOG', 'Gene', '79923', (47, 52))
63099	31137841	Targeting of CD133+ cells with an anti-CD133 antibody-toxin conjugate was shown to inhibit the progression of ovarian cancer.	('progression', 'CPA', (95, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('ovarian cancer', 'Disease', (110, 124))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('anti-CD133', 'Var', (34, 44))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('inhibit', 'NegReg', (83, 90))	('anti-CD133', 'Gene', (34, 44))
63100	31137841	ALDH1 overexpression in ovarian CSCs increased taxane and platinum resistance, and conversely, ALDH1 knockdown overcomes the resistance, enhancing growth inhibition in the presence of chemotherapeutic agents.	('enhancing', 'PosReg', (137, 146))	('ALDH1', 'Gene', '216', (0, 5))	('taxane', 'MPA', (47, 53))	('ALDH', 'molecular_function', 'GO:0004030', ('95', '99'))	('ovarian CSC', 'Disease', 'MESH:D010051', (24, 35))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('growth inhibition', 'CPA', (147, 164))	('increased', 'PosReg', (37, 46))	('overexpression', 'PosReg', (6, 20))	('ALDH1', 'Gene', (0, 5))	('ALDH1', 'Gene', (95, 100))	('taxane', 'Chemical', 'MESH:C080625', (47, 53))	('ALDH1', 'Gene', '216', (95, 100))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))	('ovarian CSC', 'Disease', (24, 35))	('knockdown', 'Var', (101, 110))
63113	31137841	reported that motesanib decreased the expression of survival-related genes in the PI3K/AKT pathway, and combination treatment with motesanib synergistically enhanced the anticancer effect of cisplatin.	('decreased', 'NegReg', (24, 33))	('AKT', 'Gene', (87, 90))	('expression', 'MPA', (38, 48))	('enhanced', 'PosReg', (157, 165))	('motesanib', 'Chemical', 'MESH:C000625785', (131, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('AKT', 'Gene', '207', (87, 90))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('survival-related genes', 'Gene', (52, 74))	('combination', 'Interaction', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('motesanib', 'Chemical', 'MESH:C000625785', (14, 23))	('motesanib', 'Var', (131, 140))
63115	31137841	Among bladder cancer patients, 20 single nucleotide polymorphisms in 40 genes in the Wnt/beta-catenin pathway were associated with an increased risk of cancer.	('cancer', 'Disease', (14, 20))	('single nucleotide polymorphisms', 'Var', (34, 65))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (6, 20))	('patients', 'Species', '9606', (21, 29))	('Wnt/beta-catenin pathway', 'Pathway', (85, 109))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder cancer', 'Disease', 'MESH:D001749', (6, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('associated with', 'Reg', (115, 130))	('bladder cancer', 'Disease', (6, 20))
63125	31137841	CD133 has also been investigated as a CSC marker in HNSCC; consistent with this, CD133+ cells showed reduced sensitivity to paclitaxel.	('sensitivity to paclitaxel', 'MPA', (109, 134))	('CD133+', 'Var', (81, 87))	('reduced', 'NegReg', (101, 108))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))
63133	31137841	Examination of specimens from patients with oral lichen planus showed that high BMI1 levels were associated with a higher risk of progressing to oral squamous cell carcinoma.	('BMI1', 'Gene', (80, 84))	('high', 'Var', (75, 79))	('BMI1', 'Gene', '648', (80, 84))	('patients', 'Species', '9606', (30, 38))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (145, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('levels', 'MPA', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('oral squamous cell carcinoma', 'Disease', (145, 173))
63134	31137841	In another study, the expression of BMI1 or ALDH1 was associated with the transformation from oral erythroplakia to cancer.	('BMI1', 'Gene', (36, 40))	('ALDH', 'molecular_function', 'GO:0004030', ('44', '48'))	('expression', 'Var', (22, 32))	('oral erythroplakia', 'Phenotype', 'HP:0030934', (94, 112))	('oral erythroplakia to cancer', 'Disease', (94, 122))	('ALDH1', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BMI1', 'Gene', '648', (36, 40))	('ALDH1', 'Gene', '216', (44, 49))	('associated with', 'Reg', (54, 69))	('oral erythroplakia to cancer', 'Disease', 'MESH:D009062', (94, 122))
63135	31137841	Indeed, in several studies, BMI1 expression was associated with a lack of response to chemoradiotherapy.	('associated', 'Reg', (48, 58))	('BMI1', 'Gene', '648', (28, 32))	('BMI1', 'Gene', (28, 32))	('expression', 'Var', (33, 43))
63145	31137841	In addition, YAP1 signaling is activated by long noncoding RNAs in liver cancer, leading to the induction of self-renewal by CSCs.	('liver cancer', 'Disease', (67, 79))	('self-renewal', 'CPA', (109, 121))	('long noncoding RNAs', 'Var', (44, 63))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('YAP1', 'Gene', '10413', (13, 17))	('liver cancer', 'Phenotype', 'HP:0002896', (67, 79))	('liver cancer', 'Disease', 'MESH:D006528', (67, 79))	('YAP1', 'Gene', (13, 17))
63160	31137841	In this study, high YAP1 expression was associated with increased levels of mesenchymal markers, and YAP1 induced CSC properties, such as sphere-forming and self-renewal abilities, invasiveness and drug resistance via induction of SOX2.	('drug resistance', 'Phenotype', 'HP:0020174', (198, 213))	('induced', 'PosReg', (106, 113))	('drug resistance', 'biological_process', 'GO:0009315', ('198', '213'))	('invasiveness', 'Disease', (181, 193))	('drug resistance', 'biological_process', 'GO:0042493', ('198', '213'))	('high', 'Var', (15, 19))	('CSC properties', 'CPA', (114, 128))	('expression', 'MPA', (25, 35))	('SOX2', 'Gene', '6657', (231, 235))	('YAP1', 'Gene', '10413', (101, 105))	('SOX2', 'Gene', (231, 235))	('levels of mesenchymal markers', 'MPA', (66, 95))	('drug resistance', 'CPA', (198, 213))	('sphere-forming', 'CPA', (138, 152))	('invasiveness', 'Disease', 'MESH:D009362', (181, 193))	('YAP1', 'Gene', '10413', (20, 24))	('YAP1', 'Gene', (101, 105))	('YAP1', 'Gene', (20, 24))	('increased', 'PosReg', (56, 65))
63167	31137841	Using patient-derived xenograft mice models in which the heterogeneity of the primary human tumor was preserved, we found that simultaneous blockade of YAP1 and STAT3 by verteporfin suppressed CSC activity and tumor growth when combined with chemotherapy.	('verteporfin', 'Chemical', 'MESH:D000077362', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CSC activity', 'MPA', (193, 205))	('suppressed', 'NegReg', (182, 192))	('blockade', 'Var', (140, 148))	('tumor', 'Disease', (210, 215))	('patient', 'Species', '9606', (6, 13))	('human', 'Species', '9606', (86, 91))	('YAP1', 'Gene', (152, 156))	('YAP1', 'Gene', '10413', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
63173	30955235	MicroRNA-331-3p inhibits epithelial-mesenchymal transition by targeting ErbB2 and VAV2 through the Rac1/PAK1/beta-catenin axis in non-small-cell lung cancer MicroRNAs have been reported to play critical roles in the regulation of non-small-cell cancer (NSCLC) development, but the role of microRNA (miR)-331-3p in NSCLC is still unclear.	('microRNA (miR)-331', 'Gene', (289, 307))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('Rac1', 'Gene', '5879', (99, 103))	('PAK1', 'Gene', (104, 108))	('MicroRNA-331-3p', 'Var', (0, 15))	('NSCLC', 'Disease', (253, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('inhibits', 'NegReg', (16, 24))	('ErbB2', 'Gene', '2064', (72, 77))	('microRNA (miR)-331', 'Gene', '442903', (289, 307))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (253, 258))	('epithelial-mesenchymal transition', 'CPA', (25, 58))	('beta-catenin', 'Gene', (109, 121))	('VAV2', 'Gene', (82, 86))	('cancer', 'Disease', (150, 156))	('PAK1', 'Gene', '5058', (104, 108))	('NSCLC', 'Disease', 'MESH:D002289', (314, 319))	('3p', 'Chemical', '-', (308, 310))	('beta-catenin', 'Gene', '1499', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('3p', 'Chemical', '-', (13, 15))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('25', '58'))	('cancer', 'Disease', (245, 251))	('NSCLC', 'Disease', (314, 319))	('Rac1', 'Gene', (99, 103))	('ErbB2', 'Gene', (72, 77))	('lung cancer', 'Disease', (145, 156))	('small-cell cancer', 'Phenotype', 'HP:0030357', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('VAV2', 'Gene', '7410', (82, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (314, 319))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('non-small-cell cancer', 'Phenotype', 'HP:0030358', (230, 251))	('NSCLC', 'Disease', 'MESH:D002289', (253, 258))
63177	30955235	The downstream pathway regulated by miR-331-3p was identified by immunofluorescence, immunoprecipitation, and Rac1 activity examination.	('Rac1', 'Gene', '5879', (110, 114))	('miR-331-3p', 'Var', (36, 46))	('3p', 'Chemical', '-', (44, 46))	('Rac1', 'Gene', (110, 114))
63178	30955235	Our results showed that miR-331-3p was significantly downregulated in NSCLC tumor tissues and was correlated with clinicopathological characteristics, and miR-331-3p could be an independent prognostic marker for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('miR-331-3p', 'Gene', (24, 34))	('patients', 'Species', '9606', (218, 226))	('NSCLC tumor', 'Disease', (70, 81))	('NSCLC', 'Disease', (70, 75))	('NSCLC tumor', 'Disease', 'MESH:D009369', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('miR-331-3p', 'Var', (155, 165))	('3p', 'Chemical', '-', (163, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('3p', 'Chemical', '-', (32, 34))	('NSCLC', 'Disease', (212, 217))	('downregulated', 'NegReg', (53, 66))
63179	30955235	Furthermore, miR-331-3p significantly suppressed EMT, migration and metastasis of NSCLC cells in vitro and in vivo.	('metastasis of', 'CPA', (68, 81))	('3p', 'Chemical', '-', (21, 23))	('EMT', 'CPA', (49, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('miR-331-3p', 'Var', (13, 23))	('suppressed', 'NegReg', (38, 48))	('EMT', 'biological_process', 'GO:0001837', ('49', '52'))	('migration', 'CPA', (54, 63))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
63180	30955235	Both ErbB2 and VAV2 were direct functional targets of miR-331-3p.	('3p', 'Chemical', '-', (62, 64))	('VAV2', 'Gene', (15, 19))	('ErbB2', 'Gene', '2064', (5, 10))	('VAV2', 'Gene', '7410', (15, 19))	('ErbB2', 'Gene', (5, 10))	('miR-331-3p', 'Var', (54, 64))
63181	30955235	The activities of Rac1, PAK1, and beta-catenin were regulated by miR-331-3p through ErbB2 and VAV2 targeting.	('activities', 'MPA', (4, 14))	('ErbB2', 'Gene', '2064', (84, 89))	('VAV2', 'Gene', (94, 98))	('beta-catenin', 'Gene', '1499', (34, 46))	('PAK1', 'Gene', '5058', (24, 28))	('3p', 'Chemical', '-', (73, 75))	('VAV2', 'Gene', '7410', (94, 98))	('regulated', 'Reg', (52, 61))	('miR-331-3p', 'Var', (65, 75))	('PAK1', 'Gene', (24, 28))	('Rac1', 'Gene', (18, 22))	('Rac1', 'Gene', '5879', (18, 22))	('ErbB2', 'Gene', (84, 89))	('beta-catenin', 'Gene', (34, 46))
63182	30955235	These results indicated that miR-331-3p suppresses EMT, migratory capacity, and metastatic ability by targeting ErbB2 and VAV2 through the Rac1/PAK1/beta-catenin axis in NSCLC.	('Rac1', 'Gene', '5879', (139, 143))	('EMT', 'biological_process', 'GO:0001837', ('51', '54'))	('ErbB2', 'Gene', '2064', (112, 117))	('PAK1', 'Gene', (144, 148))	('VAV2', 'Gene', (122, 126))	('3p', 'Chemical', '-', (37, 39))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('miR-331-3p', 'Var', (29, 39))	('Rac1', 'Gene', (139, 143))	('ErbB2', 'Gene', (112, 117))	('EMT', 'CPA', (51, 54))	('beta-catenin', 'Gene', (149, 161))	('suppresses', 'NegReg', (40, 50))	('PAK1', 'Gene', '5058', (144, 148))	('NSCLC', 'Disease', (170, 175))	('beta-catenin', 'Gene', '1499', (149, 161))	('VAV2', 'Gene', '7410', (122, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('targeting', 'Reg', (102, 111))	('migratory capacity', 'CPA', (56, 74))	('metastatic ability', 'CPA', (80, 98))
63186	30955235	MicroRNA-331-3p is a miRNA that was reported to be abnormally expressed in several cancer types.	('3p', 'Chemical', '-', (13, 15))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MicroRNA-331-3p', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
63189	30955235	Herein, we found that the expression level of miR-331-3p was significantly lower in NSCLC tumor tissues than in adjacent normal tissues and negatively correlated with advanced stage and lymph node metastasis of NSCLC.	('lower', 'NegReg', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('lymph node metastasis', 'CPA', (186, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('expression level', 'MPA', (26, 42))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('NSCLC', 'Disease', (84, 89))	('NSCLC tumor', 'Disease', 'MESH:D009369', (84, 95))	('NSCLC', 'Disease', (211, 216))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('3p', 'Chemical', '-', (54, 56))	('miR-331-3p', 'Var', (46, 56))	('negatively', 'NegReg', (140, 150))	('NSCLC tumor', 'Disease', (84, 95))	('correlated', 'Reg', (151, 161))
63190	30955235	Overexpression of miR-331-3p repressed the epithelial-mesenchymal transition (EMT) phenotype, migratory capacity, and metastatic ability of NSCLC cells in vitro and vivo.	('migratory capacity', 'CPA', (94, 112))	('metastatic ability', 'CPA', (118, 136))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('repressed', 'PosReg', (29, 38))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('43', '76'))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('miR-331-3p', 'Var', (18, 28))	('3p', 'Chemical', '-', (26, 28))	('NSCLC', 'Disease', (140, 145))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
63191	30955235	Moreover, ErbB2 and VAV2 were identified as the target mRNAs of miR-331-3p, and the ErbB2/VAV2 complex and downstream Rac1/PAK1/beta-catenin activity were shown to be downregulated by miR-331-3p.	('3p', 'Chemical', '-', (192, 194))	('beta-catenin', 'Gene', (128, 140))	('PAK1', 'Gene', '5058', (123, 127))	('3p', 'Chemical', '-', (72, 74))	('beta-catenin', 'Gene', '1499', (128, 140))	('VAV2', 'Gene', (20, 24))	('downregulated', 'NegReg', (167, 180))	('Rac1', 'Gene', (118, 122))	('miR-331-3p', 'Var', (64, 74))	('ErbB2', 'Gene', (10, 15))	('VAV2', 'Gene', '7410', (20, 24))	('VAV2', 'Gene', (90, 94))	('ErbB2', 'Gene', '2064', (84, 89))	('Rac1', 'Gene', '5879', (118, 122))	('PAK1', 'Gene', (123, 127))	('miR-331-3p', 'Var', (184, 194))	('VAV2', 'Gene', '7410', (90, 94))	('ErbB2', 'Gene', (84, 89))	('ErbB2', 'Gene', '2064', (10, 15))
63192	30955235	Our findings confirmed the tumor suppressor activity of miR-331-3p in NSCLC and showed that VAV2 is a novel target of miR-331-3p.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('NSCLC', 'Disease', (70, 75))	('3p', 'Chemical', '-', (126, 128))	('VAV2', 'Gene', (92, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('miR-331-3p', 'Var', (56, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('miR-331-3p', 'Var', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('VAV2', 'Gene', '7410', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('3p', 'Chemical', '-', (64, 66))
63205	30955235	Spearman's rank correlation was used to determine the association between miR-331-3p and ErbB2/VAV2.	('miR-331-3p', 'Var', (74, 84))	('VAV2', 'Gene', '7410', (95, 99))	('ErbB2', 'Gene', (89, 94))	('VAV2', 'Gene', (95, 99))	('ErbB2', 'Gene', '2064', (89, 94))	('3p', 'Chemical', '-', (82, 84))	('association', 'Interaction', (54, 65))
63208	30955235	Our results showed that the expression level of miR-331-3p was significantly lower in NSCLC tumor tissues than in adjacent normal tissues.	('lower', 'NegReg', (77, 82))	('NSCLC tumor', 'Disease', 'MESH:D009369', (86, 97))	('3p', 'Chemical', '-', (56, 58))	('NSCLC tumor', 'Disease', (86, 97))	('miR-331-3p', 'Var', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('expression level', 'MPA', (28, 44))
63212	30955235	The expression of miR-331-3p in NSCLC tumor tissues was significantly inversely correlated with lymphatic metastasis and clinical TNM stage (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('TNM', 'Gene', '10178', (130, 133))	('correlated', 'Reg', (80, 90))	('lymphatic metastasis', 'CPA', (96, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('NSCLC tumor', 'Disease', (32, 43))	('NSCLC tumor', 'Disease', 'MESH:D009369', (32, 43))	('expression', 'MPA', (4, 14))	('TNM', 'Gene', (130, 133))	('miR-331-3p', 'Var', (18, 28))	('inversely', 'NegReg', (70, 79))	('3p', 'Chemical', '-', (26, 28))
63213	30955235	Patients who had a lower miR-331-3p expression in tumor tissues had a higher probability of lymphatic metastasis and a more advanced TNM classification.	('TNM', 'Gene', (133, 136))	('miR-331-3p', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('3p', 'Chemical', '-', (33, 35))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('lower', 'NegReg', (19, 24))	('lymphatic metastasis', 'CPA', (92, 112))	('tumor', 'Disease', (50, 55))	('TNM', 'Gene', '10178', (133, 136))
63216	30955235	Our results showed that NSCLC patients with lower miR-331-3p expression in NSCLC tissues had much shorter OS and DFS compared with those of NSCLC patients with higher miR-331-3p expression (Figure 1E,F).	('NSCLC', 'Disease', (24, 29))	('lower', 'NegReg', (44, 49))	('DFS', 'MPA', (113, 116))	('3p', 'Chemical', '-', (175, 177))	('3p', 'Chemical', '-', (58, 60))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('miR-331-3p expression', 'Var', (50, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('patients', 'Species', '9606', (30, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('patients', 'Species', '9606', (146, 154))	('shorter', 'NegReg', (98, 105))	('NSCLC', 'Disease', (140, 145))
63217	30955235	Furthermore, the Cox proportional hazards regression model was used to determine whether miR-331-3p could be an independent prognostic marker for NSCLC patients.	('miR-331-3p', 'Var', (89, 99))	('NSCLC', 'Disease', (146, 151))	('3p', 'Chemical', '-', (97, 99))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('patients', 'Species', '9606', (152, 160))
63219	30955235	Taken together, our results showed that miR-331-3p was remarkably downregulated in NSCLC tumor tissues and had an inverse correlation with lymphatic metastasis and clinical TNM stage.	('NSCLC tumor', 'Disease', 'MESH:D009369', (83, 94))	('3p', 'Chemical', '-', (48, 50))	('NSCLC tumor', 'Disease', (83, 94))	('lymphatic metastasis', 'CPA', (139, 159))	('downregulated', 'NegReg', (66, 79))	('TNM', 'Gene', '10178', (173, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('inverse', 'NegReg', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TNM', 'Gene', (173, 176))	('miR-331-3p', 'Var', (40, 50))
63220	30955235	MicroRNA-331-3p expression was correlated with OS and DFS of NSCLC patients and could act as an independent prognostic marker for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('3p', 'Chemical', '-', (13, 15))	('DFS', 'Disease', (54, 57))	('MicroRNA-331-3p expression', 'Var', (0, 26))	('patients', 'Species', '9606', (67, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('patients', 'Species', '9606', (136, 144))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', (130, 135))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('correlated', 'Reg', (31, 41))
63221	30955235	The clinicopathological statistics showed a remarkable relationship between miR-331-3p expression and metastasis.	('3p', 'Chemical', '-', (84, 86))	('miR-331-3p expression', 'Var', (76, 97))	('metastasis', 'CPA', (102, 112))	('relationship', 'Reg', (55, 67))
63223	30955235	First, we examined miR-331-3p expression in NSCLC cell lines (PC9, A549, H1299, CALU-1, H520, H1703, H1437, and H460) and a normal bronchus epithelial cell line (Beas-2b).	('H460', 'CellLine', 'CVCL:0459', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('miR-331-3p', 'Var', (19, 29))	('H1299', 'CellLine', 'CVCL:0060', (73, 78))	('3p', 'Chemical', '-', (27, 29))	('H1437', 'CellLine', 'CVCL:1472', (101, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('PC9', 'CellLine', 'CVCL:B260', (62, 65))	('H1703', 'CellLine', 'CVCL:1490', (94, 99))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('NSCLC', 'Disease', (44, 49))	('Beas-2', 'CellLine', 'CVCL:0168', (162, 168))
63224	30955235	Our results showed that NSCLC cells had significantly lower expression of miR-331-3p compared with normal bronchus cells.	('NSCLC', 'Disease', (24, 29))	('expression', 'MPA', (60, 70))	('miR-331-3p', 'Var', (74, 84))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('3p', 'Chemical', '-', (82, 84))	('lower', 'NegReg', (54, 59))
63225	30955235	Among them, A549 (with the lowest miR-331-3p expression) and H1299 (with the highest miR-331-3p expression) were selected for further assays (Figure 2A).	('miR-331-3p', 'Var', (34, 44))	('3p', 'Chemical', '-', (42, 44))	('lowest', 'NegReg', (27, 33))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('H1299', 'CellLine', 'CVCL:0060', (61, 66))	('3p', 'Chemical', '-', (93, 95))
63226	30955235	These 2 cell lines were infected with lentivirus to either cause overexpression or knockdown of miR-331-3p expression.	('miR-331-3p', 'Gene', (96, 106))	('knockdown', 'Var', (83, 92))	('3p', 'Chemical', '-', (104, 106))	('overexpression', 'PosReg', (65, 79))
63229	30955235	Our results showed that A549 cells with elevated expression levels of miR-331-3p had fewer migratory (invasive) cells in the Transwell assay (migration: WT, 61.82 +- 9.67; negative control [NC], 71.23 +- 14.26; miR-331-3p, 16.44 +- 2.71; P < .01; invasion: WT, 89.45 +- 35.85; NC, 107.38 +- 41.72; miR-331-3p, 32.64 +- 9.89; P < .001) (Figure 2D) and a significantly slower rate of closure in the wound healing assay compared with those of WT and NC cells (24 hours: WT, 37.43 +- 7.30; NC, 42.25 +- 7.69; miR-331-3p, 16.23 +- 8.91; 48 hours: WT, 58.36 +- 25.96; NC, 57.25 +- 13.37; miR-331-3p, 28.38 +- 14.80; P < .05) (Figure 2E).	('closure in the wound healing assay', 'CPA', (382, 416))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('3p', 'Chemical', '-', (219, 221))	('wound healing', 'biological_process', 'GO:0042060', ('397', '410'))	('slower', 'NegReg', (367, 373))	('miR-331-3p', 'Var', (70, 80))	('3p', 'Chemical', '-', (306, 308))	('3p', 'Chemical', '-', (513, 515))	('fewer', 'NegReg', (85, 90))	('3p', 'Chemical', '-', (590, 592))	('3p', 'Chemical', '-', (78, 80))
63231	30955235	Anti-miR-331-3p-transfected H1299 cells showed more migratory (invasive) cells in the Transwell assay (migration: WT, 88.43 +- 13.95; NC, 57.88 +- 10.86; anti-miR-331-3p, 210.08 +- 39.29; P < 0.001; invasion: WT, 79.5 +- 11.09; NC, 77.43 +- 18.02; anti-miR-331-3p, 275.77 +- 35.73; P < 0.01) (Figure 2F) and a faster rate of closure in the wound healing assay compared with those of the NC group (24 hours: WT, 29.10 +- 6.67; NC, 39.57 +- 9.42; anti-miR-331-3p, 60.02 +- 10.75; 48 hours: WT, 54.35 +- 10.32; NC, 62.16 +- 7.20; anti-miR-331-3p, 91.08 +- 11.23; P < 0.001) (Figure 2G).	('3p', 'Chemical', '-', (13, 15))	('more', 'PosReg', (47, 51))	('Anti-miR-331-3p-transfected', 'Var', (0, 27))	('3p', 'Chemical', '-', (261, 263))	('3p', 'Chemical', '-', (540, 542))	('faster', 'PosReg', (310, 316))	('closure in the wound healing assay', 'CPA', (325, 359))	('3p', 'Chemical', '-', (458, 460))	('H1299', 'CellLine', 'CVCL:0060', (28, 33))	('3p', 'Chemical', '-', (167, 169))	('migratory', 'CPA', (52, 61))	('wound healing', 'biological_process', 'GO:0042060', ('340', '353'))
63233	30955235	Interestingly, miR-331-3p upregulated A549, showing observably enhanced expression of the epithelial marker E-cadherin and remarkably reduced expression of the mesenchymal markers N-cadherin and vimentin.	('vimentin', 'Gene', (195, 203))	('mesenchymal', 'CPA', (160, 171))	('miR-331-3p', 'Var', (15, 25))	('vimentin', 'cellular_component', 'GO:0045098', ('195', '203'))	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('enhanced', 'PosReg', (63, 71))	('expression', 'MPA', (72, 82))	('reduced', 'NegReg', (134, 141))	('3p', 'Chemical', '-', (23, 25))	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('upregulated', 'PosReg', (26, 37))	('vimentin', 'cellular_component', 'GO:0045099', ('195', '203'))	('expression', 'MPA', (142, 152))	('A549', 'Gene', (38, 42))	('N-cadherin', 'Gene', (180, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('N-cadherin', 'Gene', '1000', (180, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('vimentin', 'Gene', '7431', (195, 203))
63235	30955235	Together, these results indicated that miR-331-3p acts as an EMT suppressor and impairs the migratory and metastatic capacity of tumor cells in NSCLC.	('NSCLC', 'Disease', (144, 149))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('miR-331-3p', 'Var', (39, 49))	('tumor', 'Disease', (129, 134))	('3p', 'Chemical', '-', (47, 49))	('impairs', 'NegReg', (80, 87))
63236	30955235	After identifying the inhibitory effect of miR-331-3p on NSCLC cell migration and invasion in vitro, we examined whether miR-331-3p had an impact on NSCLC metastasis in vivo.	('impact', 'Reg', (139, 145))	('3p', 'Chemical', '-', (51, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Disease', (149, 154))	('invasion', 'CPA', (82, 90))	('miR-331-3p', 'Var', (121, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('3p', 'Chemical', '-', (129, 131))	('cell migration', 'biological_process', 'GO:0016477', ('63', '77'))	('NSCLC', 'Disease', (57, 62))	('NSCLC metastasis', 'Disease', (149, 165))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (149, 165))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
63239	30955235	Our results showed that miR-331-3p-overexpressing A549-injected mice had weaker luminescence intensity compared with those injected with NC cells (0.023 +- 0.004 vs 0.053 +- 0.006; P < 0.05) (Figures 3D,E, and S2).	('miR-331-3p-overexpressing', 'Var', (24, 49))	('A549-injected', 'Var', (50, 63))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('3p', 'Chemical', '-', (32, 34))	('luminescence intensity', 'MPA', (80, 102))	('weaker', 'NegReg', (73, 79))	('mice', 'Species', '10090', (64, 68))
63242	30955235	The immunohistochemistry results showed that the metastatic nodes from the miR-331-3p group had noticeably lower expression of ErbB2 and VAV2 compared with those of the NC (Figure 3A).	('expression', 'MPA', (113, 123))	('ErbB2', 'Gene', '2064', (127, 132))	('3p', 'Chemical', '-', (83, 85))	('lower', 'NegReg', (107, 112))	('VAV2', 'Gene', (137, 141))	('ErbB2', 'Gene', (127, 132))	('VAV2', 'Gene', '7410', (137, 141))	('miR-331-3p', 'Var', (75, 85))
63243	30955235	To gain further insight into the molecular mechanisms by which miR-331-3p regulates NSCLC cell migration, we used 4 miRNA target databases (miRDB,18 miRWalk,19 TargetScan,20 and miRTarBase21) to predict the putative targets of miR-331-3p.	('cell migration', 'biological_process', 'GO:0016477', ('90', '104'))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('regulates', 'Reg', (74, 83))	('miR-331-3p', 'Var', (63, 73))	('NSCLC', 'Disease', (84, 89))	('3p', 'Chemical', '-', (71, 73))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('3p', 'Chemical', '-', (235, 237))
63247	30955235	To validate these two targets, we established WT luciferase reporter constructs that included the 3'-UTR of the ErbB2 and VAV2 genes and mutant type (Mut) reporter constructs, which contained mutant binding sequences of miR-331-3p (Figure 4B).	('ErbB2', 'Gene', (112, 117))	('VAV2', 'Gene', '7410', (122, 126))	('mutant', 'Var', (192, 198))	('ErbB2', 'Gene', '2064', (112, 117))	('3p', 'Chemical', '-', (228, 230))	('VAV2', 'Gene', (122, 126))	('binding', 'molecular_function', 'GO:0005488', ('199', '206'))
63249	30955235	Compared with the miR-NC transfected cells, 293T cells transfected with miR-331-3p showed significantly decreased luciferase activity compared with the WT constructs.	('luciferase activity', 'molecular_function', 'GO:0047077', ('114', '133'))	('3p', 'Chemical', '-', (80, 82))	('activity', 'MPA', (125, 133))	('decreased', 'NegReg', (104, 113))	('miR-331-3p', 'Var', (72, 82))	('luciferase activity', 'molecular_function', 'GO:0045289', ('114', '133'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('114', '133'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('114', '133'))	('293T', 'CellLine', 'CVCL:0063', (44, 48))	('luciferase activity', 'molecular_function', 'GO:0050397', ('114', '133'))	('luciferase', 'Enzyme', (114, 124))
63252	30955235	Furthermore, western blot analysis was carried out, and the results showed that both ErbB2 and VAV2 were dramatically suppressed in the miR-331-3p-overexpressing A549 cells compared with those of the WT or NC cell lines.	('miR-331-3p-overexpressing', 'Var', (136, 161))	('ErbB2', 'Gene', (85, 90))	('A549', 'CellLine', 'CVCL:0023', (162, 166))	('VAV2', 'Gene', (95, 99))	('ErbB2', 'Gene', '2064', (85, 90))	('VAV2', 'Gene', '7410', (95, 99))	('3p', 'Chemical', '-', (144, 146))	('suppressed', 'NegReg', (118, 128))
63253	30955235	Otherwise, miR-331-3p-knockdown H1299 cells showed enhancement of ErbB2 and VAV2 compared with those of untreated cells or the blank virus group (Figure 4D).	('enhancement', 'PosReg', (51, 62))	('VAV2', 'Gene', (76, 80))	('ErbB2', 'Gene', (66, 71))	('VAV2', 'Gene', '7410', (76, 80))	('H1299', 'CellLine', 'CVCL:0060', (32, 37))	('3p', 'Chemical', '-', (19, 21))	('miR-331-3p-knockdown', 'Var', (11, 31))	('ErbB2', 'Gene', '2064', (66, 71))
63254	30955235	Interestingly, although western blot analysis showed a regulatory relationship between ErbB2/VAV2 and miR-331-3p, qRT-PCR did not detect observable ErbB2/VAV2 mRNA changes at the transcriptional level after miR-331-3p-related treatment in either A549 or H1299 cells (Figure 4E).	('ErbB2', 'Gene', '2064', (87, 92))	('VAV2', 'Gene', '7410', (154, 158))	('VAV2', 'Gene', (93, 97))	('VAV2', 'Gene', '7410', (93, 97))	('3p', 'Chemical', '-', (110, 112))	('ErbB2', 'Gene', (148, 153))	('ErbB2', 'Gene', (87, 92))	('ErbB2', 'Gene', '2064', (148, 153))	('VAV2', 'Gene', (154, 158))	('3p', 'Chemical', '-', (215, 217))	('A549', 'CellLine', 'CVCL:0023', (246, 250))	('H1299', 'CellLine', 'CVCL:0060', (254, 259))	('miR-331-3p-related', 'Var', (207, 225))
63255	30955235	These results suggest that miR-331-3p silences ErbB2 and VAV2 expression by inhibiting the translation of their mRNAs.	('ErbB2', 'Gene', (47, 52))	('miR-331-3p', 'Var', (27, 37))	('3p', 'Chemical', '-', (35, 37))	('silences', 'NegReg', (38, 46))	('translation', 'MPA', (91, 102))	('expression', 'MPA', (62, 72))	('translation', 'biological_process', 'GO:0006412', ('91', '102'))	('VAV2', 'Gene', (57, 61))	('inhibiting', 'NegReg', (76, 86))	('ErbB2', 'Gene', '2064', (47, 52))	('VAV2', 'Gene', '7410', (57, 61))	('mRNAs', 'MPA', (112, 117))
63258	30955235	Taken together, our data indicated that both ErbB2 and VAV2 were direct targets of miR-331-3p.	('VAV2', 'Gene', (55, 59))	('VAV2', 'Gene', '7410', (55, 59))	('ErbB2', 'Gene', (45, 50))	('3p', 'Chemical', '-', (91, 93))	('miR-331-3p', 'Var', (83, 93))	('ErbB2', 'Gene', '2064', (45, 50))
63260	30955235	ErbB2 and VAV2 mimic/shRNA plasmids were constructed and cotransfected into A549/H1299 cells with miR-331-3p/anti-miR-331-3p (Figures 5A and S3a).	('miR-331-3p/anti-miR-331-3p', 'Var', (98, 124))	('ErbB2', 'Gene', (0, 5))	('VAV2', 'Gene', '7410', (10, 14))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('ErbB2', 'Gene', '2064', (0, 5))	('H1299', 'CellLine', 'CVCL:0060', (81, 86))	('VAV2', 'Gene', (10, 14))	('3p', 'Chemical', '-', (122, 124))	('3p', 'Chemical', '-', (106, 108))
63261	30955235	Our results showed that the restoration of neither ErbB2 nor VAV2 alone could fully recover the inhibitory effect on metastasis of miR-331-3p in A549 cells.	('ErbB2', 'Gene', '2064', (51, 56))	('VAV2', 'Gene', '7410', (61, 65))	('inhibitory effect', 'MPA', (96, 113))	('miR-331-3p', 'Var', (131, 141))	('3p', 'Chemical', '-', (139, 141))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('VAV2', 'Gene', (61, 65))	('ErbB2', 'Gene', (51, 56))	('metastasis', 'CPA', (117, 127))
63262	30955235	Elevation of ErbB2 or VAV2 alone partly attenuated miR-331-3p-mediated inhibition of migration and invasion.	('miR-331-3p-mediated', 'Var', (51, 70))	('3p', 'Chemical', '-', (59, 61))	('ErbB2', 'Gene', (13, 18))	('VAV2', 'Gene', (22, 26))	('inhibition', 'NegReg', (71, 81))	('ErbB2', 'Gene', '2064', (13, 18))	('attenuated', 'NegReg', (40, 50))	('VAV2', 'Gene', '7410', (22, 26))
63266	30955235	After blocking both ErbB2 and VAV2, the migratory capacity of anti-miR-331-3p-transfected H1299 cells was fully suppressed to levels comparable to that of the NC level (Figure S3b-e).	('VAV2', 'Gene', '7410', (30, 34))	('anti-miR-331-3p-transfected', 'Var', (62, 89))	('suppressed', 'NegReg', (112, 122))	('ErbB2', 'Gene', (20, 25))	('H1299', 'CellLine', 'CVCL:0060', (90, 95))	('migratory capacity', 'CPA', (40, 58))	('ErbB2', 'Gene', '2064', (20, 25))	('VAV2', 'Gene', (30, 34))	('3p', 'Chemical', '-', (75, 77))
63267	30955235	Overall, our results indicated that miR-331-3p impaired the migratory ability of NSCLC cells by repressing the expression of ErbB2 and VAV2.	('VAV2', 'Gene', (135, 139))	('ErbB2', 'Gene', '2064', (125, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('impaired', 'NegReg', (47, 55))	('VAV2', 'Gene', '7410', (135, 139))	('NSCLC', 'Disease', (81, 86))	('ErbB2', 'Gene', (125, 130))	('repressing', 'PosReg', (96, 106))	('miR-331-3p', 'Var', (36, 46))	('3p', 'Chemical', '-', (44, 46))
63268	30955235	In previous experiments, we confirmed that miR-331-3p exerted its antimetastatic function by targeting ErbB2 and VAV2.	('antimetastatic function', 'CPA', (66, 89))	('3p', 'Chemical', '-', (51, 53))	('VAV2', 'Gene', (113, 117))	('ErbB2', 'Gene', (103, 108))	('VAV2', 'Gene', '7410', (113, 117))	('miR-331-3p', 'Var', (43, 53))	('targeting', 'Reg', (93, 102))	('ErbB2', 'Gene', '2064', (103, 108))
63270	30955235	VAV2 is also known as a direct activator of Rac1,24, 25 and has been proved to form a complex with ErbB2.26, 27 Taken together, we hypothesized that miR-331-3p suppressed the migratory ability of NSCLC by targeting ErbB2 and VAV2 through Rac1 signaling.	('VAV2', 'Gene', '7410', (0, 4))	('Rac1', 'Gene', (238, 242))	('suppressed', 'NegReg', (160, 170))	('Rac1', 'Gene', (44, 48))	('VAV2', 'Gene', (225, 229))	('ErbB2', 'Gene', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('ErbB2', 'Gene', '2064', (215, 220))	('miR-331-3p', 'Var', (149, 159))	('3p', 'Chemical', '-', (157, 159))	('Rac1', 'Gene', '5879', (238, 242))	('NSCLC', 'Disease', (196, 201))	('VAV2', 'Gene', '7410', (225, 229))	('VAV2', 'Gene', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('243', '252'))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('ErbB2', 'Gene', (215, 220))	('Rac1', 'Gene', '5879', (44, 48))	('ErbB2', 'Gene', '2064', (99, 104))
63275	30955235	Furthermore, Rac1 activity was examined to confirm the regulation of Rac1 by miR-331-3p.	('Rac1', 'Gene', (13, 17))	('Rac1', 'Gene', '5879', (13, 17))	('Rac1', 'Gene', '5879', (69, 73))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('Rac1', 'Gene', (69, 73))	('miR-331-3p', 'Var', (77, 87))	('3p', 'Chemical', '-', (85, 87))
63276	30955235	We found that Rac1 activity was significantly repressed in the miR-331-3p-overexpressing A549 cells, and this repression was attenuated by ErbB2/VAV2 mimic transfection.	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('miR-331-3p-overexpressing', 'Var', (63, 88))	('VAV2', 'Gene', (145, 149))	('repressed', 'PosReg', (46, 55))	('ErbB2', 'Gene', '2064', (139, 144))	('Rac1', 'Gene', '5879', (14, 18))	('VAV2', 'Gene', '7410', (145, 149))	('activity', 'MPA', (19, 27))	('Rac1', 'Gene', (14, 18))	('3p', 'Chemical', '-', (71, 73))	('ErbB2', 'Gene', (139, 144))
63278	30955235	Anti-miR-331-3p transfection remarkably promoted Rac1 activation.	('3p', 'Chemical', '-', (13, 15))	('promoted', 'PosReg', (40, 48))	('Rac1', 'Gene', '5879', (49, 53))	('Rac1', 'Gene', (49, 53))	('Anti-miR-331-3p transfection', 'Var', (0, 28))
63279	30955235	This intensification was partly blocked by ErbB2/VAV2 shRNA transfection, and silencing both ErbB2 and VAV2 repressed Rac1 activity to a level lower than that of knockdown of the individual proteins (Figure 6C).	('ErbB2', 'Gene', '2064', (93, 98))	('ErbB2', 'Gene', (43, 48))	('Rac1', 'Gene', (118, 122))	('VAV2', 'Gene', '7410', (49, 53))	('VAV2', 'Gene', '7410', (103, 107))	('VAV2', 'Gene', (103, 107))	('ErbB2', 'Gene', '2064', (43, 48))	('silencing', 'Var', (78, 87))	('ErbB2', 'Gene', (93, 98))	('activity', 'MPA', (123, 131))	('Rac1', 'Gene', '5879', (118, 122))	('VAV2', 'Gene', (49, 53))
63281	30955235	Our data confirmed the inverse correlation of phospho-PAK1 levels and phospho-beta-catenin levels with miR-331-3p in both A549 and H1299 cells, and the regulation of ErbB2 and VAV2 attenuated the effects of miR-331-3p/anti-miR-331-3p.	('VAV2', 'Gene', (176, 180))	('ErbB2', 'Gene', '2064', (166, 171))	('PAK1', 'Gene', '5058', (54, 58))	('PAK1', 'Gene', (54, 58))	('H1299', 'CellLine', 'CVCL:0060', (131, 136))	('miR-331-3p', 'Var', (103, 113))	('regulation', 'biological_process', 'GO:0065007', ('152', '162'))	('VAV2', 'Gene', '7410', (176, 180))	('3p', 'Chemical', '-', (111, 113))	('3p', 'Chemical', '-', (231, 233))	('beta-catenin', 'Gene', (78, 90))	('ErbB2', 'Gene', (166, 171))	('3p', 'Chemical', '-', (215, 217))	('beta-catenin', 'Gene', '1499', (78, 90))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('attenuated', 'NegReg', (181, 191))
63282	30955235	In addition, E-cadherin, N-cadherin, and vimentin were examined as EMT markers, and western blot assays showed that the restoration of ErbB2 and VAV2 blocked the anti-EMT effect of miR-331-3p in NSCLC cells (Figure 6E,F).	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('EMT', 'biological_process', 'GO:0001837', ('167', '170'))	('vimentin', 'Gene', '7431', (41, 49))	('EMT', 'biological_process', 'GO:0001837', ('67', '70'))	('vimentin', 'Gene', (41, 49))	('ErbB2', 'Gene', '2064', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('vimentin', 'cellular_component', 'GO:0045099', ('41', '49'))	('NSCLC', 'Disease', (195, 200))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('VAV2', 'Gene', (145, 149))	('3p', 'Chemical', '-', (189, 191))	('N-cadherin', 'Gene', (25, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('anti-EMT effect', 'CPA', (162, 177))	('N-cadherin', 'Gene', '1000', (25, 35))	('ErbB2', 'Gene', (135, 140))	('restoration', 'Var', (120, 131))	('blocked', 'NegReg', (150, 157))	('VAV2', 'Gene', '7410', (145, 149))	('vimentin', 'cellular_component', 'GO:0045098', ('41', '49'))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))
63283	30955235	Taken together, our results support the hypothesis that miR-331-3p suppresses EMT and metastasis in NSCLC by regulating ErbB2/VAV2 expression through the Rac1/PAK1/beta-catenin signaling pathway (Figure 6G).	('suppresses', 'NegReg', (67, 77))	('Rac1', 'Gene', '5879', (154, 158))	('miR-331-3p', 'Var', (56, 66))	('ErbB2', 'Gene', '2064', (120, 125))	('3p', 'Chemical', '-', (64, 66))	('VAV2', 'Gene', '7410', (126, 130))	('regulating', 'Reg', (109, 119))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('PAK1', 'Gene', (159, 163))	('ErbB2', 'Gene', (120, 125))	('NSCLC', 'Disease', (100, 105))	('Rac1', 'Gene', (154, 158))	('signaling pathway', 'biological_process', 'GO:0007165', ('177', '194'))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('PAK1', 'Gene', '5058', (159, 163))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))	('beta-catenin', 'Gene', (164, 176))	('beta-catenin', 'Gene', '1499', (164, 176))	('expression', 'MPA', (131, 141))	('VAV2', 'Gene', (126, 130))
63285	30955235	Recent studies revealed that miRNAs play vital roles in the tumorigenesis and progression of NSCLC.28 In the present study, we focused on the antimetastatic function of miR-331-3p in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NSCLC', 'Disease', (183, 188))	('antimetastatic function', 'MPA', (142, 165))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('miR-331-3p', 'Var', (169, 179))	('3p', 'Chemical', '-', (177, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('tumor', 'Disease', (60, 65))
63286	30955235	The abnormal expression of miR-331-3p has been found in many types of carcinomas, but the evidence on its biological functions in the tumorigenesis of these cancers is conflicting.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('miR-331-3p', 'Var', (27, 37))	('expression', 'MPA', (13, 23))	('carcinomas', 'Disease', (70, 80))	('carcinomas', 'Disease', 'MESH:D002277', (70, 80))	('3p', 'Chemical', '-', (35, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('found', 'Reg', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
63287	30955235	Our previous study showed that miR-331-3p promotes proliferation and metastasis of hepatocellular carcinoma,15 and other researchers found similar effects of miR-331-3p in pancreatic cancer.14 However, other researchers discovered antitumor functions of miR-331-3p in urothelial cancer,29 gastric cancer,16 and cervical cancer.17 The functions of miR-331-3p in NSCLC were also ambiguous,30, 31 and little was known about the targets and signaling pathways regulated by miR-331-3p in NSCLC.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('gastric cancer', 'Disease', 'MESH:D013274', (289, 303))	('3p', 'Chemical', '-', (477, 479))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('urothelial cancer', 'Disease', (268, 285))	('3p', 'Chemical', '-', (39, 41))	('NSCLC', 'Disease', (483, 488))	('miR-331-3p', 'Var', (469, 479))	('NSCLC', 'Phenotype', 'HP:0030358', (483, 488))	('3p', 'Chemical', '-', (355, 357))	('3p', 'Chemical', '-', (262, 264))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('NSCLC', 'Disease', 'MESH:D002289', (361, 366))	('3p', 'Chemical', '-', (166, 168))	('metastasis of hepatocellular carcinoma,15', 'Disease', 'MESH:D009362', (69, 110))	('pancreatic cancer', 'Disease', (172, 189))	('NSCLC', 'Disease', (361, 366))	('NSCLC', 'Phenotype', 'HP:0030358', (361, 366))	('gastric cancer', 'Disease', (289, 303))	('cervical cancer', 'Disease', (311, 326))	('cervical cancer', 'Disease', 'MESH:D002583', (311, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('signaling', 'biological_process', 'GO:0023052', ('437', '446'))	('tumor', 'Disease', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('NSCLC', 'Disease', 'MESH:D002289', (483, 488))	('urothelial cancer', 'Disease', 'MESH:D014523', (268, 285))
63288	30955235	In the present study, we confirmed the downregulation of miR-331-3p in NSCLC tumor tissues and found that the relative expression level of miR-331-3p in NSCLC tumor tissues had an correlation with metastasis stage, clinical TNM stage, overall survival, and disease-free survival.	('metastasis stage', 'CPA', (197, 213))	('3p', 'Chemical', '-', (147, 149))	('NSCLC tumor', 'Disease', 'MESH:D009369', (153, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('TNM', 'Gene', '10178', (224, 227))	('3p', 'Chemical', '-', (65, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('NSCLC tumor', 'Disease', 'MESH:D009369', (71, 82))	('NSCLC tumor', 'Disease', (153, 164))	('NSCLC tumor', 'Disease', (71, 82))	('disease-free survival', 'CPA', (257, 278))	('overall survival', 'CPA', (235, 251))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('miR-331-3p', 'Var', (139, 149))	('miR-331-3p', 'Gene', (57, 67))	('TNM', 'Gene', (224, 227))	('downregulation', 'NegReg', (39, 53))
63289	30955235	The Cox regression multivariate analysis results showed that the expression of miR-331-3p in tumor tissues could be an independent prognostic marker for NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('miR-331-3p', 'Var', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('3p', 'Chemical', '-', (87, 89))	('tumor', 'Disease', (93, 98))	('NSCLC', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
63290	30955235	Next, we showed that overexpression of miR-331-3p suppressed the migration and invasion of NSCLC cells and that the EMT process was also inhibited by miR-331-3p elevation.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('suppressed', 'NegReg', (50, 60))	('miR-331-3p', 'Var', (150, 160))	('inhibited', 'NegReg', (137, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('EMT', 'biological_process', 'GO:0001837', ('116', '119'))	('EMT process', 'CPA', (116, 127))	('elevation', 'PosReg', (161, 170))	('overexpression', 'PosReg', (21, 35))	('miR-331-3p', 'Var', (39, 49))	('NSCLC', 'Disease', (91, 96))	('3p', 'Chemical', '-', (158, 160))	('3p', 'Chemical', '-', (47, 49))
63291	30955235	In addition, the downregulation of miR-331-3p promoted the EMT-induced migratory and invasive capacity of NSCLC cells.	('promoted', 'PosReg', (46, 54))	('EMT', 'biological_process', 'GO:0001837', ('59', '62'))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('miR-331-3p', 'Var', (35, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('downregulation', 'NegReg', (17, 31))	('3p', 'Chemical', '-', (43, 45))	('NSCLC', 'Disease', (106, 111))
63292	30955235	Although miR-331-3p plays a role as a cancer suppressor gene and could be a potential prognostic marker in NSCLC, its therapeutic application would be limited because of its various functions across multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (208, 214))	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('miR-331-3p', 'Var', (9, 19))	('3p', 'Chemical', '-', (17, 19))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
63293	30955235	Lung-targeted pharmaceutical approaches should be used to enhance the targeting ability of miR-331-3p.	('miR-331-3p', 'Var', (91, 101))	('3p', 'Chemical', '-', (99, 101))	('targeting', 'MPA', (70, 79))
63295	30955235	Our results confirmed the regulation of miR-331-3p on ErbB2 and discovered that VAV2 was a novel direct target of miR-331-3p.	('ErbB2', 'Gene', (54, 59))	('VAV2', 'Gene', (80, 84))	('3p', 'Chemical', '-', (48, 50))	('ErbB2', 'Gene', '2064', (54, 59))	('VAV2', 'Gene', '7410', (80, 84))	('miR-331-3p', 'Var', (114, 124))	('3p', 'Chemical', '-', (122, 124))	('regulation', 'biological_process', 'GO:0065007', ('26', '36'))
63296	30955235	ErbB2 (HER2) was identified as a classical oncogene that promotes tumorigenesis in many malignancies, especially breast cancer, and the involvement of ErbB2 in NSCLC has also been known for many years.32, 33 However, clinical studies targeting ErbB2 mutations have yielded disappointing results.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('ErbB2', 'Gene', '2064', (0, 5))	('NSCLC', 'Disease', (160, 165))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (66, 71))	('malignancies', 'Disease', (88, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ErbB2', 'Gene', '2064', (244, 249))	('HER2', 'Gene', '2064', (7, 11))	('ErbB2', 'Gene', '2064', (151, 156))	('ErbB2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('ErbB2', 'Gene', (244, 249))	('mutations', 'Var', (250, 259))	('ErbB2', 'Gene', (151, 156))	('HER2', 'Gene', (7, 11))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
63299	30955235	Our research first found that both ErbB2 and VAV2 were direct targets of miR-331-3p and that miR-331-3p functions not by degrading target mRNAs but by suppressing the translation of ErbB2/VAV2 mRNAs.	('3p', 'Chemical', '-', (81, 83))	('ErbB2', 'Gene', '2064', (35, 40))	('VAV2', 'Gene', '7410', (45, 49))	('translation', 'biological_process', 'GO:0006412', ('167', '178'))	('ErbB2', 'Gene', (182, 187))	('suppressing', 'NegReg', (151, 162))	('miR-331-3p', 'Var', (93, 103))	('translation', 'MPA', (167, 178))	('VAV2', 'Gene', (188, 192))	('VAV2', 'Gene', (45, 49))	('ErbB2', 'Gene', (35, 40))	('3p', 'Chemical', '-', (101, 103))	('VAV2', 'Gene', '7410', (188, 192))	('ErbB2', 'Gene', '2064', (182, 187))
63300	30955235	Moreover, we first indicated that miR-331-3p exerted its antimigration function in NSCLC by direct regulation of the ErbB2/VAV2/Rac1 pathway.	('miR-331-3p', 'Var', (34, 44))	('3p', 'Chemical', '-', (42, 44))	('antimigration function', 'MPA', (57, 79))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('VAV2', 'Gene', (123, 127))	('ErbB2', 'Gene', (117, 122))	('Rac1', 'Gene', '5879', (128, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('Rac1', 'Gene', (128, 132))	('regulation', 'Reg', (99, 109))	('VAV2', 'Gene', '7410', (123, 127))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('ErbB2', 'Gene', '2064', (117, 122))
63301	30955235	The EMT process comprises a spectrum of intermediate states between epithelial and mesenchymal phenotypes and plays a critical role in the invasion and metastasis of lung cancer.28, 36, 37 In this study, we examined key biomarkers of EMT, such as E-cadherin, N-cadherin, and vimentin, and found that miR-331-3p suppressed EMT activation in NSCLC cells.	('suppressed', 'NegReg', (311, 321))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (152, 177))	('NSCLC', 'Disease', 'MESH:D002289', (340, 345))	('metastasis of lung cancer', 'Disease', (152, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('261', '269'))	('EMT', 'biological_process', 'GO:0001837', ('234', '237'))	('NSCLC', 'Disease', (340, 345))	('cadherin', 'molecular_function', 'GO:0008014', ('249', '257'))	('vimentin', 'cellular_component', 'GO:0045099', ('275', '283'))	('miR-331-3p', 'Var', (300, 310))	('EMT', 'biological_process', 'GO:0001837', ('322', '325'))	('NSCLC', 'Phenotype', 'HP:0030358', (340, 345))	('3p', 'Chemical', '-', (308, 310))	('EMT', 'biological_process', 'GO:0001837', ('4', '7'))	('EMT activation', 'CPA', (322, 336))	('E-cadherin', 'Gene', (247, 257))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('E-cadherin', 'Gene', '999', (247, 257))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('vimentin', 'Gene', '7431', (275, 283))	('vimentin', 'Gene', (275, 283))	('vimentin', 'cellular_component', 'GO:0045098', ('275', '283'))	('N-cadherin', 'Gene', (259, 269))	('N-cadherin', 'Gene', '1000', (259, 269))
63303	30955235	Numerous pieces of evidence have shown that Rho proteins, especially Rac1 activation, have a vital role in both junctional assembly and disassembly.38 Our data showed that Rac1 activity was significantly repressed, and the phosphorylation of PAK1, a downstream effector of Rac1, was remarkably impaired after miR-331-3p transfection.	('PAK1', 'Gene', '5058', (242, 246))	('PAK1', 'Gene', (242, 246))	('repressed', 'PosReg', (204, 213))	('Rac1', 'Gene', (273, 277))	('miR-331-3p transfection', 'Var', (309, 332))	('Rac1', 'Gene', '5879', (273, 277))	('phosphorylation', 'MPA', (223, 238))	('3p', 'Chemical', '-', (317, 319))	('impaired', 'NegReg', (294, 302))	('activity', 'MPA', (177, 185))	('Rac1', 'Gene', '5879', (172, 176))	('Rac1', 'Gene', '5879', (69, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('223', '238'))	('Rac1', 'Gene', (172, 176))	('Rac1', 'Gene', (69, 73))
63304	30955235	Furthermore, the activity of beta-catenin, another key effector of EMT, was also impeded in miR-331-3p-overexpressing NSCLC cells.	('impeded', 'NegReg', (81, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('3p', 'Chemical', '-', (100, 102))	('NSCLC', 'Disease', (118, 123))	('beta-catenin', 'Gene', (29, 41))	('beta-catenin', 'Gene', '1499', (29, 41))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('activity', 'MPA', (17, 25))	('EMT', 'biological_process', 'GO:0001837', ('67', '70'))	('miR-331-3p-overexpressing', 'Var', (92, 117))
63306	30955235	Taken together, our results indicated that miR-331-3p suppressed the EMT process in NSCLC cells by targeting ErbB2/VAV2 through the Rac1/PAK1/beta-catenin pathway.	('ErbB2', 'Gene', (109, 114))	('PAK1', 'Gene', (137, 141))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('Rac1', 'Gene', (132, 136))	('VAV2', 'Gene', (115, 119))	('targeting', 'Reg', (99, 108))	('beta-catenin', 'Gene', (142, 154))	('PAK1', 'Gene', '5058', (137, 141))	('beta-catenin', 'Gene', '1499', (142, 154))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('suppressed', 'NegReg', (54, 64))	('VAV2', 'Gene', '7410', (115, 119))	('ErbB2', 'Gene', '2064', (109, 114))	('Rac1', 'Gene', '5879', (132, 136))	('miR-331-3p', 'Var', (43, 53))	('EMT process in', 'CPA', (69, 83))	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('3p', 'Chemical', '-', (51, 53))
63307	30955235	Our findings reveal that miR-331-3p is downregulated in NSCLC tumor tissues, and its expression level has an correlation with tumor metastasis and patient survival.	('expression', 'MPA', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor metastasis', 'Disease', 'MESH:D009362', (126, 142))	('miR-331-3p', 'Var', (25, 35))	('patient', 'Species', '9606', (147, 154))	('NSCLC tumor', 'Disease', 'MESH:D009369', (56, 67))	('correlation', 'Reg', (109, 120))	('NSCLC tumor', 'Disease', (56, 67))	('tumor metastasis', 'Disease', (126, 142))	('3p', 'Chemical', '-', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('downregulated', 'NegReg', (39, 52))
63308	30955235	MicroRNA-331-3p suppresses EMT activation, migration, and invasion of NSCLC cells by targeting ErbB2/VAV2 through the Rac1/PAK1/beta-catenin pathway.	('EMT', 'biological_process', 'GO:0001837', ('27', '30'))	('EMT activation', 'CPA', (27, 41))	('VAV2', 'Gene', (101, 105))	('beta-catenin', 'Gene', (128, 140))	('PAK1', 'Gene', '5058', (123, 127))	('beta-catenin', 'Gene', '1499', (128, 140))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('MicroRNA-331-3p', 'Var', (0, 15))	('targeting', 'NegReg', (85, 94))	('Rac1', 'Gene', (118, 122))	('NSCLC', 'Disease', (70, 75))	('VAV2', 'Gene', '7410', (101, 105))	('ErbB2', 'Gene', '2064', (95, 100))	('invasion', 'CPA', (58, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('suppresses', 'NegReg', (16, 26))	('3p', 'Chemical', '-', (13, 15))	('migration', 'CPA', (43, 52))	('Rac1', 'Gene', '5879', (118, 122))	('ErbB2', 'Gene', (95, 100))	('PAK1', 'Gene', (123, 127))
63519	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))
63551	30291293	ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.	('EGFR', 'Gene', '1956', (63, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('EGFR', 'Gene', (63, 67))	('patients', 'Species', '9606', (81, 89))	('ANKRD1', 'Gene', '27063', (0, 6))	('inhibition', 'Var', (7, 17))	('NSCLC', 'Disease', (75, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('ANKRD1', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
63554	30291293	The most frequent EGFR-sensitizing mutations are exon 19 deletions and exon 21 L858R mutation.	('EGFR', 'Gene', '1956', (18, 22))	('L858R', 'Var', (79, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', (18, 22))	('L858R', 'Mutation', 'rs121434568', (79, 84))	('exon 19 deletions', 'Var', (49, 66))
63557	30291293	The gatekeeper Thr790Met mutation (T790M) is responsible for almost 60% of the resistant mechanisms against EGFR-TKIs.	('Thr790Met', 'SUBSTITUTION', 'None', (15, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('Thr790Met', 'Var', (15, 24))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('T790M', 'Mutation', 'rs121434569', (35, 40))	('gatekeeper', 'Species', '111938', (4, 14))	('T790M', 'Var', (35, 40))
63558	30291293	The third-generation EGFR-TKI, osimertinib, targets T790M and EGFR-activating mutations.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (62, 66))	('osimertinib', 'Chemical', 'MESH:C000603933', (31, 42))	('EGFR', 'Gene', (62, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('T790M', 'Mutation', 'rs121434569', (52, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('T790M', 'Var', (52, 57))
63560	30291293	The C797S secondary mutation was already reported to be 20-30% of the mechanism of resistance to osimertinib in T790M-positive NSCLC patients.	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('C797S', 'Mutation', 'rs1057519861', (4, 9))	('T790M', 'Mutation', 'rs121434569', (112, 117))	('patients', 'Species', '9606', (133, 141))	('osimertinib', 'Chemical', 'MESH:C000603933', (97, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('C797S', 'Var', (4, 9))	('T790M-positive', 'Var', (112, 126))
63565	30291293	Inhibition of ANKRD1 led to induction of apoptosis by afatinib or osimertinib in adenocarcinoma cells, providing a critical therapeutic target for resistance to EGFR-TKIs in lung adenocarcinoma.	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (81, 100))	('adenocarcinoma cell', 'Disease', (81, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))	('EGFR', 'Gene', (161, 165))	('osimertinib', 'Chemical', 'MESH:C000603933', (66, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('28', '50'))	('apoptosis', 'CPA', (41, 50))	('Inhibition', 'Var', (0, 10))	('afatinib', 'Chemical', 'MESH:D000077716', (54, 62))	('ANKRD1', 'Gene', '27063', (14, 20))	('lung adenocarcinoma', 'Disease', (174, 193))	('EGFR', 'Gene', '1956', (161, 165))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))	('ANKRD1', 'Gene', (14, 20))
63571	30291293	No secondary mutations including T790M and C797S were found by whole exome sequencing.	('T790M', 'Mutation', 'rs121434569', (33, 38))	('C797S', 'Mutation', 'rs1057519861', (43, 48))	('T790M', 'Var', (33, 38))	('C797S', 'Var', (43, 48))
63572	30291293	Furthermore, EGFR minor mutations such as EGFR L718Q and G796D and some novel mutations including MET amplification and BRAF V600E were not also observed in four resistant NSCLC cells.	('MET amplification', 'Var', (98, 115))	('EGFR', 'Gene', '1956', (42, 46))	('G796D', 'Mutation', 'rs1224584642', (57, 62))	('NSCLC', 'Disease', (172, 177))	('L718Q', 'Var', (47, 52))	('BRAF', 'Gene', '673', (120, 124))	('EGFR', 'Gene', (42, 46))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('L718Q', 'Mutation', 'p.L718Q', (47, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('BRAF', 'Gene', (120, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('G796D', 'Var', (57, 62))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('V600E', 'Mutation', 'rs113488022', (125, 130))
63575	30291293	These findings demonstrated that activation of another bypassing pathway, but not secondary mutation including T790M and C797S, was mainly involved in the drug resistance to afatinib and osimertinib of EGFR-mutant NSCLC cells.	('C797S', 'Var', (121, 126))	('EGFR', 'Gene', (202, 206))	('drug resistance', 'biological_process', 'GO:0009315', ('155', '170'))	('EGFR', 'Gene', '1956', (202, 206))	('NSCLC', 'Phenotype', 'HP:0030358', (214, 219))	('drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('EGFR', 'molecular_function', 'GO:0005006', ('202', '206'))	('involved', 'Reg', (139, 147))	('drug resistance', 'biological_process', 'GO:0042493', ('155', '170'))	('osimertinib', 'Chemical', 'MESH:C000603933', (187, 198))	('C797S', 'Mutation', 'rs1057519861', (121, 126))	('NSCLC', 'Disease', (214, 219))	('NSCLC', 'Disease', 'MESH:D002289', (214, 219))	('drug resistance', 'MPA', (155, 170))	('T790M', 'Mutation', 'rs121434569', (111, 116))	('bypassing pathway', 'Pathway', (55, 72))	('afatinib', 'Chemical', 'MESH:D000077716', (174, 182))	('T790M', 'Var', (111, 116))
63582	30291293	ZEB1 was increased in HCC827-AR and HCC827-OR.	('ZEB1', 'Gene', '6935', (0, 4))	('HCC827-AR', 'Var', (22, 31))	('ZEB1', 'Gene', (0, 4))	('increased', 'PosReg', (9, 18))
63583	30291293	Increased expression of vimentin was observed in PC9-OR, HCC827-AR and HCC827-OR, suggesting the presence of EMT phenomenon in EGFR-TKIs-resistant cells (Fig.	('vimentin', 'cellular_component', 'GO:0045098', ('24', '32'))	('HCC827-AR', 'Var', (57, 66))	('PC9', 'Gene', '255738', (49, 52))	('vimentin', 'Gene', (24, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('PC9', 'Gene', (49, 52))	('expression', 'MPA', (10, 20))	('Increased', 'PosReg', (0, 9))	('vimentin', 'cellular_component', 'GO:0045099', ('24', '32'))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('vimentin', 'Gene', '7431', (24, 32))	('HCC827-OR', 'Var', (71, 80))
63590	30291293	HCC827-AR and HCC827-OR were increased migration abilities than parental cell lines, PC-9-AR and PC9-OR had the tendency to increase migration abilities (Supplemental Fig.	('increase', 'PosReg', (124, 132))	('HCC827-AR', 'Var', (0, 9))	('HCC827-OR', 'Var', (14, 23))	('PC9', 'Gene', '255738', (97, 100))	('migration abilities', 'CPA', (133, 152))	('increased', 'PosReg', (29, 38))	('migration abilities', 'CPA', (39, 58))	('PC9', 'Gene', (97, 100))	('PC-9', 'Gene', (85, 89))	('PC-9', 'Gene', '255738', (85, 89))
63602	30291293	After ANKRD1 silencing, decreased level of BCL-2 and increased level of cleaved PARP indicating apoptotic activity were observed in the four resistant cell lines (Fig.	('decreased', 'NegReg', (24, 33))	('BCL-2', 'Gene', (43, 48))	('level', 'MPA', (34, 39))	('BCL-2', 'molecular_function', 'GO:0015283', ('43', '48'))	('PARP', 'Gene', '1302', (80, 84))	('ANKRD1', 'Gene', '27063', (6, 12))	('apoptotic', 'CPA', (96, 105))	('increased', 'PosReg', (53, 62))	('ANKRD1', 'Gene', (6, 12))	('PARP', 'Gene', (80, 84))	('BCL-2', 'Gene', '596', (43, 48))	('silencing', 'Var', (13, 22))
63605	30291293	Silencing of ANKRD1 could overcome the resistance to afatinib and osimertinib of EGFR-TKI-resistant cell lines, except for HCC-827-OR.	('afatinib', 'Chemical', 'MESH:D000077716', (53, 61))	('ANKRD1', 'Gene', '27063', (13, 19))	('overcome', 'PosReg', (26, 34))	('osimertinib', 'Chemical', 'MESH:C000603933', (66, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('resistance to', 'MPA', (39, 52))	('ANKRD1', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('HCC-827', 'CellLine', 'CVCL:2063', (123, 130))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
63622	30291293	First-or second-generation EGFR-TKIs are key drugs for NSCLC patients with EGFR mutation.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('NSCLC', 'Disease', (55, 60))	('patients', 'Species', '9606', (61, 69))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('mutation', 'Var', (80, 88))	('EGFR', 'Gene', (75, 79))
63623	30291293	Osimertinib which was originally developed for tumors that developed tolerance to first- or second-generation EGFR-TKIs, targeting T790M, showed a dramatic response in T790M-positive NSCLC patients.	('T790M', 'Var', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('T790M-positive', 'Var', (168, 182))	('NSCLC', 'Disease', (183, 188))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('T790M', 'Mutation', 'rs121434569', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('patients', 'Species', '9606', (189, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('T790M', 'Mutation', 'rs121434569', (131, 136))
63624	30291293	However, the C797S mutation was already observed as a mechanism of resistance in T790M-positive NSCLC patients after osimertinib treatment.	('T790M-positive', 'Var', (81, 95))	('NSCLC', 'Disease', (96, 101))	('C797S', 'Mutation', 'rs1057519861', (13, 18))	('T790M', 'Mutation', 'rs121434569', (81, 86))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('osimertinib', 'Chemical', 'MESH:C000603933', (117, 128))	('C797S', 'Var', (13, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
63625	30291293	A recent report demonstrated that brigatinib combined with anti-EGFR antibody could rescue osimertinib resistance by overcoming all of the activating-mutations, T790M and C797S, in EGFR-mutated NSCLC patients.	('C797S', 'Mutation', 'rs1057519861', (171, 176))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('brigatinib', 'Chemical', 'MESH:C000598580', (34, 44))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('activating-mutations', 'PosReg', (139, 159))	('EGFR', 'Gene', '1956', (181, 185))	('T790M', 'Mutation', 'rs121434569', (161, 166))	('rescue', 'PosReg', (84, 90))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('EGFR', 'Gene', (64, 68))	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('NSCLC', 'Disease', (194, 199))	('C797S', 'Var', (171, 176))	('T790M', 'Var', (161, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('EGFR', 'Gene', (181, 185))	('patients', 'Species', '9606', (200, 208))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('overcoming', 'PosReg', (117, 127))	('osimertinib resistance', 'MPA', (91, 113))	('EGFR', 'Gene', '1956', (64, 68))	('osimertinib', 'Chemical', 'MESH:C000603933', (91, 102))
63626	30291293	However, C797S was found in only 20% in osimertinib-resistant NSCLC patients.	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('patients', 'Species', '9606', (68, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('C797S', 'Mutation', 'rs1057519861', (9, 14))	('osimertinib', 'Chemical', 'MESH:C000603933', (40, 51))	('C797S', 'Var', (9, 14))
63629	30291293	A recent study demonstrated that EGFR T790M mutation as a resistant mechanism can occur in both pre-existing T790M clones and in the evolution of drug-tolerant cells without T790M.	('EGFR', 'Gene', (33, 37))	('pre', 'molecular_function', 'GO:0003904', ('96', '99'))	('EGFR', 'Gene', '1956', (33, 37))	('T790M', 'Mutation', 'rs121434569', (109, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('T790M', 'Mutation', 'rs121434569', (174, 179))	('T790M', 'Mutation', 'rs121434569', (38, 43))	('T790M', 'Var', (109, 114))	('T790M', 'Var', (38, 43))
63630	30291293	Late-evolving EGFR T790M in cancer cells that acquired resistance showed a decreased apoptotic response to EGFR-TKI.	('apoptotic response', 'CPA', (85, 103))	('T790M', 'Mutation', 'rs121434569', (19, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('T790M', 'Var', (19, 24))	('EGFR', 'Gene', (107, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('decreased', 'NegReg', (75, 84))
63633	30291293	In these resistant cells, no secondary gatekeeper mutations such as T790M and C797S were observed.	('C797S', 'Mutation', 'rs1057519861', (78, 83))	('gatekeeper', 'Species', '111938', (39, 49))	('C797S', 'Var', (78, 83))	('T790M', 'Mutation', 'rs121434569', (68, 73))	('T790M', 'Var', (68, 73))
63663	30291293	NCI-HCC827 (HCC827) with a deletion in exon 19, A549 (EGFR wild type cell line) and BET2A (normal lung cell line) were purchased from the American Type Culture Collection (ATCC, Manassas, VA).	('NCI-HCC827', 'Gene', (0, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('deletion', 'Var', (27, 35))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))
63678	30291293	During the period from 2009 through 2016, 10 lung adenocarcinoma patients with EGFR mutation underwent re-biopsy after EGFR-TKIs therapy at Nippon Medical School Hospital.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (45, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'Gene', '1956', (119, 123))	('patients', 'Species', '9606', (65, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('EGFR', 'Gene', (119, 123))	('lung adenocarcinoma', 'Disease', (45, 64))	('mutation', 'Var', (84, 92))
63772	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))
63885	29983983	Screening tests for opportunistic infection were negative, including cytomegalovirus pp65-antigenemia, serum beta-D-glucan, anti-Aspergillus antibody, and galactomannan antigen.	('pp65-antigenemia', 'Var', (85, 101))	('antibody', 'molecular_function', 'GO:0003823', ('141', '149'))	('opportunistic infection', 'Phenotype', 'HP:0031690', (20, 43))	('anti-Aspergillus antibody', 'Phenotype', 'HP:0002724', (124, 149))	('antibody', 'cellular_component', 'GO:0042571', ('141', '149'))	('opportunistic infection', 'Disease', (20, 43))	('antibody', 'cellular_component', 'GO:0019815', ('141', '149'))	('serum beta-D-glucan', 'MPA', (103, 122))	('beta-D-glucan', 'Chemical', '-', (109, 122))	('opportunistic infection', 'Disease', 'MESH:D009894', (20, 43))	('man', 'Species', '9606', (162, 165))	('antibody', 'cellular_component', 'GO:0019814', ('141', '149'))
63908	29465809	In our previous study, we found that IDH2 polymorphism rs11540478 is a risk factor for lung cancer.	('risk', 'Reg', (71, 75))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('IDH2', 'Gene', (37, 41))	('rs11540478', 'Var', (55, 65))	('IDH2', 'Gene', '3418', (37, 41))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('rs11540478', 'Mutation', 'rs11540478', (55, 65))
63924	29465809	Recently, gain-of-function mutations of the isocitrate dehydrogenase 1/2 (IDH) enzymes have been found in multiple cancers (Clark et al., 2016; Flavahan et al., 2016; Zou et al., 2015).	('mutations', 'Var', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('isocitrate dehydrogenase', 'Gene', (44, 68))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('isocitrate dehydrogenase', 'Gene', '3417', (44, 68))	('gain-of-function', 'PosReg', (10, 26))	('IDH', 'Gene', (74, 77))	('multiple cancers', 'Disease', (106, 122))	('IDH', 'Gene', '3417', (74, 77))	('multiple cancers', 'Disease', 'MESH:D009369', (106, 122))
63925	29465809	IDH1/2 mutations could produce the 'onco-metabolite', 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate (alpha-KG) to competitively inhibit alpha-KG-dependent dioxygenases to activate oncogenes and regulate the expression of multiple genes (Ward et al., 2010; Xu et al., 2011).	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('alpha-KG-dependent dioxygenases', 'Enzyme', (141, 172))	('expression', 'MPA', (212, 222))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (85, 104))	('inhibit', 'NegReg', (133, 140))	('activate', 'PosReg', (176, 184))	('regulate', 'Reg', (199, 207))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (54, 72))	('oncogenes', 'Gene', (185, 194))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
63931	29465809	In our previous study, we showed that idh2 rs11540478 is a risk factor for lung cancer(Li et al., 2017).	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('rs11540478', 'Mutation', 'rs11540478', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('idh2', 'Gene', '3418', (38, 42))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('idh2', 'Gene', (38, 42))	('rs11540478', 'Var', (43, 53))
63940	29465809	NCI-H460 (HTB-177), A549 (CCL-185), HCT116 (CCL-247), and HT29 (HTB-38) were cultured in RPMI 1640 with 10% FBS.	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('RPMI 1640', 'Chemical', '-', (89, 98))	('A549', 'CellLine', 'CVCL:0023', (20, 24))	('FBS', 'Disease', (108, 111))	('NCI-H460', 'CellLine', 'CVCL:0459', (0, 8))	('CCL', 'molecular_function', 'GO:0044101', ('44', '47'))	('FBS', 'Disease', 'MESH:D005198', (108, 111))	('CCL-247', 'Var', (44, 51))	('CCL', 'molecular_function', 'GO:0044101', ('26', '29'))	('HT29', 'CellLine', 'CVCL:0320', (58, 62))
63990	29465809	In a previous study, we showed that a new IDH2 genetic variant rs11540478 is associated with a risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('rs11540478', 'Var', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('IDH2', 'Gene', (42, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('rs11540478', 'Mutation', 'rs11540478', (63, 73))	('IDH2', 'Gene', '3418', (42, 46))	('associated', 'Reg', (77, 87))
64079	27880938	Image data were reconstructed with a section thickness of 1 mm using a D30f (medium smooth) kernel for the iodine-enhanced image and a D45f (medium sharp) kernel for the virtual non-enhanced image.	('iodine-enhanced', 'MPA', (107, 122))	('D30f', 'Var', (71, 75))	('iodine', 'Chemical', 'MESH:D007455', (107, 113))	('D45f', 'Var', (135, 139))	('D45f', 'Chemical', '-', (135, 139))	('D30f', 'Chemical', '-', (71, 75))
64111	27499635	The clinical integration of ADC in terms of predictive biomarker signatures is characterized by positive immunostaining for cytokeratin 7 and TTF1; however, SCC is characterized by positivity of cytokeratin 5, cytokeratin 6 and/or SOX2, and p63.	('rat', 'Species', '10116', (18, 21))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('positivity', 'Var', (181, 191))	('p63', 'Gene', (241, 244))	('rat', 'Species', '10116', (201, 204))	('cytokeratin 5', 'Gene', (195, 208))	('SCC', 'Disease', (157, 160))	('SOX2', 'Gene', '6657', (231, 235))	('SOX2', 'Gene', (231, 235))	('cytokeratin 7', 'Gene', '3855', (124, 137))	('cytokeratin 6', 'Protein', (210, 223))	('TTF1', 'Gene', (142, 146))	('p63', 'Gene', '8626', (241, 244))	('cytokeratin 5', 'Gene', '3852', (195, 208))	('TTF1', 'Gene', '7270', (142, 146))	('rat', 'Species', '10116', (130, 133))	('rat', 'Species', '10116', (216, 219))	('cytokeratin 7', 'Gene', (124, 137))
64113	27499635	For instance, EGFR, ALK, and MET mutations are always found in ADC patients.	('ALK', 'Gene', '238', (20, 23))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('patients', 'Species', '9606', (67, 75))	('ADC', 'Disease', (63, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('found', 'Reg', (54, 59))	('ALK', 'Gene', (20, 23))	('MET mutations', 'Var', (29, 42))
64114	27499635	However, DDR2, FGFR1, and FGFR2 mutations, as well as mutations in genes in the PI3K signaling pathway, are generally found more frequently in SCC.	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('DDR2', 'Gene', '4921', (9, 13))	('FGFR2', 'Gene', '2263', (26, 31))	('frequently', 'Reg', (129, 139))	('FGFR1', 'Gene', '2260', (15, 20))	('PI3K signaling', 'biological_process', 'GO:0014065', ('80', '94'))	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('DDR2', 'Gene', (9, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('found', 'Reg', (118, 123))	('SCC', 'Disease', (143, 146))	('PI3K signaling', 'Pathway', (80, 94))	('mutations', 'Var', (32, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGFR2', 'Gene', (26, 31))	('FGFR1', 'Gene', (15, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))
64117	27499635	The regulated ncRNAs can be categorized by length as follows: any ncRNA <200 nucleotides (nt) in length is a short ncRNA (siRNA, miRNA, piRNA) and those >200 nt in length are long ncRNAs (lncRNAs).	('ncRNA', 'Gene', '220202', (180, 185))	('miR', 'Gene', '220972', (129, 132))	('ncRNA', 'Gene', '220202', (66, 71))	('miR', 'Gene', (129, 132))	('<200 nucleotides', 'Var', (72, 88))	('ncRNA', 'Gene', '220202', (115, 120))	('ncRNA', 'Gene', '220202', (189, 194))	('ncRNA', 'Gene', (189, 194))	('ncRNA', 'Gene', (14, 19))	('ncRNA', 'Gene', (180, 185))	('ncRNA', 'Gene', (66, 71))	('ncRNA', 'Gene', (115, 120))	('ncRNA', 'Gene', '220202', (14, 19))
64119	27499635	Approximately 1% of lncRNAs harbor ultraconserved elements, and 7% of lncRNAs harbor disease-associated single-nucleotide polymorphisms.	('single-nucleotide polymorphisms', 'Var', (104, 135))	('ncRNA', 'Gene', (71, 76))	('ncRNA', 'Gene', '220202', (71, 76))	('ncRNA', 'Gene', (21, 26))	('ncRNA', 'Gene', '220202', (21, 26))
64121	27499635	Notably, ectopic expression of lncRNAs is associated with a great variety of diseases.	('ectopic expression', 'Var', (9, 27))	('ncRNA', 'Gene', (32, 37))	('associated', 'Reg', (42, 52))	('diseases', 'Disease', (77, 85))	('ncRNA', 'Gene', '220202', (32, 37))
64147	27499635	Another example of a molecular scaffold is Kcnq1ot1, which combines PRC2 and G9a to generate H3K27me3 and H3K9me3, leading to epigenetic silencing of genes.	('epigenetic silencing of genes', 'MPA', (126, 155))	('H3K9me3', 'Var', (106, 113))	('rat', 'Species', '10116', (88, 91))	('Kcnq1ot1', 'Gene', '10984', (43, 51))	('Kcnq1ot1', 'Gene', (43, 51))	('H3K27me3', 'Var', (93, 101))
64165	27499635	Xist gives rise to stable epigenetic silencing of large-scale genes in the X-chromosome by tethering PRC2 to the transcriptional site, inducing the formation of H3K27me3 to inactivate heterochromatin.	('inactivate', 'NegReg', (173, 183))	('epigenetic', 'MPA', (26, 36))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('H3K27me3', 'Protein', (161, 169))	('PRC2', 'Gene', (101, 105))	('Xist', 'Gene', '7503', (0, 4))	('tethering', 'Var', (91, 100))	('heterochromatin', 'MPA', (184, 199))	('heterochromatin', 'cellular_component', 'GO:0000792', ('184', '199'))	('inducing', 'Reg', (135, 143))	('X-chromosome', 'cellular_component', 'GO:0000805', ('75', '87'))	('Xist', 'Gene', (0, 4))
64175	27499635	Lung cancer is often associated with aberrant lncRNA transcriptomes, including onco-lncRNAs and tumor suppressor lncRNAs.	('ncRNA', 'Gene', (114, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ncRNA', 'Gene', (47, 52))	('ncRNA', 'Gene', (85, 90))	('associated', 'Reg', (21, 31))	('ncRNA', 'Gene', '220202', (114, 119))	('tumor', 'Disease', (96, 101))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('ncRNA', 'Gene', '220202', (47, 52))	('Lung cancer', 'Disease', (0, 11))	('ncRNA', 'Gene', '220202', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('aberrant', 'Var', (37, 45))
64176	27499635	Here, we discuss recent discoveries that implicate aberrant lncRNAs in lung cancer (Table 1).	('ncRNA', 'Gene', (61, 66))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('aberrant', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ncRNA', 'Gene', '220202', (61, 66))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
64186	27499635	After modification, MALAT1 generates a second small mascRNA that is localized to the cytoplasm.	('MALAT1', 'Gene', (20, 26))	('modification', 'Var', (6, 18))	('cytoplasm', 'cellular_component', 'GO:0005737', ('85', '94'))	('MALAT1', 'Gene', '378938', (20, 26))	('rat', 'Species', '10116', (31, 34))
64187	27499635	MALAT1 binds to the unmethylated PRC2 protein, therefore contributing to PRC2 preferential binding to H2AK5ac and H2AK13ac, marking transcriptional activation.	('H2AK13ac', 'Chemical', '-', (114, 122))	('MALAT1', 'Gene', '378938', (0, 6))	('H2AK5ac', 'Protein', (102, 109))	('PRC2', 'Gene', (73, 77))	('MALAT1', 'Gene', (0, 6))	('transcriptional', 'MPA', (132, 147))	('binding', 'Interaction', (91, 98))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('H2AK5ac', 'Chemical', '-', (102, 109))	('preferential', 'PosReg', (78, 90))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('H2AK13ac', 'Var', (114, 122))
64195	27499635	In A549 cells, inhibition of MALAT1 downregulates the expression of motility-associated genes, including HMMR, AIM1, SLC26A2, LAYN, CCT4, ROD1, CTHRC, and FHL1.	('LAYN', 'Gene', '143903', (126, 130))	('SLC26A2', 'Gene', (117, 124))	('CTHRC', 'Gene', (144, 149))	('SLC26A2', 'Gene', '1836', (117, 124))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('LAYN', 'Gene', (126, 130))	('downregulates', 'NegReg', (36, 49))	('FHL1', 'Gene', '2273', (155, 159))	('FHL1', 'Gene', (155, 159))	('AIM1', 'Gene', (111, 115))	('MALAT1', 'Gene', (29, 35))	('inhibition', 'Var', (15, 25))	('MALAT1', 'Gene', '378938', (29, 35))	('CCT4', 'Gene', (132, 136))	('AIM1', 'Gene', '202', (111, 115))	('HMMR', 'Gene', '3161', (105, 109))	('expression', 'MPA', (54, 64))	('CCT4', 'Gene', '10575', (132, 136))	('motility-associated genes', 'Gene', (68, 93))	('ROD1', 'Gene', (138, 142))	('ROD1', 'Gene', '9991', (138, 142))	('HMMR', 'Gene', (105, 109))
64201	27499635	Moreover, a meta-analysis and various studies have shown that high MALAT1 expression is related to poor overall survival in NSCLC.	('expression', 'MPA', (74, 84))	('overall', 'MPA', (104, 111))	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('poor', 'NegReg', (99, 103))	('MALAT1', 'Gene', '378938', (67, 73))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('MALAT1', 'Gene', (67, 73))	('high', 'Var', (62, 66))
64210	27499635	HOTAIR-mediated epigenetic gene silencing is dependent on its function as a bridge scaffold for PRC2 and LSD1/CoREST/REST.	('HOTAIR', 'Gene', '100124700', (0, 6))	('CoREST', 'Gene', '23186', (110, 116))	('CoREST', 'Gene', (110, 116))	('LSD1', 'Gene', '23028', (105, 109))	('LSD1', 'Gene', (105, 109))	('gene silencing', 'biological_process', 'GO:0016458', ('27', '41'))	('HOTAIR', 'Gene', (0, 6))	('epigenetic gene', 'Var', (16, 31))
64218	27499635	High HOTAIR levels are associated with invasion and metastases and linked to an advanced stage of disease and poor survival in patients with lung cancer.	('metastases', 'Disease', (52, 62))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('High', 'Var', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('invasion', 'CPA', (39, 47))	('HOTAIR', 'Gene', (5, 11))	('linked to', 'Reg', (67, 76))	('lung cancer', 'Disease', (141, 152))	('patients', 'Species', '9606', (127, 135))	('HOTAIR', 'Gene', '100124700', (5, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('associated', 'Reg', (23, 33))
64238	27499635	With respect to the mechanism of SOX2-OT, Hou et al showed that knockdown of SOX2-OT expression leads to cell cycle arrest at G2/M phase through the modulation of the expression of EZH2.	('EZH2', 'Gene', '2146', (181, 185))	('M phase', 'biological_process', 'GO:0000279', ('129', '136'))	('expression', 'MPA', (167, 177))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (105, 122))	('EZH2', 'Gene', (181, 185))	('SOX2-OT', 'Gene', (77, 84))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('105', '122'))	('knockdown', 'Var', (64, 73))	('modulation', 'Reg', (149, 159))	('cell cycle arrest at G2/M phase', 'CPA', (105, 136))
64240	27499635	This study further indicates that high SOX2-OT expression predicts poor survival in lung cancer patients.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('poor', 'NegReg', (67, 71))	('high', 'Var', (34, 38))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('SOX2-OT expression', 'MPA', (39, 57))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
64249	27499635	siRNA-mediated knockdown of ANRIL results in the inhibition of cell proliferation and the promotion of apoptosis both in vitro and in vivo.	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('49', '81'))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('knockdown', 'Var', (15, 24))	('rat', 'Species', '10116', (75, 78))	('ANRIL', 'Gene', '100048912', (28, 33))	('promotion', 'PosReg', (90, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('cell proliferation', 'CPA', (63, 81))	('apoptosis', 'CPA', (103, 112))	('ANRIL', 'Gene', (28, 33))	('inhibition', 'NegReg', (49, 59))
64269	27499635	Furthermore, knockdown of H19 can reverse the tumorigenic and scattering effect of HGF/SF on A549 cells.	('reverse', 'NegReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('scattering effect', 'CPA', (62, 79))	('tumor', 'Disease', (46, 51))	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('HGF/SF', 'Gene', '3082', (83, 89))	('H19', 'Gene', '283120', (26, 29))	('HGF/SF', 'Gene', (83, 89))	('H19', 'Gene', (26, 29))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
64280	27499635	siRNA-mediated knockdown of MVIH inhibits cell proliferation and invasion, partly via modulating the expression of MMP2 and MMP9.	('MMP2', 'Gene', '4313', (115, 119))	('knockdown', 'Var', (15, 24))	('MMP9', 'Gene', '4318', (124, 128))	('modulating', 'Reg', (86, 96))	('MMP9', 'Gene', (124, 128))	('cell proliferation', 'CPA', (42, 60))	('rat', 'Species', '10116', (54, 57))	('MMP9', 'molecular_function', 'GO:0004229', ('124', '128'))	('MMP2', 'Gene', (115, 119))	('MMP2', 'molecular_function', 'GO:0004228', ('115', '119'))	('MVIH', 'Gene', (28, 32))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('invasion', 'CPA', (65, 73))	('inhibits', 'NegReg', (33, 41))	('expression', 'MPA', (101, 111))
64300	27499635	Ectopic expression of SPRY4-IT1 is associated with tumor size, advanced pathological stage, lymph node metastasis, and overall survival time in NSCLC patients.	('NSCLC', 'Disease', (144, 149))	('SPRY4-IT1', 'Gene', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (22, 31))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', (51, 56))	('Ectopic expression', 'Var', (0, 18))	('lymph node metastasis', 'CPA', (92, 113))	('patients', 'Species', '9606', (150, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
64332	27499635	TUG1, which is induced by p53, is found binding to PRC2 and epigenetically regulates the expression of HOXB7.	('expression', 'MPA', (89, 99))	('TUG1', 'Gene', (0, 4))	('regulates', 'Reg', (75, 84))	('epigenetically', 'Var', (60, 74))	('HOXB7', 'Gene', (103, 108))	('p53', 'Gene', (26, 29))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('p53', 'Gene', '7157', (26, 29))	('binding', 'Interaction', (40, 47))	('TUG1', 'Gene', '55000', (0, 4))	('HOXB7', 'Gene', '3217', (103, 108))
64339	27499635	In addition, deregulated expression of BANCR is associated with increased tumor size, advanced pathological stage, lymph node metastasis, and poor survival in NSCLC patients.	('poor', 'NegReg', (142, 146))	('lymph node metastasis', 'CPA', (115, 136))	('BANCR', 'Gene', '100885775', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NSCLC', 'Disease', (159, 164))	('expression', 'MPA', (25, 35))	('deregulated', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('tumor', 'Disease', (74, 79))	('patients', 'Species', '9606', (165, 173))	('BANCR', 'Gene', (39, 44))	('increased', 'PosReg', (64, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))
64341	27499635	Furthermore, knockdown of BANCR expression leads to the promotion of cell migration and invasion but inhibition of metastasis.	('promotion', 'PosReg', (56, 65))	('invasion', 'CPA', (88, 96))	('inhibition', 'NegReg', (101, 111))	('metastasis', 'CPA', (115, 125))	('rat', 'Species', '10116', (77, 80))	('cell migration', 'biological_process', 'GO:0016477', ('69', '83'))	('cell migration', 'CPA', (69, 83))	('BANCR', 'Gene', '100885775', (26, 31))	('knockdown', 'Var', (13, 22))	('BANCR', 'Gene', (26, 31))
64342	27499635	It is plausible that downregulated BANCR promotes cell proliferation by downregulating p21 expression.	('expression', 'MPA', (91, 101))	('p21', 'Gene', '1026', (87, 90))	('downregulating', 'NegReg', (72, 86))	('p21', 'Gene', (87, 90))	('BANCR', 'Gene', (35, 40))	('promotes', 'PosReg', (41, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('downregulated', 'Var', (21, 34))	('rat', 'Species', '10116', (62, 65))	('BANCR', 'Gene', '100885775', (35, 40))	('cell proliferation', 'CPA', (50, 68))
64389	33823009	However, tumors with a large low iodine density tumor area ratio showed an increased local recurrence rate, with the prognostic accuracy almost similar to that in previous studies using average iodine densities.	('a', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (24, 25))	('a', 'Gene', '351', (103, 104))	('low', 'Var', (29, 32))	('a', 'Gene', '351', (72, 73))	('iodine density', 'MPA', (33, 47))	('a', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (128, 129))	('a', 'Gene', '351', (190, 191))	('iodine', 'Chemical', 'MESH:D007455', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('a', 'Gene', '351', (157, 158))	('a', 'Gene', '351', (149, 150))	('tumor', 'Disease', (9, 14))	('iodine', 'Chemical', 'MESH:D007455', (33, 39))	('a', 'Gene', '351', (54, 55))	('a', 'Gene', '351', (133, 134))	('a', 'Gene', '351', (21, 22))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (48, 53))	('a', 'Gene', '351', (186, 187))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('a', 'Gene', '351', (60, 61))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('a', 'Gene', '351', (57, 58))	('tumors', 'Disease', (9, 15))	('a', 'Gene', '351', (88, 89))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
64410	33823009	A total of 14, 65, 49, 26 and 4 patients had T1a, T1b, T1c, T2a and T2b, respectively.	('a', 'Gene', '351', (64, 65))	('A', 'Gene', '351', (0, 1))	('patients', 'Species', '9606', (32, 40))	('T1b', 'Disease', (50, 53))	('a', 'Gene', '351', (42, 43))	('a', 'Gene', '351', (62, 63))	('T1c', 'Var', (55, 58))	('a', 'Gene', '351', (33, 34))	('a', 'Gene', '351', (5, 6))	('T2b', 'Var', (68, 71))	('a', 'Gene', '351', (47, 48))	('a', 'Gene', '351', (26, 27))
64465	33823009	After evaluating the correlation between low iodine density tumor area and the local recurrence rate, no significant difference was found in local recurrence rates according to low iodine density tumor area, with a cut-off median low iodine density tumor area of 130 mm2 (P = 0.745) (Fig.	('a', 'Gene', '351', (129, 130))	('a', 'Gene', '351', (255, 256))	('tumor', 'Disease', (196, 201))	('iodine', 'Chemical', 'MESH:D007455', (181, 187))	('iodine', 'Chemical', 'MESH:D007455', (45, 51))	('a', 'Gene', '351', (159, 160))	('a', 'Gene', '351', (8, 9))	('tumor', 'Disease', (249, 254))	('a', 'Gene', '351', (71, 72))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (60, 65))	('a', 'Gene', '351', (213, 214))	('low', 'Var', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('iodine', 'Chemical', 'MESH:D007455', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('a', 'Gene', '351', (205, 206))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (258, 259))	('a', 'Gene', '351', (164, 165))	('a', 'Gene', '351', (227, 228))	('a', 'Gene', '351', (69, 70))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (27, 28))	('a', 'Gene', '351', (11, 12))	('a', 'Gene', '351', (202, 203))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (97, 98))	('a', 'Gene', '351', (113, 114))	('a', 'Gene', '351', (144, 145))
64473	33823009	Although prognostic accuracy was almost the same with both predictors, it was slightly higher with the low iodine density tumor area ratio (Fig.	('low', 'Var', (103, 106))	('a', 'Gene', '351', (20, 21))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (131, 132))	('iodine', 'Chemical', 'MESH:D007455', (107, 113))	('a', 'Gene', '351', (45, 46))	('higher', 'PosReg', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('a', 'Gene', '351', (33, 34))	('a', 'Gene', '351', (128, 129))	('a', 'Gene', '351', (75, 76))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('prognostic', 'MPA', (9, 19))	('a', 'Gene', '351', (134, 135))	('tumor', 'Disease', (122, 127))	('a', 'Gene', '351', (30, 31))
64475	33823009	Low iodine density tumor area was more strongly correlated with the maximum diameter of the tumor.	('a', 'Gene', '351', (25, 26))	('iodine', 'Chemical', 'MESH:D007455', (4, 10))	('a', 'Gene', '351', (31, 32))	('a', 'Gene', '351', (28, 29))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('a', 'Gene', '351', (69, 70))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', (92, 97))	('a', 'Gene', '351', (78, 79))	('a', 'Gene', '351', (54, 55))	('Low', 'Var', (0, 3))
64505	33823009	On the other hand, tumors with an increased low iodine density tumor area ratio have a lower proportion of oxygenated tumor cells that die in the early stages of irradiation.	('tumors', 'Disease', (19, 25))	('a', 'Gene', '351', (168, 169))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('a', 'Gene', '351', (72, 73))	('low', 'Var', (44, 47))	('a', 'Gene', '351', (39, 40))	('tumor', 'Disease', (19, 24))	('a', 'Gene', '351', (165, 166))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('a', 'Gene', '351', (31, 32))	('a', 'Gene', '351', (14, 15))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('a', 'Gene', '351', (85, 86))	('tumor', 'Disease', (63, 68))	('iodine', 'Chemical', 'MESH:D007455', (48, 54))	('lower', 'NegReg', (87, 92))	('a', 'Gene', '351', (69, 70))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('a', 'Gene', '351', (132, 133))	('a', 'Gene', '351', (75, 76))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('a', 'Gene', '351', (154, 155))	('a', 'Gene', '351', (147, 148))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('a', 'Gene', '351', (81, 82))	('a', 'Gene', '351', (113, 114))
64507	33823009	For this reason, a correlation was observed between low iodine density tumor area proportion and prognosis.	('a', 'Gene', '351', (11, 12))	('a', 'Gene', '351', (17, 18))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (93, 94))	('iodine', 'Chemical', 'MESH:D007455', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('a', 'Gene', '351', (80, 81))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('a', 'Gene', '351', (32, 33))	('tumor', 'Disease', (71, 76))	('prognosis', 'CPA', (97, 106))	('a', 'Gene', '351', (77, 78))	('low', 'Var', (52, 55))
64667	33907418	GSEC was significantly upregulated in TNBC tissues and cancer cell lines, and high level of GSEC was associated with advanced tumor stage, positive lymph-node metastasis and the poor prognosis of TNBC patients.	('patients', 'Species', '9606', (201, 209))	('positive lymph-node metastasis', 'CPA', (139, 169))	('upregulated', 'PosReg', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('GSEC', 'Chemical', '-', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('associated', 'Reg', (101, 111))	('GSEC', 'Gene', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('high level', 'Var', (78, 88))	('GSEC', 'Chemical', '-', (0, 4))	('cancer', 'Disease', (55, 61))	('tumor', 'Disease', (126, 131))
64671	33907418	Meanwhile, overexpression of AXL obviously reversed the inhibitory effects of miR-202-5p mimics in TNBC progression in vitro.	('AXL', 'Gene', '558', (29, 32))	('AXL', 'Gene', (29, 32))	('miR-202-5p', 'Chemical', '-', (78, 88))	('TNBC', 'Disease', (99, 103))	('miR-202-5p', 'Var', (78, 88))
64678	33907418	PVT1 is highly expressed in prostate cancer, and knockdown of PVT1 significantly suppresses prostate cancer development both in vivo and in vitro.	('knockdown', 'Var', (49, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('suppresses', 'NegReg', (81, 91))	('prostate cancer', 'Disease', (92, 107))	('PVT1', 'Gene', (0, 4))	('PVT1', 'Gene', (62, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('prostate cancer', 'Disease', (28, 43))	('PVT1', 'Gene', '5820', (0, 4))	('PVT1', 'Gene', '5820', (62, 66))
64680	33907418	LINC02273 is significantly upregulated in metastatic lymph nodes of breast cancer, and overexpression of LINC02273 promotes the metastasis of breast cancer by upregulating AGR2 transcription.	('metastasis', 'CPA', (128, 138))	('AGR2', 'Gene', '10551', (172, 176))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('upregulating', 'PosReg', (159, 171))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancer', 'Disease', (142, 155))	('LINC02273', 'Var', (105, 114))	('upregulated', 'PosReg', (27, 38))	('AGR2', 'Gene', (172, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('promotes', 'PosReg', (115, 123))	('transcription', 'biological_process', 'GO:0006351', ('177', '190'))	('transcription', 'MPA', (177, 190))
64688	33907418	Our results demonstrated that knockdown of GSEC prevented against TNBC progression partially through regulating the miR-202-5p/AXL axis, suggesting that GSEC/miR-202-5p/AXL might be potential diagnostic and therapeutic targets for TNBC.	('regulating', 'Reg', (101, 111))	('TNBC', 'Disease', (66, 70))	('GSEC', 'Chemical', '-', (153, 157))	('miR-202-5p/AXL', 'Gene', (158, 172))	('miR-202-5p/AXL', 'Gene', (116, 130))	('prevented', 'NegReg', (48, 57))	('GSEC', 'Chemical', '-', (43, 47))	('miR-202-5p/AXL', 'Gene', '558', (116, 130))	('knockdown', 'Var', (30, 39))	('GSEC', 'Gene', (43, 47))	('miR-202-5p/AXL', 'Gene', '558', (158, 172))
64697	33907418	The sh-RNAs, overexpression vectors or miR-202-5p mimic/inhibitor were transfected into BT-549 and MDA-MB-468 cells using Lipofectamine 2000 reagent (Invitrogen).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (122, 140))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (99, 109))	('miR-202-5p', 'Chemical', '-', (39, 49))	('sh-RNAs', 'Gene', (4, 11))	('miR-202-5p', 'Var', (39, 49))	('BT-549', 'CellLine', 'CVCL:1092', (88, 94))
64703	33907418	The membranes were incubated with specific primary antibodies including anti-AXL (1:500, Abcam, USA), anti-N-cadherin (1:500, Abcam, USA), anti-E-cadherin (1:500, Abcam, USA), anti-Vimentin (1:500, Abcam, USA) and anti-GAPDH (1:500, Abcam, Cambridge, Britain) at 4 C overnight.	('AXL', 'Gene', '558', (77, 80))	('Vimentin', 'Gene', (181, 189))	('GAPDH', 'Gene', '2597', (219, 224))	('Vimentin', 'cellular_component', 'GO:0045098', ('181', '189'))	('GAPDH', 'Gene', (219, 224))	('Vimentin', 'Gene', '7431', (181, 189))	('N-cadherin', 'Gene', (107, 117))	('Vimentin', 'cellular_component', 'GO:0045099', ('181', '189'))	('cadherin', 'molecular_function', 'GO:0008014', ('109', '117'))	('cadherin', 'molecular_function', 'GO:0008014', ('146', '154'))	('AXL', 'Gene', (77, 80))	('E-cadherin', 'Gene', (144, 154))	('E-cadherin', 'Gene', '999', (144, 154))	('N-cadherin', 'Gene', '1000', (107, 117))	('1:500', 'Var', (156, 161))
64712	33907418	Starbase was used to predict the putative binding site between GSEC and miR-202-5p, and between miR-202-5p and AXL.	('miR-202-5p', 'Chemical', '-', (96, 106))	('miR-202-5p', 'Var', (96, 106))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('binding', 'Interaction', (42, 49))	('AXL', 'Gene', (111, 114))	('AXL', 'Gene', '558', (111, 114))	('GSEC', 'Chemical', '-', (63, 67))	('miR-202-5p', 'Chemical', '-', (72, 82))
64713	33907418	The wild-type (WT) or mutant (MUT) GSEC and AXL containing the putative miR-202-5p binding site were synthesized by GenePharma (Shanghai, China) and cloned into pGL3 Basic vector (Promega).	('AXL', 'Gene', '558', (44, 47))	('GSEC', 'Chemical', '-', (35, 39))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('AXL', 'Gene', (44, 47))	('mutant', 'Var', (22, 28))	('pGL', 'molecular_function', 'GO:0004598', ('161', '164'))	('miR-202-5p', 'Chemical', '-', (72, 82))
64725	33907418	Pearson's correlation analysis was used to evaluate the correlation between the expression levels of GSEC, miR-202-5p and AXL in TNBC tissues.	('GSEC', 'Chemical', '-', (101, 105))	('miR-202-5p', 'Chemical', '-', (107, 117))	('miR-202-5p', 'Var', (107, 117))	('GSEC', 'Gene', (101, 105))	('AXL', 'Gene', '558', (122, 125))	('AXL', 'Gene', (122, 125))
64728	33907418	In addition, high expression levels of GSEC were positively associated with advanced tumor stage (p < 0.01, Figure 1C) and lymph-node metastasis (p < 0.01, Figure 1D) in TNBC patients.	('tumor', 'Disease', (85, 90))	('high', 'Var', (13, 17))	('lymph-node metastasis', 'CPA', (123, 144))	('GSEC', 'Chemical', '-', (39, 43))	('GSEC', 'Protein', (39, 43))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('associated', 'Reg', (60, 70))
64733	33907418	The results of CCK-8 assay and EdU staining assay both showed that sh-GSEC significantly inhibited cell proliferation compared with sh-NC in two cell lines (p < 0.01, Figure 2B and C).	('sh-GSEC', 'Var', (67, 74))	('cell proliferation', 'CPA', (99, 117))	('EdU', 'Chemical', '-', (31, 34))	('CCK-8', 'Chemical', 'MESH:D012844', (15, 20))	('sh-GSEC', 'Chemical', '-', (67, 74))	('inhibited', 'NegReg', (89, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))
64735	33907418	The effects of GSEC on epithelial-mesenchymal transition (EMT) related genes were also explored, and it showed that knockdown of GSEC markedly upregulated the expression of E-cadherin, while downregulated the expression of N-cadherin and Vimentin in both BT-549 and MDA-MB-231 cells (p < 0.01, Figure 2F).	('E-cadherin', 'Gene', (173, 183))	('E-cadherin', 'Gene', '999', (173, 183))	('expression', 'MPA', (209, 219))	('Vimentin', 'Gene', (238, 246))	('knockdown', 'Var', (116, 125))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (266, 276))	('Vimentin', 'cellular_component', 'GO:0045099', ('238', '246'))	('GSEC', 'Chemical', '-', (129, 133))	('BT-549', 'CellLine', 'CVCL:1092', (255, 261))	('expression', 'MPA', (159, 169))	('downregulated', 'NegReg', (191, 204))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('23', '56'))	('cadherin', 'molecular_function', 'GO:0008014', ('225', '233'))	('N-cadherin', 'Gene', (223, 233))	('cadherin', 'molecular_function', 'GO:0008014', ('175', '183'))	('EMT', 'biological_process', 'GO:0001837', ('58', '61'))	('N-cadherin', 'Gene', '1000', (223, 233))	('Vimentin', 'cellular_component', 'GO:0045098', ('238', '246'))	('GSEC', 'Chemical', '-', (15, 19))	('upregulated', 'PosReg', (143, 154))	('GSEC', 'Gene', (129, 133))	('Vimentin', 'Gene', '7431', (238, 246))
64736	33907418	These results demonstrated that knockdown of GSEC could effectively inhibit cell proliferation, invasion and migration while promoted EMT process in TNBC.	('EMT process', 'CPA', (134, 145))	('EMT', 'biological_process', 'GO:0001837', ('134', '137'))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('knockdown', 'Var', (32, 41))	('inhibit', 'NegReg', (68, 75))	('cell proliferation', 'CPA', (76, 94))	('TNBC', 'Disease', (149, 153))	('invasion', 'CPA', (96, 104))	('migration', 'CPA', (109, 118))	('GSEC', 'Chemical', '-', (45, 49))	('promoted', 'PosReg', (125, 133))	('GSEC', 'Gene', (45, 49))
64741	33907418	In both BT-549 and MDA-MB-231 cells, sh-GSEC significantly increased the expression levels of miR-202-5p compared with sh-NC (p < 0.01), and overexpression of GSEC obviously reduced the expression levels of miR-202-5p compared with pc-NC (p < 0.01, Figure 3E).	('miR-202-5p', 'MPA', (94, 104))	('miR-202-5p', 'Chemical', '-', (94, 104))	('GSEC', 'Chemical', '-', (159, 163))	('sh-GSEC', 'Var', (37, 44))	('GSEC', 'Chemical', '-', (40, 44))	('expression levels', 'MPA', (73, 90))	('miR-202-5p', 'Chemical', '-', (207, 217))	('expression levels', 'MPA', (186, 203))	('sh-GSEC', 'Chemical', '-', (37, 44))	('BT-549', 'CellLine', 'CVCL:1092', (8, 14))	('reduced', 'NegReg', (174, 181))	('increased', 'PosReg', (59, 68))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (19, 29))
64742	33907418	Next, we found that the expression of miR-202-5p was significantly downregulated in TNBC tissues compared with that in adjacent normal tissues (n = 45, p < 0.01, Figure 3F).	('miR-202-5p', 'Var', (38, 48))	('expression', 'MPA', (24, 34))	('TNBC', 'Disease', (84, 88))	('miR-202-5p', 'Chemical', '-', (38, 48))	('downregulated', 'NegReg', (67, 80))
64743	33907418	Meanwhile, low expression levels of miR-202-5p was related to advanced tumor stage (p < 0.01, Figure 3G) and positive lymph-node metastasis (p < 0.01, Figure 3H) in TNBC patients.	('patients', 'Species', '9606', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('low', 'NegReg', (11, 14))	('positive lymph-node metastasis', 'CPA', (109, 139))	('expression levels', 'MPA', (15, 32))	('miR-202-5p', 'Chemical', '-', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('miR-202-5p', 'Var', (36, 46))	('tumor', 'Disease', (71, 76))	('TNBC', 'Disease', (165, 169))
64748	33907418	The results of CCK-8 assay and EdU staining assay showed that compared with sh-NC group, sh-GSEC significantly inhibited cell proliferation (p < 0.05), and miR-202-5p inhibitor markedly enhanced cell proliferation (p < 0.05), while co-transfection of sh-GSEC with miR-202-5p inhibitor obviously eliminated the inhibitory effect of sh-GSEC on cell proliferation (p < 0.05, Figure 4A and B).	('EdU', 'Chemical', '-', (31, 34))	('cell proliferation', 'CPA', (195, 213))	('CCK-8', 'Chemical', 'MESH:D012844', (15, 20))	('sh-GSEC', 'Chemical', '-', (331, 338))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('miR-202-5p', 'Chemical', '-', (156, 166))	('sh-GSEC', 'Chemical', '-', (89, 96))	('cell proliferation', 'CPA', (121, 139))	('miR-202-5p', 'Chemical', '-', (264, 274))	('miR-202-5p', 'Var', (156, 166))	('cell proliferation', 'biological_process', 'GO:0008283', ('342', '360'))	('enhanced', 'PosReg', (186, 194))	('sh-GSEC', 'Chemical', '-', (251, 258))	('inhibited', 'NegReg', (111, 120))	('cell proliferation', 'CPA', (342, 360))
64749	33907418	Transwell assay showed that sh-GSEC significantly inhibited cell invasion and migration ability compared with sh-NC group (p < 0.05), and miR-202-5p inhibitor significantly enhanced cell invasion and migration ability compared with sh-NC group (p < 0.05), while co-transfection of sh-GSEC with miR-202-5p inhibitor obviously eliminated the inhibitory effect of sh-GSEC on cell invasion and migration (p < 0.05, Figure 4C and D).	('miR-202-5p', 'Chemical', '-', (138, 148))	('sh-GSEC', 'Chemical', '-', (361, 368))	('miR-202-5p', 'Var', (138, 148))	('cell invasion', 'CPA', (182, 195))	('cell invasion', 'CPA', (372, 385))	('cell invasion', 'CPA', (60, 73))	('sh-GSEC', 'Chemical', '-', (281, 288))	('miR-202-5p', 'Chemical', '-', (294, 304))	('enhanced', 'PosReg', (173, 181))	('sh-GSEC', 'Chemical', '-', (28, 35))	('migration ability', 'CPA', (200, 217))	('inhibited', 'NegReg', (50, 59))
64750	33907418	In addition, compared with sh-NC group, sh-GSEC significantly upregulated E-cadherin, while downregulated N-cadherin and Vimentin; and miR-202-5p inhibitor downregulated E-cadherin, while upregulated N-cadherin and Vimentin; meanwhile, the effects of sh-GSEC on the expression of these EMT-related proteins were obviously reversed by co-transfection of sh-GSEC with miR-202-5p inhibitor (p < 0.01, Figure 4E).	('upregulated', 'PosReg', (188, 199))	('miR-202-5p', 'Var', (135, 145))	('Vimentin', 'Gene', (121, 129))	('Vimentin', 'cellular_component', 'GO:0045099', ('215', '223'))	('sh-GSEC', 'Chemical', '-', (40, 47))	('EMT', 'biological_process', 'GO:0001837', ('286', '289'))	('Vimentin', 'Gene', (215, 223))	('Vimentin', 'cellular_component', 'GO:0045099', ('121', '129'))	('cadherin', 'molecular_function', 'GO:0008014', ('108', '116'))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('sh-GSEC', 'Chemical', '-', (251, 258))	('N-cadherin', 'Gene', (200, 210))	('Vimentin', 'cellular_component', 'GO:0045098', ('215', '223'))	('N-cadherin', 'Gene', '1000', (200, 210))	('Vimentin', 'cellular_component', 'GO:0045098', ('121', '129'))	('E-cadherin', 'Gene', (170, 180))	('E-cadherin', 'Gene', '999', (170, 180))	('E-cadherin', 'Gene', (74, 84))	('N-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (74, 84))	('sh-GSEC', 'Chemical', '-', (353, 360))	('N-cadherin', 'Gene', '1000', (106, 116))	('miR-202-5p', 'Chemical', '-', (366, 376))	('downregulated', 'NegReg', (156, 169))	('downregulated', 'NegReg', (92, 105))	('miR-202-5p', 'Chemical', '-', (135, 145))	('cadherin', 'molecular_function', 'GO:0008014', ('202', '210'))	('Vimentin', 'Gene', '7431', (121, 129))	('upregulated', 'PosReg', (62, 73))	('Vimentin', 'Gene', '7431', (215, 223))	('cadherin', 'molecular_function', 'GO:0008014', ('172', '180'))
64751	33907418	These results demonstrated that inhibition of miR-202-5p could effectively attenuate knockdown of GSEC induced inhibition of TNBC progression in vitro.	('attenuate', 'NegReg', (75, 84))	('TNBC', 'Disease', (125, 129))	('miR-202-5p', 'Chemical', '-', (46, 56))	('knockdown', 'Var', (85, 94))	('GSEC', 'Chemical', '-', (98, 102))	('GSEC', 'Gene', (98, 102))	('inhibition', 'NegReg', (111, 121))
64752	33907418	Then, Starbase v2.0 was also used to predict the potential targets of miR-202-5p and it showed that there was a putative binding site between miR-202-5p and AXL (Figure 5A).	('miR-202-5p', 'Chemical', '-', (70, 80))	('AXL', 'Gene', '558', (157, 160))	('miR-202-5p', 'Chemical', '-', (142, 152))	('miR-202-5p', 'Var', (142, 152))	('binding', 'Interaction', (121, 128))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('AXL', 'Gene', (157, 160))
64755	33907418	In addition, overexpression of GSEC significantly increased the expression levels of AXL compared with the negative control (pc-NC) in two cell lines (p < 0.01), and sh-GSEC significantly decreased the expression levels of AXL compared with sh-NC in two cells (p < 0.01, Figure 5D).	('AXL', 'Gene', (223, 226))	('decreased', 'NegReg', (188, 197))	('GSEC', 'Chemical', '-', (31, 35))	('sh-GSEC', 'Chemical', '-', (166, 173))	('AXL', 'Gene', '558', (85, 88))	('expression levels', 'MPA', (202, 219))	('GSEC', 'Chemical', '-', (169, 173))	('increased', 'PosReg', (50, 59))	('overexpression', 'PosReg', (13, 27))	('AXL', 'Gene', '558', (223, 226))	('expression levels', 'MPA', (64, 81))	('AXL', 'Gene', (85, 88))	('sh-GSEC', 'Var', (166, 173))
64757	33907418	Pearson's correlation analysis showed that the expression levels of miR-202-5p was negatively correlated to the expression levels AXL in TNBC tissues (n = 45, p < 0.01, r = -0.741, Figure 5F).	('negatively', 'NegReg', (83, 93))	('expression levels', 'MPA', (112, 129))	('AXL', 'Gene', '558', (130, 133))	('miR-202-5p', 'Chemical', '-', (68, 78))	('AXL', 'Gene', (130, 133))	('miR-202-5p', 'Var', (68, 78))	('expression', 'MPA', (47, 57))
64758	33907418	These results indicated that AXL was a target of miR-202-5p in TNBC.	('miR-202-5p', 'Chemical', '-', (49, 59))	('AXL', 'Gene', '558', (29, 32))	('miR-202-5p', 'Var', (49, 59))	('TNBC', 'Gene', (63, 67))	('AXL', 'Gene', (29, 32))
64763	33907418	These data demonstrated that overexpression of AXL could effectively attenuate miR-202-5p mimics-induced inhibition on TNBC progression in vitro.	('miR-202-5p', 'Var', (79, 89))	('attenuate', 'NegReg', (69, 78))	('AXL', 'Gene', '558', (47, 50))	('inhibition', 'NegReg', (105, 115))	('TNBC', 'Disease', (119, 123))	('AXL', 'Gene', (47, 50))	('miR-202-5p', 'Chemical', '-', (79, 89))
64767	33907418	Moreover, Ki-67 IHC staining in tumor tissues showed that sh-GSEC reduced cell proliferation, miR-202-5p inhibitor exacerbated cell proliferation, while co-transfection of sh-GSEC with miR-202-5p inhibitor effectively reversed the inhibitory effect of sh-GSEC on cell proliferation in vivo (Figure 7D).	('reduced', 'NegReg', (66, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('cell proliferation', 'CPA', (74, 92))	('miR-202-5p', 'Chemical', '-', (94, 104))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('miR-202-5p', 'Var', (94, 104))	('cell proliferation', 'CPA', (127, 145))	('exacerbated', 'PosReg', (115, 126))	('sh-GSEC', 'Chemical', '-', (172, 179))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('sh-GSEC', 'Chemical', '-', (252, 259))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('sh-GSEC', 'Chemical', '-', (58, 65))	('cell proliferation', 'biological_process', 'GO:0008283', ('263', '281'))	('tumor', 'Disease', (32, 37))	('miR-202-5p', 'Chemical', '-', (185, 195))
64773	33907418	GSEC promoted TNBC development partially through miR-202-5p mediated upregulation of AXL.	('upregulation', 'PosReg', (69, 81))	('promoted', 'PosReg', (5, 13))	('miR-202-5p', 'Chemical', '-', (49, 59))	('TNBC development', 'CPA', (14, 30))	('AXL', 'Gene', '558', (85, 88))	('miR-202-5p', 'Var', (49, 59))	('AXL', 'Gene', (85, 88))	('GSEC', 'Chemical', '-', (0, 4))
64776	33907418	For example, the expression of GSEC is significantly upregulated in osteosarcoma cell lines, and overexpression of GSEC enhances the proliferating and migratory ability, while reduces the apoptotic rate of osteosarcoma cells in vitro.	('GSEC', 'Chemical', '-', (31, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (206, 218))	('osteosarcoma', 'Disease', 'MESH:D012516', (68, 80))	('osteosarcoma', 'Disease', (206, 218))	('GSEC', 'Chemical', '-', (115, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (206, 218))	('expression', 'MPA', (17, 27))	('GSEC', 'Gene', (31, 35))	('GSEC', 'Gene', (115, 119))	('reduces', 'NegReg', (176, 183))	('enhances', 'PosReg', (120, 128))	('overexpression', 'Var', (97, 111))	('osteosarcoma', 'Phenotype', 'HP:0002669', (68, 80))	('upregulated', 'PosReg', (53, 64))	('osteosarcoma', 'Disease', (68, 80))	('apoptotic rate', 'CPA', (188, 202))
64777	33907418	GSEC is also upregulated in colorectal cancer, and knockdown of GSEC reduces the motility of colon cancer cells by targeting DEAH box polypeptide 36 (DHX36) RNA helicase.	('upregulated', 'PosReg', (13, 24))	('GSEC', 'Gene', (64, 68))	('targeting', 'Reg', (115, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('RNA', 'cellular_component', 'GO:0005562', ('157', '160'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('knockdown', 'Var', (51, 60))	('DHX36', 'Gene', (150, 155))	('DEAH box polypeptide 36', 'Gene', (125, 148))	('GSEC', 'Chemical', '-', (64, 68))	('DEAH box polypeptide 36', 'Gene', '170506', (125, 148))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('GSEC', 'Chemical', '-', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('DHX36', 'Gene', '170506', (150, 155))	('motility of colon cancer', 'Disease', (81, 105))	('colorectal cancer', 'Disease', (28, 45))	('motility of colon cancer', 'Disease', 'MESH:D015179', (81, 105))	('reduces', 'NegReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
64781	33907418	Moreover, knockdown of GSEC effectively inhibited cell proliferation, invasion and migration of TNBC cell lines.	('migration of', 'CPA', (83, 95))	('inhibited', 'NegReg', (40, 49))	('GSEC', 'Chemical', '-', (23, 27))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('GSEC', 'Gene', (23, 27))	('knockdown', 'Var', (10, 19))	('invasion', 'CPA', (70, 78))	('cell proliferation', 'CPA', (50, 68))
64782	33907418	In addition, knockdown of GSEC downregulated N-cadherin and Vimentin, and upregulated E-cadherin involved in EMT process in TNBC cell lines.	('Vimentin', 'cellular_component', 'GO:0045099', ('60', '68'))	('upregulated', 'PosReg', (74, 85))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('Vimentin', 'Gene', '7431', (60, 68))	('N-cadherin', 'Gene', (45, 55))	('Vimentin', 'Gene', (60, 68))	('GSEC', 'Chemical', '-', (26, 30))	('E-cadherin', 'Gene', '999', (86, 96))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('downregulated', 'NegReg', (31, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('Vimentin', 'cellular_component', 'GO:0045098', ('60', '68'))	('GSEC', 'Gene', (26, 30))	('E-cadherin', 'Gene', (86, 96))	('knockdown', 'Var', (13, 22))	('N-cadherin', 'Gene', '1000', (45, 55))
64788	33907418	MiR-202-5p is often downregulated and has been identified to act as a tumor suppressor in different types of human cancer such as osteosarcoma, colorectal carcinoma, thyroid carcinoma and ovarian cancer.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (144, 164))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (166, 183))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('MiR-202-5p', 'Chemical', '-', (0, 10))	('MiR-202-5p', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('osteosarcoma', 'Disease', (130, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('downregulated', 'NegReg', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal carcinoma', 'Disease', (144, 164))	('thyroid carcinoma and ovarian cancer', 'Disease', 'MESH:D010051', (166, 202))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
64789	33907418	Recent studies revealed that low expression levels of miR-202-5p reduces doxorubicin resistance and proliferation, while induces the apoptosis of TNBC cells in vitro.	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('apoptosis', 'CPA', (133, 142))	('reduces', 'NegReg', (65, 72))	('proliferation', 'CPA', (100, 113))	('miR-202-5p', 'Var', (54, 64))	('induces', 'Reg', (121, 128))	('miR-202-5p', 'Chemical', '-', (54, 64))	('doxorubicin', 'Chemical', 'MESH:D004317', (73, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('doxorubicin resistance', 'MPA', (73, 95))
64790	33907418	In this study, luciferase reporter assay and RIP assay confirmed the interaction between GSEC and miR-202-5p.	('GSEC', 'Gene', (89, 93))	('interaction', 'Interaction', (69, 80))	('miR-202-5p', 'Chemical', '-', (98, 108))	('miR-202-5p', 'Var', (98, 108))	('GSEC', 'Chemical', '-', (89, 93))
64791	33907418	Meanwhile, we found that miR-202-5p was downregulated in TNBC tissues and cell lines.	('downregulated', 'NegReg', (40, 53))	('miR-202-5p', 'Var', (25, 35))	('TNBC', 'Disease', (57, 61))	('miR-202-5p', 'Chemical', '-', (25, 35))
64792	33907418	Overexpression of miR-202-5p exhibited a similar inhibitory effect as knockdown of GSEC on TNBC progression in vitro, while downregulation of miR-202-5p obviously enhanced the aggressive phenotypes including proliferation, invasion, migration and EMT process.	('miR-202-5p', 'Chemical', '-', (18, 28))	('EMT process', 'CPA', (247, 258))	('miR-202-5p', 'Chemical', '-', (142, 152))	('miR-202-5p', 'Var', (142, 152))	('EMT', 'biological_process', 'GO:0001837', ('247', '250'))	('enhanced', 'PosReg', (163, 171))	('invasion', 'CPA', (223, 231))	('downregulation', 'NegReg', (124, 138))	('migration', 'CPA', (233, 242))	('GSEC', 'Chemical', '-', (83, 87))
64793	33907418	Moreover, downregulation of miR-202-5p attenuated the protective effects of GSEC knockdown on TNBC development both in vitro and in vivo.	('GSEC', 'Chemical', '-', (76, 80))	('protective effects', 'CPA', (54, 72))	('GSEC', 'Gene', (76, 80))	('knockdown', 'Var', (81, 90))	('attenuated', 'NegReg', (39, 49))	('downregulation', 'NegReg', (10, 24))	('TNBC', 'Gene', (94, 98))	('miR-202-5p', 'Chemical', '-', (28, 38))	('miR-202-5p', 'Var', (28, 38))
64794	33907418	Our study revealed a tumor suppressive role of miR-202-5p and mediated the function of miR-202-5p in TNBC development.	('miR-202-5p', 'Chemical', '-', (87, 97))	('TNBC', 'Disease', (101, 105))	('tumor', 'Disease', (21, 26))	('miR-202-5p', 'Var', (87, 97))	('miR-202-5p', 'Chemical', '-', (47, 57))	('miR-202-5p', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
64800	33907418	MiR-25-3p promotes cell proliferation of TNBC cells through directly targeting BTG2.	('cell proliferation', 'biological_process', 'GO:0008283', ('19', '37'))	('promotes', 'PosReg', (10, 18))	('targeting', 'Reg', (69, 78))	('MiR-25-3p', 'Var', (0, 9))	('MiR-25-3p', 'Chemical', '-', (0, 9))	('BTG2', 'Gene', (79, 83))	('cell proliferation', 'CPA', (19, 37))	('BTG2', 'Gene', '7832', (79, 83))
64801	33907418	In this study, we identified AXL receptor tyrosine kinase as the target of miR-202-5p.	('AXL receptor tyrosine kinase', 'Gene', '558', (29, 57))	('miR-202-5p', 'Chemical', '-', (75, 85))	('AXL receptor tyrosine kinase', 'Gene', (29, 57))	('miR-202-5p', 'Var', (75, 85))
64894	33800560	When DWI and T2WI had supporting results, the sensitivity [95.8% (203/212)] of lung cancers by both DWI and T2WI was significantly higher than that [30.3% (10/33)] of lung cancers which were judged as benign by both DWI and T2WI (p < 0.001).	('lung cancers', 'Disease', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('T2WI', 'Var', (108, 112))	('DWI', 'Var', (100, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('lung cancers', 'Disease', 'MESH:D008175', (167, 179))	('lung cancers', 'Phenotype', 'HP:0100526', (167, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))	('lung cancers', 'Disease', (167, 179))	('higher', 'PosReg', (131, 137))
64924	33800560	Diagnostic possibilities would be increased after fused T2WI and DWI for lung cancers and BPNMs.	('Diagnostic possibilities', 'CPA', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('DWI', 'Var', (65, 68))	('lung cancers', 'Disease', (73, 85))	('BPNMs', 'Disease', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('T2WI', 'Var', (56, 60))	('lung cancers', 'Disease', 'MESH:D008175', (73, 85))	('fused T2WI', 'Var', (50, 60))	('increased', 'PosReg', (34, 43))	('lung cancers', 'Phenotype', 'HP:0100526', (73, 85))	('BPNM', 'Chemical', '-', (90, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))
64927	33800560	Furthermore, combining T2WI, DWI and ADC values provides increased accuracy for differentiation between benign and malignant lesions, compared with DCE (dynamic contrast-enhanced)-MRI.	('ADC', 'Chemical', '-', (37, 40))	('ADC values', 'Var', (37, 47))	('DCE', 'Chemical', '-', (148, 151))	('increased', 'PosReg', (57, 66))	('T2WI', 'Var', (23, 27))	('DWI', 'Var', (29, 32))
64966	33842408	Dr. Liby's talk "Targeting the Immune System for the Prevention of KRAS-Driven Cancers", described the role of combinations of rexinoids, selective agonists for retinoid X receptors, and the synthetic oleanane triterpenoid bardoxolone methyl, an activator of the cytoprotective Nuclear factor E2-related factor 2 (Nrf2) pathway, as attractive drugs for preventing lung and pancreatic cancer because they are active in preclinical models of lung and pancreatic cancer driven by Kras mutations.	('driven by', 'Reg', (467, 476))	('Cancers', 'Disease', (79, 86))	('Cancers', 'Phenotype', 'HP:0002664', (79, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (449, 466))	('Kras', 'Gene', '3845', (477, 481))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (373, 390))	('pancreatic cancer', 'Disease', (449, 466))	('rexinoids', 'Chemical', '-', (127, 136))	('Kras', 'Gene', (477, 481))	('lung', 'Disease', (364, 368))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('mutations', 'Var', (482, 491))	('bardoxolone', 'Chemical', 'MESH:C116817', (223, 234))	('Nuclear factor E2-related factor 2', 'Gene', (278, 312))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancers', 'Disease', 'MESH:D009369', (79, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (373, 390))	('Nuclear factor E2-related factor 2', 'Gene', '4780', (278, 312))	('lung', 'Disease', (440, 444))	('triterpenoid', 'Chemical', 'MESH:D014315', (210, 222))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (449, 466))	('oleanane', 'Chemical', 'MESH:C413246', (201, 209))	('P', 'Chemical', 'MESH:D010758', (53, 54))	('pancreatic cancer', 'Disease', (373, 390))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
64969	33842408	Surprisingly, they found a higher tumor burden and a novel immune signature in the lungs and tumors of Nrf2 knockout (KO) mice compared to wildtype mice with lung cancer.	('lung cancer', 'Disease', (158, 169))	('mice', 'Species', '10090', (148, 152))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mice', 'Species', '10090', (122, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('immune signature', 'MPA', (59, 75))	('higher', 'PosReg', (27, 33))	('Nrf2', 'Gene', (103, 107))	('tumors', 'Disease', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('knockout', 'Var', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
64988	33842408	Thus, interventions with broccoli sprout-based preparations enhance the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.	('rat', 'Species', '10116', (52, 55))	('attenuate', 'NegReg', (147, 156))	('interventions', 'Var', (6, 19))	('enhance', 'PosReg', (60, 67))	('detoxication of some airborne pollutants', 'MPA', (72, 112))
64996	33842408	CS3D also reduced both incidence and size of lung tumors that arose over time, and induced apoptosis in the airways, while showing no discernable toxicity.	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('lung tumors', 'Disease', 'MESH:D008175', (45, 56))	('reduced', 'NegReg', (10, 17))	('apoptosis', 'CPA', (91, 100))	('lung tumor', 'Phenotype', 'HP:0100526', (45, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('CS3D', 'Var', (0, 4))	('toxicity', 'Disease', (146, 154))	('lung tumors', 'Phenotype', 'HP:0100526', (45, 56))	('lung tumors', 'Disease', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('induced', 'Reg', (83, 90))
64998	33842408	Phospho-STAT3 protein was reduced both during and after treatment with CS3D, remaining suppressed 8 weeks after the end of the treatment course.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('CS3D', 'Var', (71, 75))	('men', 'Species', '9606', (61, 64))	('men', 'Species', '9606', (132, 135))	('Phospho-STAT3 protein', 'MPA', (0, 21))	('reduced', 'NegReg', (26, 33))	('suppressed', 'NegReg', (87, 97))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))
64999	33842408	Other pathways downregulated by CS3D were NF-kappaB, COX-2, IL-6, and VEGF.	('CS3D', 'Var', (32, 36))	('VEGF', 'Gene', (70, 74))	('downregulated', 'NegReg', (15, 28))	('COX-2', 'Gene', '4513', (53, 58))	('IL-6', 'Gene', (60, 64))	('COX-2', 'Gene', (53, 58))	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('IL-6', 'Gene', '3569', (60, 64))	('VEGF', 'Gene', '7422', (70, 74))	('NF-kappaB', 'Protein', (42, 51))
65000	33842408	CS3D also produced a less immunosuppressive microenvironment in the lungs, with fewer M2 macrophages and MDSC cells.	('CS3D', 'Var', (0, 4))	('men', 'Species', '9606', (56, 59))	('fewer', 'NegReg', (80, 85))
65002	33842408	These results suggest that blocking STAT3 may be a useful strategy for lung cancer prevention and may involve both inhibition of oncogenic signaling and enhanced anti-tumor immunity.	('inhibition', 'NegReg', (115, 125))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('lung cancer', 'Disease', (71, 82))	('blocking', 'Var', (27, 35))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('STAT3', 'Gene', (36, 41))	('oncogenic', 'CPA', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('enhanced', 'PosReg', (153, 161))	('tumor', 'Disease', (167, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
65015	33842408	Importantly, the immunoprevention was a bona fide feature of SA-4-1BBL as agonistic Abs to CD137 receptor had no impact on the tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('Abs', 'Var', (84, 87))	('CD137', 'Gene', (91, 96))	('CD137', 'Gene', '3604', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('SA-4-1BBL', 'Chemical', '-', (61, 70))
65016	33842408	The cancer immunoprevention effect of SA-4-1BBL operated through an innate immune surveillance mechanism that evolved within three weeks of treatment, lasted for months, and did not involve CD8+ T cells.	('CD8', 'Gene', '925', (190, 193))	('SA-4-1BBL', 'Chemical', '-', (38, 47))	('men', 'Species', '9606', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('SA-4-1BBL', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('CD8', 'Gene', (190, 193))	('rat', 'Species', '10116', (51, 54))
65069	33842408	Dr. Lipkin's talk "Frameshift neoantigen vaccination prevent Lynch syndrome mouse model intestinal cancer", focused on microsatellite-unstable (MSI) cancers occurring in the context of Lynch syndrome.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('Frameshift', 'Var', (19, 29))	('intestinal cancer', 'Disease', 'MESH:D007414', (88, 105))	('mouse', 'Species', '10090', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Lynch syndrome', 'Disease', (61, 75))	('intestinal cancer', 'Disease', (88, 105))	('Lynch syndrome', 'Disease', 'MESH:D003123', (185, 199))	('Lynch syndrome', 'Disease', (185, 199))	('Lynch syndrome', 'Disease', 'MESH:D003123', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
65070	33842408	These tumors elicit pronounced tumor-specific immune responses directed against frameshift peptide (FSP) neoantigens, which result from mismatch repair (MMR) deficiency-induced insertion/deletion mutations in coding microsatellites (cMS).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('P', 'Chemical', 'MESH:D010758', (102, 103))	('elicit', 'Reg', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', (31, 36))	('tumors', 'Disease', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('insertion/deletion mutations', 'Var', (177, 205))	('mismatch repair', 'biological_process', 'GO:0006298', ('136', '151'))	('MMR', 'biological_process', 'GO:0006298', ('153', '156'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (6, 11))
65074	33842408	Subsequently, intestinal tumors obtained from Lynch syndrome mice (Msh2flox/flox VpC+/+) were evaluated for mutations affecting these candidate microsatellites.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (61, 65))	('mutations', 'Var', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('Lynch syndrome', 'Disease', (46, 60))	('intestinal tumors', 'Disease', (14, 31))	('Lynch syndrome', 'Disease', 'MESH:D003123', (46, 60))	('intestinal tumors', 'Disease', 'MESH:D007414', (14, 31))
65077	33842408	Four FSP neoantigens derived from cMS mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses.	('Senp6', 'Gene', '26054', (84, 89))	('Nacad', 'Gene', (61, 66))	('Senp6', 'Gene', (84, 89))	('Maz', 'Gene', '4150', (68, 71))	('Xirp1', 'Gene', (73, 78))	('mutations', 'Var', (38, 47))	('Maz', 'Gene', (68, 71))	('elicited', 'Reg', (90, 98))	('P', 'Chemical', 'MESH:D010758', (7, 8))	('Xirp1', 'Gene', '165904', (73, 78))	('antigen-specific cellular immune responses', 'CPA', (106, 148))	('Nacad', 'Gene', '23148', (61, 66))
65080	33842408	Additionally, NSAIDs, which have chemopreventive efficacy for Lynch syndrome, increase T cell immunity against neoantigens, thus supporting the further development of vaccination strategies for preventing cancers associated with Lynch syndrome.	('Lynch syndrome', 'Disease', (62, 76))	('NSAIDs', 'Var', (14, 20))	('men', 'Species', '9606', (159, 162))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('increase T', 'Disease', 'MESH:D006973', (78, 88))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('increase T cell', 'Phenotype', 'HP:0100828', (78, 93))	('Lynch syndrome', 'Disease', (229, 243))	('rat', 'Species', '10116', (181, 184))	('Lynch syndrome', 'Disease', 'MESH:D003123', (229, 243))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('increase T', 'Disease', (78, 88))
65097	33842408	Fusion with calreticulin (CRT) profoundly enhances the potency of DNA vaccines in generating HPV antigen-specific CD8+ T cell mediated immune responses even in CD4-depleted animals.	('Fusion', 'Var', (0, 6))	('calreticulin', 'Gene', '811', (12, 24))	('enhances', 'PosReg', (42, 50))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('CD8', 'Gene', '925', (114, 117))	('potency', 'MPA', (55, 62))	('CD8', 'Gene', (114, 117))	('calreticulin', 'Gene', (12, 24))	('P', 'Chemical', 'MESH:D010758', (94, 95))	('CRT', 'Gene', (26, 29))	('rat', 'Species', '10116', (86, 89))
65098	33842408	In addition, vaccination with the CRTE6E7L2 DNA vaccine induces both L2-specific neutralizing antibodies and protection from experimental vaginal challenge.	('men', 'Species', '9606', (131, 134))	('L2-specific', 'Protein', (69, 80))	('induces', 'PosReg', (56, 63))	('CRTE6E7L2', 'Var', (34, 43))	('protection', 'CPA', (109, 119))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))
65101	33842408	His group has previously shown that electroporation is a much more effective DNA vaccine administration method to generate HPV-specific CD8+ T cell immune responses as compared to conventional intramuscular injection or epidermal delivery via gene gun.	('rat', 'Species', '10116', (97, 100))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('rat', 'Species', '10116', (118, 121))	('CD8', 'Gene', (136, 139))	('electroporation', 'Var', (36, 51))	('CD8', 'Gene', '925', (136, 139))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('rat', 'Species', '10116', (45, 48))
65105	33842408	KRAS mutations can occur in up to one third of lung adenocarcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (47, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (19, 24))	('lung adenocarcinomas', 'Disease', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('KRAS', 'Gene', (0, 4))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (47, 67))
65106	33842408	Through a collaborative effort, his group is examining whether vaccines can be used to target mutant KRAS by mobilizing the immune system.	('KRAS', 'Gene', (101, 105))	('mutant', 'Var', (94, 100))	('rat', 'Species', '10116', (17, 20))
65110	33842408	Using an inducible KRAS mouse model, they demonstrated that the multi-peptide vaccine was able to significantly reduce tumor burden when administered prior to induction of mutant KRAS expression.	('mutant', 'Var', (172, 178))	('tumor', 'Disease', (119, 124))	('mouse', 'Species', '10090', (24, 29))	('reduce', 'NegReg', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('KRAS', 'Gene', (179, 183))	('rat', 'Species', '10116', (49, 52))
65148	33842408	With respect to immunomodulatory agents, NSAIDs inhibit COX-2 and the downstream production of pro-tumorigenic prostaglandins that promote local inflammation.	('tumor', 'Disease', (99, 104))	('inflammation', 'Disease', 'MESH:D007249', (145, 157))	('inflammation', 'Disease', (145, 157))	('prostaglandins', 'Chemical', 'MESH:D011453', (111, 125))	('COX-2', 'Gene', (56, 61))	('inhibit', 'NegReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inflammation', 'biological_process', 'GO:0006954', ('145', '157'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NSAIDs', 'Var', (41, 47))	('COX-2', 'Gene', '4513', (56, 61))	('promote', 'PosReg', (131, 138))
65165	33842408	Surprisingly, aspirin was associated with increased all-cause mortality that was driven primarily by cancer deaths that was not accompanied by an increase in cancer incidence over 4.7 years.	('increased', 'PosReg', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('mortality', 'Disease', 'MESH:D003643', (62, 71))	('aspirin', 'Var', (14, 21))	('cancer', 'Disease', (158, 164))	('aspirin', 'Chemical', 'MESH:D001241', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mortality', 'Disease', (62, 71))	('cancer deaths', 'Disease', 'MESH:D009369', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer deaths', 'Disease', (101, 114))
65172	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))
65175	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))	('KRAS', 'Gene', '3845', (81, 85))	('mutations', 'Var', (86, 95))	('men', 'Species', '9606', (374, 377))	('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', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', '1956', (57, 61))	('MET', 'Gene', (105, 108))
65176	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', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (4, 8))
65177	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', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (4, 8))
65178	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))
65185	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))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('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))
65188	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))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('RET', 'Gene', '5979', (95, 98))	('MET', 'Gene', '79811', (84, 87))	('NTRK', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
65205	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%).	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('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))
65207	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).	('RET', 'Gene', '5979', (240, 243))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('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))
65209	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', 'molecular_function', 'GO:0005006', ('94', '98'))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('L858R', 'Var', (8, 13))
65210	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))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('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))	('L861Q', 'Mutation', 'rs121913444', (111, 116))	('V834L', 'Var', (181, 186))	('E709X', 'Var', (155, 160))	('EGFR', 'Gene', '1956', (6, 10))
65211	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', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (34, 42))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
65212	33300283	The most common complex mutation was T790M with another mutation (n = 172, 4.5% of EGFR mutations).	('EGFR', 'Gene', '1956', (83, 87))	('T790M', 'Mutation', 'rs121434569', (37, 42))	('T790M', 'Var', (37, 42))	('EGFR', 'Gene', (83, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))
65213	33300283	Table 3 identifies the 10 complex EGFR mutation types found with the highest frequency.	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'Gene', '1956', (34, 38))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))
65214	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))
65215	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).	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('ligand', 'molecular_function', 'GO:0005488', ('35', '41'))	('ligand', 'molecular_function', 'GO:0005488', ('99', '105'))	('mutations', 'Var', (5, 14))	('HER2', 'Gene', (0, 4))	('transmembrane', 'cellular_component', 'GO:0044214', ('172', '185'))	('transmembrane', 'cellular_component', 'GO:0016021', ('172', '185'))	('HER2', 'Gene', '2064', (0, 4))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))
65217	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))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (102, 114))	('G776delinsVV', 'Mutation', 'c.776delinsG,VV', (154, 166))	('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))
65218	33300283	S310F mutations in the HER2 extracellular region were identified in 13 patients.	('extracellular region', 'cellular_component', 'GO:0005576', ('28', '48'))	('HER2', 'Gene', (23, 27))	('S310F', 'Var', (0, 5))	('patients', 'Species', '9606', (71, 79))	('HER2', 'Gene', '2064', (23, 27))	('S310F', 'Mutation', 'rs1057519816', (0, 5))
65220	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))	('RET', 'Gene', (71, 74))	('women', 'Species', '9606', (163, 168))	('men', 'Species', '9606', (104, 107))	('BRAF', 'Gene', '673', (56, 60))	('mutation', 'Var', (61, 69))	('men', 'Species', '9606', (173, 176))	('ALK', 'Gene', '238', (131, 134))	('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))	('BRAF', 'Gene', (56, 60))
65221	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))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('decrease', 'NegReg', (47, 55))	('EGFR', 'Gene', (18, 22))	('KRAS', 'Gene', (104, 108))
65222	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))
65225	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.	('patients', 'Species', '9606', (12, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))
65226	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))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('men', 'Species', '9606', (101, 104))	('alterations', 'Var', (54, 65))	('HER2', 'Gene', '2064', (49, 53))
65227	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))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('mutation', 'Var', (127, 135))	('KRAS', 'Gene', '3845', (162, 166))	('patients', 'Species', '9606', (58, 66))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
65228	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))
65229	33300283	EGFR mutations include typical and atypical EGFR mutations.	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (49, 58))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
65230	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))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))
65232	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))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
65233	33300283	Patients with atypical EGFR mutations have been reported to have variable efficacy to EGFR TKIs.	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('EGFR', 'Gene', (86, 90))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
65234	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.	('EGFR', 'Gene', (146, 150))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (204, 208))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))	('mutations', 'Var', (70, 79))	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('patients', 'Species', '9606', (159, 167))	('EGFR', 'Gene', (204, 208))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('EGFR', 'Gene', (118, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
65235	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', 'molecular_function', 'GO:0005006', ('225', '229'))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', '1956', (225, 229))	('mutation', 'Var', (230, 238))	('EGFR', 'Gene', (225, 229))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('decrease', 'NegReg', (46, 54))	('EGFR', 'Gene', '1956', (4, 8))
65236	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))
65237	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))
65238	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))
65240	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('elevated', 'PosReg', (102, 110))	('activated', 'PosReg', (47, 56))	('HER2', 'Gene', '2064', (8, 12))	('formation', 'biological_process', 'GO:0009058', ('214', '223'))	('extracellular', 'cellular_component', 'GO:0005576', ('13', '26'))	('covalent dimerization', 'MPA', (150, 171))
65241	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))
65242	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))
65243	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))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (35, 47))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (18, 30))	('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))
65245	33300283	13  Further clinical trials involving variable HER2 mutations are required.	('mutations', 'Var', (52, 61))	('HER2', 'Gene', '2064', (47, 51))	('HER2', 'Gene', (47, 51))
65246	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))
65247	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))
65249	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))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('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))
65251	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))	('MET', 'Gene', (88, 91))	('men', 'Species', '9606', (5, 8))	('MET', 'Gene', '79811', (88, 91))	('skipping', 'NegReg', (100, 108))	('mutations', 'Var', (21, 30))
65252	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))
65253	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))
65256	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))
65258	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))
65260	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))
65261	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))
65262	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))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', '673', (85, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
65267	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))
65270	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', 'molecular_function', 'GO:0005006', ('41', '45'))	('EGFR', 'Gene', '1956', (41, 45))	('mutation', 'Var', (46, 54))	('prevalent', 'Reg', (65, 74))	('patients', 'Species', '9606', (90, 98))
65300	33537342	Many of these mediators that are triggered after lung damage in ARDS are also central in the pathophysiology of PH, where injury to endothelial cells and increased levels of ET-1 and TF also contribute to increased vascular tone and remodeling in PH (Moloney and Evans,; Tamosiuniene et al.,; Antoniak et al.,).	('ARDS', 'Disease', (64, 68))	('lung damage', 'Disease', 'MESH:D008171', (49, 60))	('PH', 'Gene', '5053', (112, 114))	('injury', 'Var', (122, 128))	('vascular tone', 'CPA', (215, 228))	('PH', 'Gene', '5053', (247, 249))	('lung damage', 'Disease', (49, 60))	('increased', 'PosReg', (205, 214))	('ET-1', 'Gene', '1906', (174, 178))	('ARDS', 'Phenotype', 'HP:0011948', (64, 68))	('remodeling', 'CPA', (233, 243))	('ARDS', 'Disease', 'MESH:D012128', (64, 68))	('TF', 'Gene', '2152', (183, 185))	('increased', 'PosReg', (154, 163))	('ET-1', 'Gene', (174, 178))
65308	33537342	ARDS is a complex disease with multifactorial consequences; as such, in addition to elevated mPAP, other parameters have been strongly associated with mortality such as partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), or PaO2/fraction of inspired oxygen (FiO2).	('mPAP', 'Gene', (93, 97))	('mPAP', 'Gene', '19012', (93, 97))	('PaO2/fraction', 'Var', (251, 264))	('oxygen', 'Chemical', 'MESH:D010100', (233, 239))	('partial pressure of', 'MPA', (213, 232))	('ARDS', 'Disease', (0, 4))	('carbon dioxide', 'Chemical', 'MESH:D002245', (189, 203))	('partial pressure of carbon dioxide', 'MPA', (169, 203))	('associated', 'Reg', (135, 145))	('mortality', 'Disease', 'MESH:D003643', (151, 160))	('PaCO2', 'Chemical', '-', (205, 210))	('ARDS', 'Phenotype', 'HP:0011948', (0, 4))	('FiO2', 'Chemical', '-', (285, 289))	('mortality', 'Disease', (151, 160))	('oxygen', 'Chemical', 'MESH:D010100', (277, 283))	('ARDS', 'Disease', 'MESH:D012128', (0, 4))
65311	33537342	These findings are summarized in Table 2 and underscore disruptions in the lung vasculature in ARDS as potential disease-amplifying effects that are not fully understood.	('ARDS', 'Disease', 'MESH:D012128', (95, 99))	('disruptions', 'Var', (56, 67))	('ARDS', 'Phenotype', 'HP:0011948', (95, 99))	('ARDS', 'Disease', (95, 99))
65322	33537342	Genetic variants in the RAS pathway have recently been implicated in the onset and severity of ARDS, specifically angiotensin-converting enzyme (ACE), and its derivatives (Imai et al.,).	('angiotensin-converting enzyme', 'Gene', '1636', (114, 143))	('ARDS', 'Disease', (95, 99))	('ARDS', 'Phenotype', 'HP:0011948', (95, 99))	('angiotensin-converting enzyme', 'molecular_function', 'GO:0004246', ('114', '143'))	('angiotensin-converting enzyme', 'Gene', (114, 143))	('RAS pathway', 'Pathway', (24, 35))	('Genetic variants', 'Var', (0, 16))	('implicated', 'Reg', (55, 65))	('ARDS', 'Disease', 'MESH:D012128', (95, 99))
65335	33537342	In addition, the ACE D/D allele correlates with increased mortality in ARDS especially in comparison with the ACE I/I allele which shows increased survival rate, marking the I/D polymorphism as a significant prognostic factor for ARDS outcome (Jerng et al.,).	('ARDS', 'Phenotype', 'HP:0011948', (230, 234))	('ARDS', 'Disease', 'MESH:D012128', (230, 234))	('ARDS', 'Disease', (71, 75))	('rat', 'Species', '10116', (156, 159))	('ARDS', 'Disease', (230, 234))	('ACE D/D', 'Var', (17, 24))	('mortality', 'Disease', 'MESH:D003643', (58, 67))	('ARDS', 'Phenotype', 'HP:0011948', (71, 75))	('ARDS', 'Disease', 'MESH:D012128', (71, 75))	('mortality', 'Disease', (58, 67))
65336	33537342	Thus, it is conceivable that the D allele may worsen PH in ARDS.	('ARDS', 'Disease', 'MESH:D012128', (59, 63))	('D allele', 'Var', (33, 41))	('worsen', 'NegReg', (46, 52))	('ARDS', 'Disease', (59, 63))	('PH', 'Gene', '5053', (53, 55))	('ARDS', 'Phenotype', 'HP:0011948', (59, 63))
65340	33537342	While a significant decrease in ACE2 activity was observed in human pulmonary arterial hypertension (PAH) patients (Hemnes et al.,), ACE2 knockout mice display worsened lung function, increased vascular permeability, enhanced lung edema, and neutrophil accumulation, attributed to a downregulation of ACE2 (Imai et al.,).	('ACE2', 'Gene', (133, 137))	('vascular permeability', 'CPA', (194, 215))	('enhanced', 'PosReg', (217, 225))	('AH', 'Disease', 'MESH:D007039', (102, 104))	('knockout', 'Var', (138, 146))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (68, 99))	('worsened lung function', 'Phenotype', 'HP:0005952', (160, 182))	('PAH', 'molecular_function', 'GO:0033972', ('101', '104'))	('lung edema', 'Disease', (226, 236))	('downregulation', 'NegReg', (283, 297))	('mice', 'Species', '10090', (147, 151))	('decrease', 'NegReg', (20, 28))	('neutrophil accumulation', 'CPA', (242, 265))	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (68, 99))	('human', 'Species', '9606', (62, 67))	('edema', 'Phenotype', 'HP:0000969', (231, 236))	('increased', 'PosReg', (184, 193))	('activity', 'MPA', (37, 45))	('patients', 'Species', '9606', (106, 114))	('lung edema', 'Phenotype', 'HP:0100598', (226, 236))	('worsened', 'NegReg', (160, 168))	('pulmonary arterial hypertension', 'Disease', (68, 99))	('enhanced lung edema', 'Phenotype', 'HP:0100598', (217, 236))	('lung function', 'CPA', (169, 182))	('PAH', 'Phenotype', 'HP:0002092', (101, 104))	('lung edema', 'Disease', 'MESH:D004487', (226, 236))	('hypertension', 'Phenotype', 'HP:0000822', (87, 99))
65346	33537342	In contrast to the results of experimental ACE2 deletion, ACE knockout and AT1Ra-deficient mice showed marked improvement in ALI symptoms (Imai et al.,).	('mice', 'Species', '10090', (91, 95))	('ALI symptoms', 'MPA', (125, 137))	('AT1R', 'Gene', '185', (75, 79))	('improvement', 'PosReg', (110, 121))	('AT1R', 'Gene', (75, 79))	('deletion', 'Var', (48, 56))	('ACE2', 'Gene', (43, 47))
65356	33537342	Potential treatment of COVID-19, with the understanding of the role of ACE2 as a receptor for SARS-CoV-2, could include inhibition of the ACE2 receptor, spike protein-based vaccine, inhibition of transmembrane protease activity, or administration of soluble ACE2 (Cheng et al.,).	('ACE2 receptor', 'Protein', (138, 151))	('SARS-CoV-2', 'Species', '2697049', (94, 104))	('inhibition', 'Var', (120, 130))	('COVID-19', 'Disease', 'MESH:C000657245', (23, 31))	('soluble', 'cellular_component', 'GO:0005625', ('250', '257'))	('protease activity', 'molecular_function', 'GO:0008233', ('210', '227'))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('COVID-19', 'Disease', (23, 31))	('inhibition', 'Var', (182, 192))	('spike', 'Gene', (153, 158))	('spike', 'Gene', '43740568', (153, 158))	('transmembrane', 'cellular_component', 'GO:0044214', ('196', '209'))	('transmembrane', 'cellular_component', 'GO:0016021', ('196', '209'))	('rat', 'Species', '10116', (240, 243))
65360	33537342	Through an LPS model of ARDS, they identified that the production of ceramide and IL-6 in rat PASMCs resulted in failed hypoxic vasoconstriction (HPV), endothelial dysfunction, and hyperresponsiveness to pulmonary vasoconstriction induced by serotonin (Pandolfi et al.,).	('ARDS', 'Phenotype', 'HP:0011948', (24, 28))	('rat', 'Species', '10116', (90, 93))	('ARDS', 'Disease', 'MESH:D012128', (24, 28))	('failed hypoxic vasoconstriction', 'Disease', 'MESH:D055111', (113, 144))	('hyperresponsiveness to pulmonary vasoconstriction', 'Disease', (181, 230))	('ARDS', 'Disease', (24, 28))	('ceramide', 'Chemical', 'MESH:D002518', (69, 77))	('endothelial dysfunction', 'Disease', 'MESH:C536439', (152, 175))	('serotonin', 'Chemical', 'MESH:D012701', (242, 251))	('IL-6', 'Gene', (82, 86))	('vasoconstriction', 'biological_process', 'GO:0042310', ('214', '230'))	('IL-6', 'molecular_function', 'GO:0005138', ('82', '86'))	('hyperresponsiveness to pulmonary vasoconstriction', 'Disease', 'MESH:D008171', (181, 230))	('failed hypoxic vasoconstriction', 'Disease', (113, 144))	('pulmonary vasoconstriction', 'Phenotype', 'HP:0005308', (204, 230))	('vasoconstriction', 'biological_process', 'GO:0042310', ('128', '144'))	('endothelial dysfunction', 'Disease', (152, 175))	('production', 'Var', (55, 65))
65361	33537342	Interestingly, blockade of aSMAse attenuated the progression of PH (Pandolfi et al.,).	('blockade', 'Var', (15, 23))	('aSMAse', 'Gene', '6609', (27, 33))	('PH', 'Gene', '5053', (64, 66))	('aSMAse', 'Gene', (27, 33))	('attenuated', 'NegReg', (34, 44))
65376	33537342	There are currently multiple clinical trials attempting to elucidate the role of anti-IL6 therapies to attenuate ARDS in COVID-19 (clinicaltrials.gov: NCT 00531856; NCT04363853; NCT04335071).	('COVID-19', 'Disease', (121, 129))	('NCT04335071', 'Var', (178, 189))	('attenuate', 'NegReg', (103, 112))	('NCT04363853; NCT04335071', 'Var', (165, 189))	('IL6', 'Gene', '3569', (86, 89))	('IL6', 'Gene', (86, 89))	('ARDS', 'Phenotype', 'HP:0011948', (113, 117))	('ARDS', 'Disease', 'MESH:D012128', (113, 117))	('IL6', 'molecular_function', 'GO:0005138', ('86', '89'))	('COVID-19', 'Disease', 'MESH:C000657245', (121, 129))	('ARDS', 'Disease', (113, 117))
65382	33537342	An association has been found between polymorphisms in the surfactant protein-B (SP-B) gene and an increased risk of developing ARDS (Gong et al.,).	('ARDS', 'Phenotype', 'HP:0011948', (128, 132))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('ARDS', 'Disease', 'MESH:D012128', (128, 132))	('polymorphisms', 'Var', (38, 51))	('SP-B', 'Gene', (81, 85))	('ARDS', 'Disease', (128, 132))	('B (SP-B)', 'Species', '94832', (78, 86))
65394	33537342	Moreover, CXCL10/CXCL4-CXCR3 axis dysregulation in pulmonary artery endothelial cells led to the loss of recanalization of blocked vessels in CTEPH and impaired angiogenesis (Zabini et al.,).	('impaired', 'NegReg', (152, 160))	('loss', 'NegReg', (97, 101))	('dysregulation', 'Var', (34, 47))	('recanalization', 'CPA', (105, 119))	('CXCL4', 'Gene', '5196', (17, 22))	('angiogenesis', 'CPA', (161, 173))	('CXCR3', 'Gene', '2833', (23, 28))	('angiogenesis', 'biological_process', 'GO:0001525', ('161', '173'))	('CXCL10', 'Gene', '3627', (10, 16))	('CXCL4', 'Gene', (17, 22))	('PH', 'Gene', '5053', (145, 147))	('CXCL10', 'Gene', (10, 16))	('CXCR3', 'Gene', (23, 28))
65405	33537342	TF is a potent activator of the extrinsic coagulation cascade, and experimental models show inhibition of TF-Factor VIIa-Factor X complex reduces the extent of PH in ARDS (Welty-Wolf et al.,; MacKman,).	('PH', 'Gene', '5053', (160, 162))	('inhibition', 'Var', (92, 102))	('reduces', 'NegReg', (138, 145))	('ARDS', 'Phenotype', 'HP:0011948', (166, 170))	('TF', 'Gene', '2152', (0, 2))	('TF', 'Gene', '2152', (106, 108))	('ARDS', 'Disease', 'MESH:D012128', (166, 170))	('coagulation', 'biological_process', 'GO:0050817', ('42', '53'))	('ARDS', 'Disease', (166, 170))
65417	33537342	Furthermore, the use of low molecular weight heparin leads to reduced mortality in severe COVID-19 patients (Tang et al.,).	('mortality', 'Disease', (70, 79))	('COVID-19', 'Disease', (90, 98))	('patients', 'Species', '9606', (99, 107))	('mortality', 'Disease', 'MESH:D003643', (70, 79))	('low', 'Var', (24, 27))	('low molecular weight heparin', 'Chemical', 'MESH:D006495', (24, 52))	('COVID-19', 'Disease', 'MESH:C000657245', (90, 98))	('reduced', 'NegReg', (62, 69))
65420	33537342	HPV is a unique and complex feature of the pulmonary circulation whereby hypoxic conditions lead to vasoconstriction, in contrast to the systemic circulation where hypoxia leads to vasodilation (Lumb and Slinger,).	('lead to', 'Reg', (92, 99))	('hypoxia', 'Disease', (164, 171))	('vasodilation', 'MPA', (181, 193))	('vasoconstriction', 'MPA', (100, 116))	('hypoxia', 'Disease', 'MESH:D000860', (164, 171))	('Slinger', 'Species', '655099', (204, 211))	('hypoxic', 'Var', (73, 80))	('vasodilation', 'biological_process', 'GO:0042311', ('181', '193'))	('vasoconstriction', 'biological_process', 'GO:0042310', ('100', '116'))
65424	33537342	Herein, studies in mice have revealed that inhibition of ATP-regulated potassium channel Kir6.1, which is elevated after endotoxemia, was able to restore HPV in mice; however, the effects on lung inflammation were not assessed (Turzo et al.,).	('mice', 'Species', '10090', (161, 165))	('inflammation', 'biological_process', 'GO:0006954', ('196', '208'))	('inhibition', 'Var', (43, 53))	('HPV', 'MPA', (154, 157))	('endotoxemia', 'Disease', (121, 132))	('endotoxemia', 'Disease', 'MESH:D019446', (121, 132))	('lung inflammation', 'Disease', 'MESH:D011014', (191, 208))	('elevated', 'PosReg', (106, 114))	('Kir6.1', 'Gene', '16523', (89, 95))	('restore', 'PosReg', (146, 153))	('lung inflammation', 'Disease', (191, 208))	('Kir6.1', 'Gene', (89, 95))	('mice', 'Species', '10090', (19, 23))
65431	33537342	In ALI, the stabilization of HIF1A and HIF2A have been shown to limit injury (Karmouty-Quintana et al.,; Gong et al.,; Huang et al.,).	('injury', 'CPA', (70, 76))	('HIF2A', 'Gene', (39, 44))	('stabilization', 'Var', (12, 25))	('HIF1A', 'Gene', '3091', (29, 34))	('HIF1A', 'Gene', (29, 34))	('HIF2A', 'Gene', '2034', (39, 44))
65432	33537342	Deletion of endothelial cell HIF-1A expression inhibited endothelial proliferation and attenuated vascular repair processes in a model of sepsis-induced lung injury (Huang et al.,).	('inhibited', 'NegReg', (47, 56))	('vascular repair processes', 'CPA', (98, 123))	('rat', 'Species', '10116', (76, 79))	('lung injury', 'Disease', 'MESH:D055370', (153, 164))	('HIF-1A', 'Gene', '3091', (29, 35))	('lung injury', 'Disease', (153, 164))	('attenuated', 'NegReg', (87, 97))	('endothelial proliferation', 'CPA', (57, 82))	('HIF-1A', 'Gene', (29, 35))	('sepsis', 'Disease', (138, 144))	('sepsis', 'Phenotype', 'HP:0100806', (138, 144))	('sepsis', 'Disease', 'MESH:D018805', (138, 144))	('Deletion', 'Var', (0, 8))
65433	33537342	Similarly, abrogation of endothelial HIF-2A resulted in defective adherens junction that was exacerbated after endotoxin challenge in mice, resulting in worsened lung injury (Gong et al.,).	('mice', 'Species', '10090', (134, 138))	('lung injury', 'Disease', 'MESH:D055370', (162, 173))	('adherens', 'MPA', (66, 74))	('lung injury', 'Disease', (162, 173))	('exacerbated', 'PosReg', (93, 104))	('adherens junction', 'cellular_component', 'GO:0005912', ('66', '83'))	('abrogation', 'Var', (11, 21))	('defective', 'NegReg', (56, 65))	('worsened', 'PosReg', (153, 161))
65439	33537342	This duality is perhaps best highlighted by studies that determined the prevalence of HIF2A and PHD2 polymorphisms that are associated with improved adaptation to hypoxia in high-altitude residents in patients with ARDS.	('patients', 'Species', '9606', (201, 209))	('improved', 'PosReg', (140, 148))	('HIF2A', 'Gene', '2034', (86, 91))	('ARDS', 'Phenotype', 'HP:0011948', (215, 219))	('PHD', 'molecular_function', 'GO:0050175', ('96', '99'))	('ARDS', 'Disease', 'MESH:D012128', (215, 219))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('HIF2A', 'Gene', (86, 91))	('polymorphisms', 'Var', (101, 114))	('PHD2', 'Gene', (96, 100))	('hypoxia', 'Disease', (163, 170))	('ARDS', 'Disease', (215, 219))
65440	33537342	This study demonstrated that the PHD2 polymorphism PHD2 RS516651-TT, which is associated with increased adaptation to high altitude, was associated with a higher 30-days mortality risk within 30 days of the onset of ARDS (Dotsch et al.,).	('rat', 'Species', '10116', (18, 21))	('ARDS', 'Phenotype', 'HP:0011948', (216, 220))	('PHD', 'molecular_function', 'GO:0050175', ('51', '54'))	('mortality', 'Disease', (170, 179))	('PHD2', 'Gene', (33, 37))	('ARDS', 'Disease', (216, 220))	('PHD', 'molecular_function', 'GO:0050175', ('33', '36'))	('RS516651-TT', 'Var', (56, 67))	('mortality', 'Disease', 'MESH:D003643', (170, 179))	('PHD2', 'Gene', (51, 55))	('ARDS', 'Disease', 'MESH:D012128', (216, 220))
65442	33537342	These observations are significant because inhibition of ET-1 is an important strategy in the treatment of PH (Clozel et al.,).	('inhibition', 'Var', (43, 53))	('rat', 'Species', '10116', (80, 83))	('ET-1', 'Gene', '1906', (57, 61))	('ET-1', 'Gene', (57, 61))	('PH', 'Gene', '5053', (107, 109))
65452	33537342	Activation of this receptor has been shown to promote hyaluronan production through increased expression of hyaluronan synthases (HAS)-1 and 2 (Karmouty-Quintana et al.,; Mertens et al.,).	('promote', 'PosReg', (46, 53))	('hyaluronan production', 'MPA', (54, 75))	('hyaluronan', 'Chemical', 'MESH:D006820', (108, 118))	('increased', 'PosReg', (84, 93))	('Activation', 'Var', (0, 10))	('expression', 'MPA', (94, 104))	('hyaluronan synthases (HAS)-1 and 2', 'Gene', '3036;3037', (108, 142))	('hyaluronan', 'Chemical', 'MESH:D006820', (54, 64))
65454	33537342	Recent publications from our group have also demonstrated that inhibition of hyaluronan by 4-methylumbelliferone (4MU) attenuated PH by diminishing vascular remodeling (Collum et al.,).	('rat', 'Species', '10116', (52, 55))	('4MU', 'Chemical', 'MESH:D006923', (114, 117))	('PH', 'Gene', '5053', (130, 132))	('4-methylumbelliferone', 'Chemical', 'MESH:D006923', (91, 112))	('hyaluronan', 'Protein', (77, 87))	('diminishing', 'NegReg', (136, 147))	('inhibition', 'Var', (63, 73))	('hyaluronan', 'Chemical', 'MESH:D006820', (77, 87))	('attenuated', 'NegReg', (119, 129))	('vascular remodeling', 'CPA', (148, 167))
65485	33537342	As such, the role of disrupted vascular regulation in patients with severe COVID-19 warrants further investigation.	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('patients', 'Species', '9606', (54, 62))	('COVID-19', 'Disease', 'MESH:C000657245', (75, 83))	('COVID-19', 'Disease', (75, 83))	('severe', 'Var', (68, 74))
65490	33537342	In the early stages of ALI, damage to the endothelium and subsequent increase of vasoactive mediators such as ET-1, IL-6, and TNF-A can promote pulmonary vasoconstriction leading to increased PVR.	('increased', 'PosReg', (182, 191))	('pulmonary vasoconstriction', 'MPA', (144, 170))	('increase', 'PosReg', (69, 77))	('ET-1', 'Gene', (110, 114))	('PVR', 'Disease', (192, 195))	('damage', 'Var', (28, 34))	('promote', 'PosReg', (136, 143))	('TNF-A', 'Gene', '7124', (126, 131))	('ET-1', 'Gene', '1906', (110, 114))	('pulmonary vasoconstriction', 'Phenotype', 'HP:0005308', (144, 170))	('IL-6', 'molecular_function', 'GO:0005138', ('116', '120'))	('vasoconstriction', 'biological_process', 'GO:0042310', ('154', '170'))	('TNF-A', 'Gene', (126, 131))	('increased PVR', 'Phenotype', 'HP:0008151', (182, 195))
65491	33537342	Similarly, loss of ACE2, such as after viral infections, leading to increased AngII and subsequent activation of AT2 receptors can also promote pulmonary vasoconstrictor responses.	('AT2 receptors', 'Protein', (113, 126))	('promote', 'PosReg', (136, 143))	('pulmonary vasoconstrictor responses', 'MPA', (144, 179))	('viral infections', 'Disease', (39, 55))	('loss', 'Var', (11, 15))	('viral infections', 'Disease', 'MESH:D001102', (39, 55))	('AngII', 'CPA', (78, 83))	('activation', 'PosReg', (99, 109))	('ACE2', 'Gene', (19, 23))	('increased', 'PosReg', (68, 77))
65506	33050659	ClueGO predicted cell projection morphogenesis, chemosensory behavior, and glycosaminoglycan binding, and the PI3K-Akt signaling pathways were enriched metabolic interactions regulating miRNA-1245 overlapping TGs in LUAD.	('Akt', 'Gene', '207', (115, 118))	('TGs', 'biological_process', 'GO:0006342', ('209', '212'))	('glycosaminoglycan binding', 'molecular_function', 'GO:0005539', ('75', '100'))	('chemosensory behavior', 'biological_process', 'GO:0007635', ('48', '69'))	('glycosaminoglycan', 'Protein', (75, 92))	('Akt', 'Gene', (115, 118))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('Akt signaling', 'biological_process', 'GO:0043491', ('115', '128'))	('cell projection morphogenesis', 'CPA', (17, 46))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (75, 92))	('chemosensory behavior', 'CPA', (48, 69))	('cell projection morphogenesis', 'biological_process', 'GO:0048858', ('17', '46'))	('cell projection', 'cellular_component', 'GO:0042995', ('17', '32'))	('LUAD', 'Phenotype', 'HP:0030078', (216, 220))	('miRNA-1245', 'Var', (186, 196))
65516	33050659	Aberrant changes in the level of miRNA, correlated with tumor growth, results in metastasis, invasion, drug resistance, and progression in LUAD patients.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('drug resistance', 'biological_process', 'GO:0042493', ('103', '118'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('results in', 'Reg', (70, 80))	('drug resistance', 'CPA', (103, 118))	('patients', 'Species', '9606', (144, 152))	('correlated', 'Reg', (40, 50))	('metastasis', 'CPA', (81, 91))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('Aberrant changes', 'Var', (0, 16))	('invasion', 'CPA', (93, 101))	('drug resistance', 'biological_process', 'GO:0009315', ('103', '118'))	('miRNA', 'MPA', (33, 38))
65518	33050659	Upregulated oncogenic miRNAs (miR-130b, miR-182-5p, miRNA-17, and miRNA-222) were reported to cause the development and progression of LUAD; moreover, downregulated miRNAs (miR-486-5p, miR-101, miR-133a), also called tumor-suppressive miRNAs, were reported to repress the development of NSCLC.	('miR-486-5p', 'Var', (173, 183))	('miR-182', 'Gene', (40, 47))	('miRNA-222', 'Gene', '407007', (66, 75))	('miR-182', 'Gene', '406958', (40, 47))	('tumor', 'Disease', (217, 222))	('miR-133a', 'Var', (194, 202))	('miRNA-17', 'Gene', '406952', (52, 60))	('miRNA-222', 'Gene', (66, 75))	('LUAD', 'Phenotype', 'HP:0030078', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cause', 'Reg', (94, 99))	('miRNA-17', 'Gene', (52, 60))	('miR-101', 'Var', (185, 192))	('downregulated', 'NegReg', (151, 164))	('LUAD', 'Disease', (135, 139))	('NSCLC', 'Disease', 'MESH:D002289', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('NSCLC', 'Disease', (287, 292))	('miR-130b', 'Gene', '406920', (30, 38))	('repress', 'NegReg', (260, 267))	('miR-130b', 'Gene', (30, 38))
65584	33050659	The immune-histochemistry of pathological slides of the human protein atlas database (HPAD) indicated that the protein expressions of PTGs were drastically higher in LUAD tissues compared with adjacent normal tissues (Figure 10).	('PTGs', 'biological_process', 'GO:0016441', ('134', '138'))	('higher', 'PosReg', (156, 162))	('LUAD', 'Disease', (166, 170))	('HPAD', 'Disease', 'None', (86, 90))	('human', 'Species', '9606', (56, 61))	('LUAD', 'Phenotype', 'HP:0030078', (166, 170))	('HPAD', 'Disease', (86, 90))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('protein expressions', 'MPA', (111, 130))	('PTGs', 'Var', (134, 138))	('PTGs', 'Chemical', '-', (134, 138))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
65604	33050659	Based on those findings, we speculated that the regulation of miRNAs in glycosaminoglycan binding might improve the efficacy of LUAD therapeutics theoretically.	('glycosaminoglycan binding', 'molecular_function', 'GO:0005539', ('72', '97'))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (72, 89))	('efficacy', 'MPA', (116, 124))	('LUAD', 'Phenotype', 'HP:0030078', (128, 132))	('binding', 'Interaction', (90, 97))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('improve', 'PosReg', (104, 111))	('regulation', 'Var', (48, 58))	('miRNAs', 'Var', (62, 68))	('glycosaminoglycan', 'Protein', (72, 89))
65614	33050659	Accordingly, we hypothesized that post-translational modification of protein like UBE2C plays key roles in protein degradation, and protein interactions and their dysregulations in the earlier stage may lead to LUAD.	('UBE2C', 'Gene', (82, 87))	('dysregulations', 'Var', (163, 177))	('post-translational modification', 'biological_process', 'GO:0043687', ('34', '65'))	('interactions', 'Interaction', (140, 152))	('protein degradation', 'MPA', (107, 126))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('protein', 'Protein', (132, 139))	('LUAD', 'Phenotype', 'HP:0030078', (211, 215))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('LUAD', 'Disease', (211, 215))	('lead to', 'Reg', (203, 210))	('post-translational', 'Var', (34, 52))	('UBE2C', 'Gene', '11065', (82, 87))	('protein degradation', 'biological_process', 'GO:0030163', ('107', '126'))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
65641	33050659	Additionally, underexpression of TNNI3, TNNT1, and PITX2 might involve four independent pathways of cardiac muscle contraction, adrenergic signaling in cardiomyocytes, hypertrophic cardiomyopathy, and dilated cardiomyopathy, which are also incidentally associated through some somatic mutation and proto-oncogenic activities in LUAD.	('cardiac muscle contraction', 'biological_process', 'GO:0060048', ('100', '126'))	('TNNI3', 'Gene', (33, 38))	('PITX2', 'Gene', (51, 56))	('TNNI3', 'Gene', '7137', (33, 38))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (201, 223))	('underexpression', 'Var', (14, 29))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('adrenergic signaling', 'MPA', (128, 148))	('TNNT1', 'Gene', (40, 45))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (209, 223))	('dilated cardiomyopathy', 'Disease', (201, 223))	('TNNT1', 'Gene', '7138', (40, 45))	('PITX2', 'Gene', '5308', (51, 56))	('cardiac muscle contraction', 'MPA', (100, 126))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (201, 223))	('involve', 'Reg', (63, 70))	('hypertrophic cardiomyopathy', 'Phenotype', 'HP:0001639', (168, 195))	('hypertrophic cardiomyopathy', 'Disease', (168, 195))	('hypertrophic cardiomyopathy', 'Disease', 'MESH:D002312', (168, 195))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (181, 195))	('LUAD', 'Phenotype', 'HP:0030078', (328, 332))
65670	33142912	However, diaphragm weight significantly decreased in LC 30-days animals compared to NI-control mice, while spleen weight was significantly greater in the two LC-cachexia groups compared to NI-control animals (Table 1).	('LC 30-days', 'Var', (53, 63))	('mice', 'Species', '10090', (95, 99))	('cachexia', 'Phenotype', 'HP:0004326', (161, 169))	('diaphragm weight', 'CPA', (9, 25))	('spleen weight', 'CPA', (107, 120))	('greater', 'PosReg', (139, 146))	('LC-cachexia', 'Disease', (158, 169))	('decreased', 'NegReg', (40, 49))	('LC-cachexia', 'Disease', 'MESH:D002100', (158, 169))
65674	33142912	Tumor weight and tumor area significantly increased in LC 30-days + 15-day I compared to LC 30-days mice (+55% change, Table 1 and Figure 1).	('increased', 'PosReg', (42, 51))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (100, 104))	('Tumor weight', 'CPA', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('LC 30-days + 15-day', 'Var', (55, 74))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
65684	33142912	Compared to unloaded (7-day I and 15-day I) mice, in gastrocnemius of animals with the two conditions (LC-cachexia and unloading), plasma troponin I levels were significantly higher in LC 30-days + 15-day I animals than in 15-day I mice (+67% change, Figure 3).	('LC 30-days + 15-day I', 'Var', (185, 206))	('cachexia', 'Phenotype', 'HP:0004326', (106, 114))	('higher', 'PosReg', (175, 181))	('LC-cachexia', 'Disease', (103, 114))	('LC-cachexia', 'Disease', 'MESH:D002100', (103, 114))	('plasma troponin I levels', 'Phenotype', 'HP:0410173', (131, 155))	('mice', 'Species', '10090', (44, 48))	('plasma troponin I levels', 'MPA', (131, 155))	('mice', 'Species', '10090', (232, 236))
65686	33142912	Compared to LC-cachexia animals, in mice with the two conditions (LC-cachexia and unloading), plasma troponin I levels were significantly increased in LC 30-days + 15-day I mice compared to LC 30-days rodents (+36% change, Figure 3).	('increased', 'PosReg', (138, 147))	('LC-cachexia', 'Disease', 'MESH:D002100', (66, 77))	('LC-cachexia', 'Disease', (12, 23))	('plasma troponin I levels', 'Phenotype', 'HP:0410173', (94, 118))	('cachexia', 'Phenotype', 'HP:0004326', (69, 77))	('mice', 'Species', '10090', (173, 177))	('LC-cachexia', 'Disease', 'MESH:D002100', (12, 23))	('plasma troponin I levels', 'MPA', (94, 118))	('mice', 'Species', '10090', (36, 40))	('LC-cachexia', 'Disease', (66, 77))	('cachexia', 'Phenotype', 'HP:0004326', (15, 23))	('LC 30-days + 15-day I', 'Var', (151, 172))
65689	33142912	Moreover, beclin-1, LC3-II/I, and cleaved caspase-3 protein levels were significantly higher in muscles of the LC 30-days mice than in NI-controls, while no differences were detected in p62 protein levels between them (Figure 5A-E).	('LC3-II', 'Chemical', '-', (20, 26))	('mice', 'Species', '10090', (122, 126))	('beclin-1', 'Gene', (10, 18))	('beclin-1', 'Gene', '56208', (10, 18))	('caspase-3', 'Gene', '12367', (42, 51))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('p62', 'Gene', '18226', (186, 189))	('tween', 'Chemical', 'MESH:D011136', (207, 212))	('LC3-II/I', 'MPA', (20, 28))	('higher', 'PosReg', (86, 92))	('LC 30-days', 'Var', (111, 121))	('p62', 'Gene', (186, 189))	('caspase-3', 'Gene', (42, 51))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
65815	32298306	Outcomes according to initial and subsequent therapies following intracranial progression in patients with EGFR-mutant lung cancer and brain metastasis In patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with brain metastases, it remains controversial whether the use of EGFR-tyrosine kinase inhibitor (TKI) alone without radiotherapy (RT) is an optimal approach.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('332', '348'))	('lung cancer', 'Disease', (119, 130))	('NSCLC', 'Disease', 'MESH:D002289', (244, 249))	('EGFR', 'Gene', (203, 207))	('EGFR', 'Gene', (107, 111))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('169', '192'))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (93, 101))	('NSCLC', 'Disease', (244, 249))	('non-small-cell lung cancer', 'Disease', (216, 242))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (216, 242))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('EGFR', 'Gene', (318, 322))	('EGFR', 'Gene', '1956', (203, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('EGFR', 'Gene', '1956', (107, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (220, 242))	('epidermal growth factor receptor', 'Gene', (169, 201))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('epidermal growth factor receptor', 'Gene', '1956', (169, 201))	('-mutant', 'Var', (208, 215))	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'molecular_function', 'GO:0005006', ('203', '207'))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (216, 242))	('brain metastases', 'Disease', 'MESH:D009362', (256, 272))	('EGFR', 'Gene', '1956', (318, 322))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('brain metastases', 'Disease', (256, 272))	('EGFR', 'molecular_function', 'GO:0005006', ('318', '322'))
65821	32298306	In multivariate analysis, upfront WBRT was associated with trends towards a lower probability of intracranial progression, whereas upfront SRS was found to be an independent risk factor for poor OS.	('SRS', 'Disease', (139, 142))	('lower', 'NegReg', (76, 81))	('SRS', 'Disease', 'MESH:C536678', (139, 142))	('upfront WBRT', 'Var', (26, 38))	('intracranial progression', 'CPA', (97, 121))
65826	32298306	However, the median overall survival (OS) has recently been increasing in patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma and brain metastases due to the introduction of targeted therapy.	('overall', 'MPA', (20, 27))	('brain metastases', 'Disease', (159, 175))	('lung adenocarcinoma', 'Disease', (135, 154))	('increasing', 'PosReg', (60, 70))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('patients', 'Species', '9606', (74, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('brain metastases', 'Disease', 'MESH:D009362', (159, 175))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('-mutant', 'Var', (127, 134))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('88', '111'))	('EGFR', 'Gene', '1956', (122, 126))	('epidermal growth factor receptor', 'Gene', (88, 120))	('EGFR', 'Gene', (122, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
65838	32298306	The following variables were collected for analysis: age, sex, TNM stage (8th edition), smoking history, EGFR mutation, Eastern Cooperative Oncology Group (ECOG) performance status at the time of initial diagnosis, number of brain metastases, size of the largest brain metastasis, presence or absence of extracranial metastases, symptoms associated with brain metastases, type of RT, pattern of progression (intracranial progression vs. systemic) and presence or absence of salvage RT after intracranial progression.	('metastases', 'Disease', 'MESH:D009362', (360, 370))	('metastases', 'Disease', (317, 327))	('TNM', 'Gene', '10178', (63, 66))	('brain metastases', 'Disease', 'MESH:D009362', (354, 370))	('metastases', 'Disease', 'MESH:D009362', (317, 327))	('EGFR', 'Gene', '1956', (105, 109))	('metastases', 'Disease', (231, 241))	('brain metastases', 'Disease', (354, 370))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('Oncology', 'Phenotype', 'HP:0002664', (140, 148))	('brain metastases', 'Disease', (225, 241))	('metastases', 'Disease', 'MESH:D009362', (231, 241))	('TNM', 'Gene', (63, 66))	('mutation', 'Var', (110, 118))	('EGFR', 'Gene', (105, 109))	('metastases', 'Disease', (360, 370))	('brain metastases', 'Disease', 'MESH:D009362', (225, 241))
65839	32298306	EGFR mutations were detected using polymerase chain reaction amplification from the paraffin-embedded tumour samples.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('EGFR', 'Gene', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('mutations', 'Var', (5, 14))	('tumour', 'Disease', (102, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('paraffin', 'Chemical', 'MESH:D010232', (84, 92))	('EGFR', 'Gene', '1956', (0, 4))
65850	32298306	There were no differences between the TKI alone and RT plus TKI groups regarding age, sex, ECOG performance status, smoking status, number of brain metastases, extracranial metastases at the time of brain metastases, EGFR mutation and EGFR-TKIs.	('EGFR', 'Gene', '1956', (217, 221))	('brain metastases', 'Disease', (199, 215))	('EGFR', 'Gene', (217, 221))	('mutation', 'Var', (222, 230))	('brain metastases', 'Disease', 'MESH:D009362', (199, 215))	('metastases', 'Disease', (173, 183))	('metastases', 'Disease', (148, 158))	('brain metastases', 'Disease', 'MESH:D009362', (142, 158))	('metastases', 'Disease', (205, 215))	('brain metastases', 'Disease', (142, 158))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', (235, 239))	('metastases', 'Disease', 'MESH:D009362', (148, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('235', '239'))
65851	32298306	Patients treated with EGFR-TKI alone were more likely to have a N2-3 (51.4% TKI alone vs. 31.8% upfront RT; P = 0.018) and M1a (18.7% TKI alone vs. 0% upfront RT; P < 0.0001) stage tumour at diagnosis.	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('N2-3', 'Var', (64, 68))	('M1a', 'Var', (123, 126))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Disease', (181, 187))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
65863	32298306	However, other variables such as sex, EGFR mutation and number of intracranial metastases did not influence OS and intracranial PFS.	('EGFR', 'Gene', '1956', (38, 42))	('intracranial metastases', 'Disease', (66, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('intracranial metastases', 'Disease', 'MESH:D009362', (66, 89))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))
65866	32298306	The p.Thr790Met point mutation (T790M) in the gene encoding EGFR is the most common cause of TKI resistance in lung cancer; it can reduce binding of TKIs to EGFR.	('T790M', 'Var', (32, 37))	('EGFR', 'Gene', '1956', (157, 161))	('lung cancer', 'Disease', (111, 122))	('p.Thr790Met point', 'Var', (4, 21))	('binding', 'Interaction', (138, 145))	('EGFR', 'Gene', '1956', (60, 64))	('reduce', 'NegReg', (131, 137))	('cause', 'Reg', (84, 89))	('TKIs', 'Protein', (149, 153))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('p.Thr790Met', 'Mutation', 'rs121434569', (4, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('EGFR', 'Gene', (157, 161))	('T790M', 'Mutation', 'rs121434569', (32, 37))	('EGFR', 'Gene', (60, 64))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))
65877	32298306	Further study will be needed for EGFR mutant NSCLC patients with initially brain metastasis who received the third generation TKIs as the first line treatment to investigate the clinical outcomes according to the use of upfront RT as well as the salvage RT following intracranial progression.	('mutant', 'Var', (38, 44))	('NSCLC', 'Disease', (45, 50))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('patients', 'Species', '9606', (51, 59))	('EGFR', 'Gene', (33, 37))
65898	31923436	Metabolic rewiring in cancer cells occurs due to the activation of oncogenes, inactivation of tumor suppressor genes, and/or other adaptive changes in cell signaling pathways.	('inactivation', 'Var', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('activation', 'PosReg', (53, 63))	('Metabolic rewiring', 'CPA', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cell signaling pathways', 'Pathway', (151, 174))	('cancer', 'Disease', (22, 28))	('oncogenes', 'Protein', (67, 76))	('tumor', 'Disease', (94, 99))	('changes', 'Reg', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
65907	31923436	This metabolic rewiring primarily takes place in response to the activation of oncogenes and/or inactivation of tumor suppressor genes that alter the expression of metabolic enzymes via transcriptional and post-transcriptional changes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('expression', 'MPA', (150, 160))	('inactivation', 'Var', (96, 108))	('alter', 'Reg', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('metabolic enzymes', 'MPA', (164, 181))	('tumor', 'Disease', (112, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))
65908	31923436	Further, mutations in genes encoding enzymes of key metabolic pathways are also associated with certain hereditary and sporadic forms of cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (9, 18))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('associated', 'Reg', (80, 90))	('cancers', 'Disease', (137, 144))	('hereditary', 'Disease', (104, 114))
65924	31923436	In some tumors, HK II promoter hypomethylation is also reported leading to its upregulation.	('HK II', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('promoter hypomethylation', 'Var', (22, 46))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('upregulation', 'PosReg', (79, 91))	('HK II', 'Gene', '3099', (16, 21))
65943	31923436	EGFR activation, mutant KRAS/B-Raf, hypoxic stress, etc., induce phosphorylation of PGK1 via activated ERK1/2.	('EGFR', 'Gene', (0, 4))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('activation', 'PosReg', (5, 15))	('PGK1', 'Gene', (84, 88))	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('PGK', 'molecular_function', 'GO:0004618', ('84', '87'))	('phosphorylation', 'MPA', (65, 80))	('PGK1', 'Gene', '5230', (84, 88))	('hypoxic stress', 'Disease', (36, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('hypoxic stress', 'Disease', 'MESH:D000079225', (36, 50))	('mutant', 'Var', (17, 23))	('ERK1', 'molecular_function', 'GO:0004707', ('103', '107'))
65945	31923436	Activation of PDK1 suppresses the activity of pyruvate dehydrogenase complex (PDC).	('activity', 'MPA', (34, 42))	('suppresses', 'NegReg', (19, 29))	('pyruvate dehydrogenase', 'Gene', '54704', (46, 68))	('PDK1', 'Gene', '5163', (14, 18))	('PDC', 'Gene', (78, 81))	('pyruvate dehydrogenase', 'Gene', (46, 68))	('PDK1', 'Gene', (14, 18))	('Activation', 'Var', (0, 10))	('PDK1', 'molecular_function', 'GO:0004740', ('14', '18'))	('pyruvate dehydrogenase complex', 'cellular_component', 'GO:0045254', ('46', '76'))	('PDC', 'Gene', '5132', (78, 81))
65948	31923436	ARD1 acetylates PGK1 at Lys388 under stress conditions, which then phosphorylates Beclin at Ser30, which is an important initial step for the formation of autophagosomes.	('ARD1', 'Gene', '5511', (0, 4))	('ARD1', 'molecular_function', 'GO:0010309', ('0', '4'))	('ARD1', 'Gene', (0, 4))	('PGK1', 'Gene', (16, 20))	('Lys388', 'Var', (24, 30))	('Ser30', 'Chemical', '-', (92, 97))	('PGK1', 'Gene', '5230', (16, 20))	('PGK', 'molecular_function', 'GO:0004618', ('16', '19'))	('formation', 'biological_process', 'GO:0009058', ('142', '151'))	('Lys388', 'Chemical', '-', (24, 30))	('Ser', 'cellular_component', 'GO:0005790', ('92', '95'))
65959	31923436	Substrate (phosphoenolpyruvate) binding affinity of PKM2 is reduced upon phosphorylation by PP60v-src-tyrosine kinase, which leads to the accumulation of different glycolytic intermediates/phosphometabolites.	('PP60v-src-tyrosine', 'Var', (92, 110))	('PKM2', 'Gene', (52, 56))	('accumulation', 'PosReg', (138, 150))	('phosphoenolpyruvate', 'Chemical', 'MESH:D010728', (11, 30))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('PKM2', 'Gene', '5315', (52, 56))	('reduced', 'NegReg', (60, 67))	('leads to', 'Reg', (125, 133))	('tyrosine', 'Chemical', 'MESH:D014443', (102, 110))	('phosphorylation', 'MPA', (73, 88))	('glycolytic intermediates/phosphometabolites', 'MPA', (164, 207))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))
65967	31923436	LDHA silencing also reduces the survival of cancer cells under both normoxia and hypoxia due to a decrease in ATP levels.	('LDHA', 'Gene', (0, 4))	('decrease', 'NegReg', (98, 106))	('hypoxia', 'Disease', (81, 88))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('reduces', 'NegReg', (20, 27))	('cancer', 'Disease', (44, 50))	('silencing', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('LDHA', 'Gene', '3939', (0, 4))	('ATP', 'Gene', (110, 113))	('ATP', 'Gene', '51761', (110, 113))	('survival', 'CPA', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
65981	31923436	In contrast, high ADP-ATP ratio and elevated pyruvate inhibit PDK and promote PDH activity.	('PDH', 'molecular_function', 'GO:0004739', ('78', '81'))	('PDK', 'molecular_function', 'GO:0004740', ('62', '65'))	('PDH', 'molecular_function', 'GO:0004246', ('78', '81'))	('PDH', 'molecular_function', 'GO:0033718', ('78', '81'))	('PDK', 'Protein', (62, 65))	('inhibit', 'NegReg', (54, 61))	('elevated', 'PosReg', (36, 44))	('high', 'Var', (13, 17))	('PDH', 'Gene', (78, 81))	('ADP', 'Chemical', 'MESH:D000244', (18, 21))	('elevated pyruvate', 'Phenotype', 'HP:0003542', (36, 53))	('pyruvate', 'Chemical', 'MESH:D019289', (45, 53))	('promote', 'PosReg', (70, 77))	('activity', 'MPA', (82, 90))	('ATP', 'Gene', '51761', (22, 25))	('PDH', 'Gene', '54704', (78, 81))	('ATP', 'Gene', (22, 25))	('pyruvate', 'MPA', (45, 53))
65983	31923436	The PDK family consists of 4 highly homologous members that phosphorylate 3 sites (Ser293, Ser300, and Ser 232) on E1-alpha of PDH.	('Ser 232', 'Var', (103, 110))	('PDH', 'molecular_function', 'GO:0004739', ('127', '130'))	('PDH', 'molecular_function', 'GO:0033718', ('127', '130'))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('Ser', 'cellular_component', 'GO:0005790', ('103', '106'))	('PDH', 'Gene', (127, 130))	('Ser', 'Chemical', 'MESH:D012694', (83, 86))	('Ser300', 'Var', (91, 97))	('Ser300', 'Chemical', '-', (91, 97))	('Ser', 'Chemical', 'MESH:D012694', (103, 106))	('PDK', 'molecular_function', 'GO:0004740', ('4', '7'))	('Ser', 'Chemical', 'MESH:D012694', (91, 94))	('E1', 'Chemical', '-', (115, 117))	('Ser293', 'Var', (83, 89))	('PDH', 'Gene', '54704', (127, 130))	('PDH', 'molecular_function', 'GO:0004246', ('127', '130'))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))
65986	31923436	Inhibition of PDKs is reported to increase PDH complex activity, mitochondrial activity, and production of reactive oxygen species (ROS) that slows tumor growth and promotes apoptosis.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (107, 130))	('promotes', 'PosReg', (165, 173))	('apoptosis', 'CPA', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('activity', 'MPA', (55, 63))	('slows', 'NegReg', (142, 147))	('PDH', 'Gene', '54704', (43, 46))	('PDKs', 'Gene', (14, 18))	('production of reactive oxygen species', 'MPA', (93, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('PDH', 'molecular_function', 'GO:0004246', ('43', '46'))	('Inhibition', 'Var', (0, 10))	('mitochondrial activity', 'CPA', (65, 87))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('increase', 'PosReg', (34, 42))	('PDH', 'molecular_function', 'GO:0033718', ('43', '46'))	('PDH', 'Gene', (43, 46))	('tumor', 'Disease', (148, 153))	('PDKs', 'Gene', '5163;5166', (14, 18))	('PDH', 'molecular_function', 'GO:0004739', ('43', '46'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
65987	31923436	Acetylation of PDH at Lys321 by acetyl-CoA acetyltransferase 1 (ACAT1) also leads to its inactivation via recruitment of PDK to its phosphorylation sites.	('Lys321', 'Var', (22, 28))	('PDH', 'Gene', (15, 18))	('inactivation', 'NegReg', (89, 101))	('PDH', 'molecular_function', 'GO:0004246', ('15', '18'))	('Lys321', 'Chemical', '-', (22, 28))	('recruitment', 'PosReg', (106, 117))	('PDH', 'Gene', '54704', (15, 18))	('PDK', 'Protein', (121, 124))	('PDH', 'molecular_function', 'GO:0004739', ('15', '18'))	('PDH', 'molecular_function', 'GO:0033718', ('15', '18'))	('Acetylation', 'MPA', (0, 11))	('acetyl-CoA acetyltransferase 1', 'Gene', (32, 62))	('acetyl-CoA acetyltransferase 1', 'Gene', '38', (32, 62))	('ACAT1', 'Gene', (64, 69))	('PDK', 'molecular_function', 'GO:0004740', ('121', '124'))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))	('ACAT1', 'Gene', '38', (64, 69))
65994	31923436	Somatic mutations in IDH1 at R132 and in IDH2 at R172 and R140 result in a gain of new function i.e.	('IDH', 'Gene', (21, 24))	('IDH', 'Gene', (41, 44))	('R140', 'Var', (58, 62))	('IDH', 'Gene', '3417', (21, 24))	('IDH', 'Gene', '3417', (41, 44))	('new function', 'MPA', (83, 95))	('gain', 'PosReg', (75, 79))
65996	31923436	Mutant IDH1 also forms heterodimers with the wild-type IDH1 and inhibits its activity.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('IDH', 'Gene', (55, 58))	('IDH', 'Gene', '3417', (55, 58))	('heterodimers', 'MPA', (23, 35))	('activity', 'MPA', (77, 85))	('Mutant', 'Var', (0, 6))	('inhibits', 'NegReg', (64, 72))	('forms', 'Reg', (17, 22))
65998	31923436	Similarly, forced expression of mutant IDH1 also inhibited wild type IDH1 by forming heterodimer and increased HIF1alpha.	('forming heterodimer', 'Interaction', (77, 96))	('IDH', 'Gene', (69, 72))	('increased', 'PosReg', (101, 110))	('IDH', 'Gene', '3417', (69, 72))	('mutant', 'Var', (32, 38))	('HIF1alpha', 'Gene', (111, 120))	('IDH', 'Gene', (39, 42))	('HIF1alpha', 'Gene', '3091', (111, 120))	('inhibited', 'NegReg', (49, 58))	('IDH', 'Gene', '3417', (39, 42))
65999	31923436	These findings suggest that conversion of alpha-KG to D-2HG by mutant IDH weakens HIF1alpha degradation to promote tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutant', 'Var', (63, 69))	('HIF1alpha', 'Gene', '3091', (82, 91))	('IDH', 'Gene', (70, 73))	('tumor', 'Disease', (115, 120))	('IDH', 'Gene', '3417', (70, 73))	('D-2HG', 'Chemical', 'MESH:C019417', (54, 59))	('degradation', 'biological_process', 'GO:0009056', ('92', '103'))	('weakens', 'NegReg', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('promote', 'PosReg', (107, 114))	('alpha-KG', 'Chemical', 'MESH:D007656', (42, 50))	('HIF1alpha', 'Gene', (82, 91))
66003	31923436	Additionally, mutations in SDHAF2/SDH5, an SDH complex assembly factor, also result in loss of function.	('SDHAF2', 'Gene', '54949', (27, 33))	('SDH', 'Gene', (43, 46))	('SDHAF2', 'Gene', (27, 33))	('SDH', 'Gene', '6390', (27, 30))	('SDH', 'Gene', (34, 37))	('SDH5', 'Gene', (34, 38))	('SDH', 'Gene', (27, 30))	('SDH', 'Gene', '6390', (43, 46))	('mutations', 'Var', (14, 23))	('SDH5', 'Gene', '54949', (34, 38))	('SDH', 'Gene', '6390', (34, 37))
66010	31923436	PCK2 mediates glycerol phosphate synthesis to support de novo synthesis of glycerophospholipid and its silencing reduces colony formation under the starved condition and in a subcutaneous mouse model of lung cancer.	('silencing', 'Var', (103, 112))	('colony formation', 'CPA', (121, 137))	('mouse', 'Species', '10090', (188, 193))	('glycerol phosphate', 'Chemical', 'MESH:D005994', (14, 32))	('PCK2', 'Gene', (0, 4))	('synthesis', 'biological_process', 'GO:0009058', ('33', '42'))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancer', 'Disease', (203, 214))	('synthesis', 'biological_process', 'GO:0009058', ('62', '71'))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('reduces', 'NegReg', (113, 120))	('glycerophospholipid', 'Chemical', 'MESH:D020404', (75, 94))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))	('de novo synthesis of glycerophospholipid', 'MPA', (54, 94))
66012	31923436	PCK1 silencing in TRCs drastically reduces glycine levels (a major metabolite of serine) and retards their growth in vitro and in vivo.	('serine', 'Chemical', 'MESH:D012694', (81, 87))	('reduces glycine levels', 'Phenotype', 'HP:0012277', (35, 57))	('retards', 'Disease', 'MESH:D008607', (93, 100))	('reduces', 'NegReg', (35, 42))	('silencing', 'Var', (5, 14))	('glycine levels', 'MPA', (43, 57))	('retards', 'Disease', (93, 100))	('growth', 'MPA', (107, 113))	('PCK1', 'Gene', (0, 4))	('PCK1', 'Gene', '5105', (0, 4))	('glycine', 'Chemical', 'MESH:D005998', (43, 50))
66023	31923436	Overexpression of G6PC is reported in ovarian cancer and associated with poor overall survival.	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('G6PC', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ovarian cancer', 'Disease', (38, 52))
66025	31923436	Low G6PC correlates with higher uptake of fluorodeoxyglucose (FDG) in poorly differentiated HCC as compared to that in moderately differentiated HCC, indicating a connection of G6PC with tumor-grade.	('uptake of fluorodeoxyglucose', 'MPA', (32, 60))	('uptake', 'biological_process', 'GO:0098739', ('32', '38'))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('uptake', 'biological_process', 'GO:0098657', ('32', '38'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('G6PC', 'Var', (4, 8))	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (42, 60))	('tumor', 'Disease', (187, 192))	('Low G6PC', 'Var', (0, 8))	('higher', 'PosReg', (25, 31))	('FDG', 'Chemical', 'MESH:D019788', (62, 65))
66039	31923436	Small molecule inhibitors of both GLS and GLS2 have been developed of which Bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) and dibenzophenanthridine-968 exhibit maximum potency.	('GLS2', 'Gene', '27165', (42, 46))	('Bis-2-', 'Var', (76, 82))	('Bis', 'molecular_function', 'GO:0033815', ('76', '79'))	('dibenzophenanthridine-968', 'Chemical', '-', (152, 177))	('GLS2', 'Gene', (42, 46))	('BPTES', 'Chemical', 'MESH:C523193', (141, 146))	('GLS', 'Gene', '2744', (34, 37))	('Bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide', 'Chemical', 'MESH:C523193', (76, 139))	('GLS', 'Gene', (34, 37))	('GLS', 'Gene', '2744', (42, 45))	('GLS', 'Gene', (42, 45))
66044	31923436	FASN silencing or pharmacological inhibition is shown to suppress the tumor growth via apoptosis induction and increased survival of breast and prostate tumor-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('increased', 'PosReg', (111, 120))	('FASN', 'Protein', (0, 4))	('prostate tumor', 'Disease', 'MESH:D011471', (144, 158))	('tumor', 'Disease', (70, 75))	('silencing', 'Var', (5, 14))	('suppress', 'NegReg', (57, 65))	('tumor', 'Disease', (153, 158))	('prostate tumor', 'Phenotype', 'HP:0100787', (144, 158))	('survival', 'CPA', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('prostate tumor', 'Disease', (144, 158))	('apoptosis induction', 'CPA', (87, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('mice', 'Species', '10090', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
66068	31923436	Glutamine metabolism is one of the indispensable pathways for macrophage activation and immune responses, and alpha-ketoglutarate derivative of glutamine induces the macrophage polarization to the M2 phenotype.	('Glutamine', 'Chemical', 'MESH:D005973', (0, 9))	('induces', 'Reg', (154, 161))	('macrophage polarization', 'CPA', (166, 189))	('Glutamine metabolism', 'biological_process', 'GO:0006541', ('0', '20'))	('alpha-ketoglutarate', 'Var', (110, 129))	('macrophage activation', 'biological_process', 'GO:0042116', ('62', '83'))	('macrophage polarization', 'biological_process', 'GO:0042116', ('166', '189'))	('glutamine', 'Chemical', 'MESH:D005973', (144, 153))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (110, 129))
66079	31923436	The anti-diabetic drug, metformin, rewires glucose metabolism in CD11b+ myeloid cells (TAMs) and induces their repolarization to the M1 phenotype leading to the suppression of the growth of osteosarcoma cells in vivo.	('CD11b', 'Gene', '3684', (65, 70))	('rewires', 'PosReg', (35, 42))	('diabetic', 'Disease', (9, 17))	('glucose metabolism', 'Disease', (43, 61))	('CD11b', 'Gene', (65, 70))	('repolarization', 'MPA', (111, 125))	('metformin', 'Var', (24, 33))	('growth of', 'CPA', (180, 189))	('TAMs', 'Chemical', '-', (87, 91))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('osteosarcoma', 'Phenotype', 'HP:0002669', (190, 202))	('glucose metabolism', 'Disease', 'MESH:D044882', (43, 61))	('osteosarcoma', 'Disease', (190, 202))	('induces', 'Reg', (97, 104))	('glucose metabolism', 'biological_process', 'GO:0006006', ('43', '61'))	('diabetic', 'Disease', 'MESH:D003920', (9, 17))	('osteosarcoma', 'Disease', 'MESH:D012516', (190, 202))	('suppression', 'NegReg', (161, 172))
66086	31923436	Hexokinase phosphorylates 2-DG, which cannot be metabolized any further by the cells, leading to its intracellular accumulation and inhibition of hexokinase activity.	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('Hexokinase', 'Gene', (0, 10))	('inhibition', 'NegReg', (132, 142))	('intracellular accumulation', 'MPA', (101, 127))	('2-DG', 'Var', (26, 30))	('hexokinase', 'Gene', (146, 156))	('2-DG', 'Chemical', 'MESH:D003847', (26, 30))	('inhibition of hexokinase activity', 'biological_process', 'GO:1903300', ('132', '165'))	('hexokinase activity', 'molecular_function', 'GO:0004396', ('146', '165'))	('hexokinase', 'Gene', '3098', (146, 156))	('Hexokinase', 'Gene', '3098', (0, 10))
66091	31923436	The ATP depleting effect of 3BP has been promising for the treatment of several cancers, and in some cases, it restored chemo-sensitivity.	('3BP', 'Var', (28, 31))	('ATP', 'Gene', '51761', (4, 7))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('ATP', 'Gene', (4, 7))	('restored', 'PosReg', (111, 119))	('3BP', 'Chemical', 'MESH:C017092', (28, 31))	('chemo-sensitivity', 'MPA', (120, 137))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
66098	31923436	3-PO has been shown to diminish the growth of many human malignant hematopoietic and adenocarcinoma cell lines in vitro and in vivo.	('adenocarcinoma', 'Disease', (85, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('3-PO', 'Chemical', 'MESH:C527590', (0, 4))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('diminish', 'NegReg', (23, 31))	('human', 'Species', '9606', (51, 56))	('growth', 'CPA', (36, 42))	('3-PO', 'Var', (0, 4))
66100	31923436	The knockdown of PKM2 sensitizes pancreatic cancer cells to gemcitabine therapy and colorectal cancer cells to oxaliplatin treatment.	('colorectal cancer', 'Disease', (84, 101))	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('PKM2', 'Gene', (17, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('PKM2', 'Gene', '5315', (17, 21))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (111, 122))	('sensitizes', 'Reg', (22, 32))	('pancreatic cancer', 'Disease', (33, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('knockdown', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
66104	31923436	Another study has suggested that CPI-613, a lipoid analog, strongly disrupts the mitochondrial metabolism by phosphorylating pyruvate dehydrogenase (PDH).	('PDH', 'molecular_function', 'GO:0004739', ('149', '152'))	('pyruvate dehydrogenase', 'Gene', '54704', (125, 147))	('PDH', 'molecular_function', 'GO:0033718', ('149', '152'))	('CPI-613', 'Var', (33, 40))	('disrupts', 'NegReg', (68, 76))	('CPI-613', 'Chemical', 'MESH:C568850', (33, 40))	('PDH', 'Gene', '54704', (149, 152))	('lipoid', 'Chemical', '-', (44, 50))	('pyruvate dehydrogenase', 'Gene', (125, 147))	('metabolism', 'biological_process', 'GO:0008152', ('95', '105'))	('PDH', 'molecular_function', 'GO:0004246', ('149', '152'))	('mitochondrial metabolism', 'MPA', (81, 105))	('PDH', 'Gene', (149, 152))
66112	31923436	Additionally, inhibition of HIF-1alpha could be a practical approach to reduce tumor growth by altering glucose metabolism.	('HIF-1alpha', 'Gene', (28, 38))	('tumor', 'Disease', (79, 84))	('glucose metabolism', 'Disease', 'MESH:D044882', (104, 122))	('glucose metabolism', 'biological_process', 'GO:0006006', ('104', '122'))	('HIF-1alpha', 'Gene', '3091', (28, 38))	('altering', 'Reg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('reduce', 'NegReg', (72, 78))	('inhibition', 'Var', (14, 24))	('glucose metabolism', 'Disease', (104, 122))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
66114	31923436	Pharmacological inhibition of gluconeogenesis enzyme, PEPCK (PEPCKi), reduces phosphoenolpyruvate (PEP) in colon cancer cells leading to an increase in PEPCK substrate, oxaloacetate, and growth inhibition.	('PEP', 'Chemical', 'MESH:D010728', (54, 57))	('PEPCK', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('phosphoenolpyruvate', 'Chemical', 'MESH:D010728', (78, 97))	('oxaloacetate', 'Chemical', 'MESH:D062907', (169, 181))	('PEPCK', 'Enzyme', (152, 157))	('PEP', 'Chemical', 'MESH:D010728', (99, 102))	('PEP', 'Chemical', 'MESH:D010728', (61, 64))	('increase', 'PosReg', (140, 148))	('inhibition', 'Var', (16, 26))	('oxaloacetate', 'MPA', (169, 181))	('colon cancer', 'Disease', (107, 119))	('growth inhibition', 'CPA', (187, 204))	('reduces', 'NegReg', (70, 77))	('inhibition of gluconeogenesis', 'biological_process', 'GO:0045721', ('16', '45'))	('inhibition of gluconeogenesis', 'Phenotype', 'HP:0005959', (16, 45))	('PEP', 'Chemical', 'MESH:D010728', (152, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))
66115	31923436	Another PEPCK inhibitor, 3-mercaptopicolinic, induces apoptosis in lung cancer cells by depleting glucose.	('apoptosis', 'CPA', (54, 63))	('depleting glucose', 'MPA', (88, 105))	('3-mercaptopicolinic', 'Chemical', '-', (25, 44))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('3-mercaptopicolinic', 'Var', (25, 44))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('induces', 'PosReg', (46, 53))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('PEP', 'Chemical', 'MESH:D010728', (8, 11))
66121	31923436	Human brain tumor-initiating cells (BTIC) require G6PC to counteract the effect of 2-DG, and its silencing reduces their survival and malignant potential under glycolysis inhibited condition.	('glycolysis', 'biological_process', 'GO:0006096', ('160', '170'))	('Human', 'Species', '9606', (0, 5))	('brain tumor', 'Phenotype', 'HP:0030692', (6, 17))	('silencing', 'Var', (97, 106))	('brain tumor', 'Disease', 'MESH:D001932', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('survival', 'CPA', (121, 129))	('reduces', 'NegReg', (107, 114))	('brain tumor', 'Disease', (6, 17))	('2-DG', 'Chemical', 'MESH:D003847', (83, 87))	('malignant potential', 'CPA', (134, 153))
66123	31923436	For example, 2-DG inhibits tumor growth by inhibiting glycolysis, but it has an unwanted effect on T cell metabolism.	('inhibiting', 'NegReg', (43, 53))	('T cell metabolism', 'MPA', (99, 116))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('2-DG', 'Var', (13, 17))	('tumor', 'Disease', (27, 32))	('inhibits', 'NegReg', (18, 26))	('glycolysis', 'MPA', (54, 64))	('2-DG', 'Chemical', 'MESH:D003847', (13, 17))	('metabolism', 'biological_process', 'GO:0008152', ('106', '116'))	('glycolysis', 'biological_process', 'GO:0006096', ('54', '64'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
66124	31923436	Although in another case, inhibition of lactic acid secretion by lenalidomide reduces tumor growth and enhances T cell activation.	('lactic acid secretion', 'MPA', (40, 61))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('T cell activation', 'biological_process', 'GO:0042110', ('112', '129'))	('lenalidomide', 'Chemical', 'MESH:D000077269', (65, 77))	('lactic acid', 'Chemical', 'MESH:D019344', (40, 51))	('tumor', 'Disease', (86, 91))	('inhibition', 'Var', (26, 36))	('lactic acid secretion', 'biological_process', 'GO:0046722', ('40', '61'))	('T cell activation', 'CPA', (112, 129))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('reduces', 'NegReg', (78, 85))	('enhances', 'PosReg', (103, 111))
66125	31923436	In colorectal cancer, inhibition of lactate production is shown to reduce tumor cell growth and improve the therapeutic response of 5-fluorouracil.	('reduce', 'NegReg', (67, 73))	('inhibition', 'Var', (22, 32))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (132, 146))	('therapeutic response of 5-fluorouracil', 'MPA', (108, 146))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('lactate', 'Chemical', 'MESH:D019344', (36, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('improve', 'PosReg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('lactate production', 'MPA', (36, 54))	('colorectal cancer', 'Disease', (3, 20))	('tumor', 'Disease', (74, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
66128	31923436	Altered metabolism not only helps cancer cells survive and grow but confers resistance to therapeutic interventions as well.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('grow', 'CPA', (59, 63))	('helps', 'PosReg', (28, 33))	('metabolism', 'biological_process', 'GO:0008152', ('8', '18'))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Altered', 'Var', (0, 7))	('cancer', 'Disease', (34, 40))
66137	31993370	The Potential of Radiomics Nomogram in Non-invasively Prediction of Epidermal Growth Factor Receptor Mutation Status and Subtypes in Lung Adenocarcinoma Purpose: Up to 50% of Asian patients with NSCLC have EGFR gene mutations, indicating that selecting eligible patients for EGFR-TKIs treatments is clinically important.	('Epidermal Growth Factor Receptor', 'Gene', (68, 100))	('patients', 'Species', '9606', (181, 189))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (68, 100))	('Lung Adenocarcinoma', 'Disease', (133, 152))	('Lung Adenocarcinoma', 'Disease', 'MESH:C538231', (133, 152))	('EGFR', 'Gene', '1956', (275, 279))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('NSCLC', 'Disease', (195, 200))	('EGFR', 'Gene', (206, 210))	('EGFR', 'molecular_function', 'GO:0005006', ('275', '279'))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('206', '210'))	('EGFR', 'Gene', (275, 279))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('68', '91'))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('mutations', 'Var', (216, 225))	('patients', 'Species', '9606', (262, 270))	('EGFR', 'Gene', '1956', (206, 210))
66138	31993370	The aim of the study is to develop and validate radiomics-based nomograms, integrating radiomics, CT features and clinical characteristics, to non-invasively predict EGFR mutation status and subtypes.	('mutation', 'Var', (171, 179))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('predict', 'Reg', (158, 165))
66139	31993370	Materials and Methods: We included 637 patients with lung adenocarcinomas, who performed the EGFR mutations analysis in the current study.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('patients', 'Species', '9606', (39, 47))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (53, 73))	('EGFR', 'Gene', (93, 97))	('lung adenocarcinomas', 'Disease', (53, 73))	('mutations', 'Var', (98, 107))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (53, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
66141	31993370	Results: The constructed R-scores achieved promising performance on predicting EGFR mutation status and subtypes, with AUCs of 0.694 and 0.708 in two validation datasets, respectively.	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
66142	31993370	Moreover, the constructed radiomics-based nomograms excelled the R-scores, clinical, CT features alone in terms of predicting EGFR mutation status and subtypes, with AUCs of 0.734 and 0.757 in two validation datasets, respectively.	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('mutation', 'Var', (131, 139))	('EGFR', 'Gene', '1956', (126, 130))	('EGFR', 'Gene', (126, 130))
66143	31993370	Conclusions: Radiomics-based nomogram, incorporating clinical characteristics, CT features and radiomic features, can non-invasively and efficiently predict the EGFR mutation status and thus potentially fulfill the ultimate purpose of precision medicine.	('EGFR', 'Gene', (161, 165))	('predict', 'Reg', (149, 156))	('EGFR', 'Gene', '1956', (161, 165))	('mutation', 'Var', (166, 174))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
66145	31993370	We developed and validated two Radiomics-based nomograms, incorporating clinical characteristics, CT features and radiomic features, to non-invasively predict the EGFR mutation status and subtypes with the aim to potentially fulfill the ultimate purpose of precision medicine.	('EGFR', 'Gene', '1956', (163, 167))	('mutation', 'Var', (168, 176))	('EGFR', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('predict', 'Reg', (151, 158))
66150	31993370	Up to 50% of Asian patients with NSCLC have EGFR gene mutations, indicating that selecting eligible patients for EGFR-TKIs treatments is clinically important.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('patients', 'Species', '9606', (19, 27))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', '1956', (113, 117))	('NSCLC', 'Disease', (33, 38))	('EGFR', 'Gene', (113, 117))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
66151	31993370	In patients with NSCLC, the most commonly found EGFR mutations are deletions in exon 19 (45%) and in exon 21 (L858R in 40%) in patients with EGFR mutations.	('NSCLC', 'Disease', (17, 22))	('EGFR', 'Gene', '1956',